Bicuspid Aortic Valve Disease: Classifications, Treatments, and Emerging Transcatheter Paradigms.

Bicuspid aortic valve (BAV) is a common congenital valvular malformation, which may lead to early aortic valve disease and bicuspid-associated aortopathy. A novel BAV classification system was recently proposed to coincide with transcatheter aortic valve replacement being increasingly considered in younger patients with symptomatic BAV, with good clinical results, yet without randomized trial evidence. Procedural technique, along with clinical outcomes, have considerably improved in BAV patients compared with tricuspid aortic stenosis patients undergoing transcatheter aortic valve replacement. The present review summarizes the novel BAV classification systems and examines contemporary surgical and transcatheter approaches.

Treatment of children with primary immunodeficiencies with a subcutaneous immunoglobulin 16.5% (cutaquig® [octanorm]).

Background: Subcutaneous human immunoglobulin (16.5%; octanorm/cutaquig®) was efficacious and well tolerated in patients with primary immunodeficiencies in a Phase III study. A subanalysis of pediatric data is presented here. Materials & methods: Children (2-16 years) previously treated with intravenous human immunoglobulin received weekly subcutaneous human immunoglobulin infusions over 64 weeks. The main objective was to assess the efficacy of cutaquig in preventing serious bacterial infections. Results: 38 children received 2213 infusions of cutaquig. No serious bacterial infections developed during the study. The rate of other infections was 3.1 per person-year and the rate of adverse drug reactions was 0.083 per infusion. Higher immunoglobulin G trough levels were achieved with cutaquig compared with previous intravenous therapy. Conclusion: Once-weekly infusions of cutaquig were efficacious and well tolerated in children with primary immunodeficiencies.

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Hybrid strategies for high-risk non-hypoplastic left heart syndrome patients.

Single-stage repair of complex cardiac abnormalities in high-risk neonates presents formidable challenges. The majority of hybrid strategies involving bilateral pulmonary artery banding (bPAB) with or without patent ductus arteriosus (PDA) stenting is described in the setting of hypoplastic left heart syndrome. We present a series of cases describing two-stage repair with initial palliative hybrid procedures involving bPAB with or without PDA stenting. This allows weight gain and stabilization of circulation before complete repair, provides good results, and may overcome risk factors associated with single-stage repair in neonates.

Conventional aortic valve replacement in 2005 elderly patients: a 32-year experience.

OBJECTIVES: Considering the good immediate results reported for transcatheter aortic valve implantation in high-risk patients, the role of conventional aortic valve replacement (AVR) is being questioned, especially in elderly patients. The aim of this study was to evaluate our long-term results of conventional AVR in octogenarians. METHODS: A total of 2005 patients aged ≥80 years underwent AVR for aortic stenosis in our institution between 1978 and 2011. Of these, 1009 (50%) patients had an associated extracardiac comorbidity and 650 (32%) patients had coronary lesions. Valve replacement was the sole procedure in 1515 (76%) patients, and 396 (19%) patients had concomitant coronary artery bypass grafting. Data were collected at the time of surgery in our database, and regularly updated by mailed questionnaires and telephone contact. RESULTS: Early mortality of isolated AVR was 5.5% for the last 10 years of the series. Significant risk factors were chronic obstructive pulmonary disease, chronic renal failure, advanced cardiac disease [left or right ventricular failure, New York Heart Association (NYHA) Class IV and atrial fibrillation] and coronary disease. Long-term follow-up was 99.5% complete (9 patients lost to follow-up), totalling 8849 patient-years. Nine hundred and one patients died at late follow-up with a median survival of 7.1 years, with 7 patients becoming centenarian. Apart from older age, main late causes of death were cardiovascular (20.5%), neurological deficit (10.2%) and cancer (10.2%). Actuarial survival was 83%, 62.5% and 25% at 2, 5 and 10 years, respectively. This survival compares favourably with that of a French-matched population. Above all, 90% of late survivors reported functional improvement. Univariable and multivariable analysis identified risk factors of late death as male gender, associated comorbidity, renal failure, advanced cardiac disease, atrial fibrillation and impaired ventricular function. Coronary lesions, associated cardiac surgery and small diameter prostheses (19 or 21 mm) did not impair long-term survival. CONCLUSIONS: AVR is effective for all age groups to treat aortic stenosis. Elderly people should not be denied surgery only because of their old age as conventional AVR provides an excellent quality of life and restores life expectancy. Percutaneous valve implantation is to be considered, in cases of non-operable or high-risk patients. However, to date, open-heart surgery remains the treatment of choice for aortic stenosis for the majority of patients.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

A Review of Differing Techniques of Mammary Artery Harvesting on Sternal Perfusion: Time for a Randomized Study?

The use of internal mammary artery (IMA) grafts for coronary artery bypass may devascularize the sternum. We performed a literature review by searching the PubMed database for studies that assessed sternal perfusion after IMA harvesting. The majority of papers describe various techniques and compared (1) IMA harvest versus no IMA harvest, (2) single versus bilateral, and (3) skeletonized versus pedicled. Evidence is inconclusive as to whether single harvesting causes significant devascularisation and whether this is increased with bilateral harvesting. Sternal ischemia may also be a transient phenomenon. However, skeletonization may preserve perfusion more than pedicled harvesting, particularly in diabetic patients.

A Randomized Trial of External Stenting for Saphenous Vein Grafts in Coronary Artery Bypass Grafting.

BACKGROUND: External stents inhibit saphenous vein graft (SVG) intimal hyperplasia in animal studies. We investigated whether external stenting inhibits SVG diffuse intimal hyperplasia 1 year after coronary artery bypass graft surgery. METHODS: Thirty patients with multivessel disease undergoing coronary artery bypass graft surgery were enrolled. In addition to an internal mammary artery graft, each patient received one external stent to a single SVG randomly allocated to either the right or left coronary territories; and one or more nonstented SVG served as the control. Graft patency was confirmed at the end of surgery in all patients. The primary endpoint was SVG intimal hyperplasia (mean area) assessed by intravascular ultrasonography at 1 year. Secondary endpoints were SVG failure, ectasia (>50% initial diameter), and overall uniformity as judged by Fitzgibbon classification. RESULTS: One-year follow-up angiography was completed in 29 patients (96.6%). All internal mammary artery grafts were patent. Overall SVG failure rates did not differ significantly between the two groups (30% stented versus 28.2% nonstented SVG, p = 0.55). The SVG mean intimal hyperplasia area, assessed in 43 SVGs, was significantly reduced in the stented group (4.37 ± 1.40 mm(2)) versus nonstented group (5.12 ± 1.35 mm(2), p = 0.04). In addition, stented SVGs demonstrated marginally significant improvement in lumen uniformity (p = 0.08) and less ectasia (6.7% versus 28.2%, p = 0.05). There was some evidence that ligation of side branches with metallic clips increased SVG failure in the stented group. CONCLUSIONS: External stenting has the potential to improve SVG lumen uniformity and reduce diffuse intimal hyperplasia 1 year after coronary artery bypass graft surgery.

Effect of bilateral internal mammary artery grafts on long-term survival: a meta-analysis approach.

BACKGROUND: Although the potential survival benefit of bilateral internal mammary artery (BIMA) grafting in comparison with single internal mammary artery (SIMA) grafting has been emphasized by many investigators, the use of BIMA is still low in clinical practice in the absence of randomized trials and long-term results. In the current study, we aimed to assess if there is a long-term survival benefit of BIMA up to 10 years after coronary bypass surgery. METHODS AND RESULTS: We selected published articles comparing survival between SIMA and BIMA patients with follow-up duration of more than a mean of 9 years. We evaluated the log hazard ratio with 95% confidence interval for included studies by using a random-effects meta-analysis. Nine eligible observational studies provided 15 583 patients (8270 SIMA and 7313 BIMA) for meta-analysis. Five studies used propensity score methods for statistical adjustment, 2 with a propensity score-based patient-matching method and 3 with quintile-based stratification. A significant reduction in mortality by using BIMA was observed (hazard ratio, 0.79; 95% confidence interval, 0.75-0.84); no study showed any significantly harmful effect of BIMA on survival. Subgroups of studies using different statistical approaches-unmatched, quintile-based propensity score analysis, and propensity score-based exact patient matching-all showed the survival benefit of BIMA grafting. CONCLUSIONS: BIMA grafting appears to have better survival with up to 10 years follow-up in comparison with SIMA grafting. Long-term survival benefit of BIMA seems to continue in the second decade after surgery. An ongoing randomized trial comparing SIMA and BIMA groups will add evidence on this issue.

The radial artery: current concepts on its use in coronary artery revascularization.

The radial artery (RA) can be used as part of an arterial revascularization strategy in coronary artery bypass grafting (CABG). It is easy to harvest and several randomized controlled trials and meta-analyses have reported superior long-term patency over saphenous vein grafts. However, the RA is not used as frequently as the saphenous vein and questions remain regarding its optimum use as a conduit. This article comprehensively appraises current evidence surrounding outcomes, patient selection, harvesting technique, intraoperative strategy, and graft spasm prophylaxis to provide a contemporary review of the use of the RA as a conduit in CABG.

Safety, efficacy and pharmacokinetics of a new 10% liquid intravenous immunoglobulin (IVIG) in patients with primary immunodeficiency.

INTRODUCTION: An investigational 10% liquid intravenous immunoglobulin (IVIG) was studied in 63 patients with primary immunodeficiency (PID) at 15 study sites. METHODS: Patients were treated every 3 or 4 weeks with 254-1029 mg/kg/infusion of IVIG. RESULTS: Overall, Biotest-IVIG infusions were well tolerated. The proportion of infusions that were associated with adverse events during infusion, and up to 72 h after infusion, including those unrelated to study product, was 27.7% with an upper 95% confidence limit ≤30.6%. Two serious bacterial infections (SBIs) were observed resulting in a serious bacterial infection rate of 0.035 per person per year and an upper one-sided 99% confidence limit of ≤0.136 SBI/patient/year. The number of days of work or school missed due to infection were relatively low at 2.28 days/patient/year. Two patients were hospitalized for infection producing a rate of 0.21 hospitalization days/patient/year. The IgG half-life was approximately 30 days with variation among individuals. CONCLUSIONS: Pharmacokinetic parameters of specific antibody activities were essentially the same as those of total IgG. Biotest-IVIG is safe and effective in the treatment of PID.

Conventional aortic valve replacement for high-risk aortic stenosis patients not suitable for trans-catheter aortic valve implantation: feasibility and outcome.

OBJECTIVE: High-risk patients with aortic stenosis are increasingly referred to specialist multidisciplinary teams (MDTs) for consideration of trans-catheter aortic valve implantation (TAVI). A subgroup of these cases is unsuitable for TAVI, and high-risk conventional aortic valve replacement (AVR) is undertaken. We have studied our outcomes in this cohort. METHODS: Data prospectively collected between March 2008 and November 2009 for patients (n = 28, nine male) undergoing high-risk AVR were analysed. The mean age was 78.4 ± 9.2 years. The mean additive EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 10.0 ± 3.6 and mean logistic EuroSCORE was 19.9 ± 18.8. Three patients had undergone previous coronary artery bypass grafting (CABG). RESULTS: The mean ejection fraction was 51 ± 16%, mean valve area 0.56 ± 0.19 cm², and mean peak gradient 91 ± 27 mm Hg. Ascending aortic, right axillary artery and femoral artery cannulation was used in 64%, 29% and 7% of cases, respectively. Median cross-clamp and cardiopulmonary bypass times were 84 (68-143) min and 111 (94-223) min. The median (range) inserted valve size was 21 (19-25) mm. Median intensive care and overall hospital stay were 5 (2-37) and 11 (5-44) days, respectively. In-hospital mortality was 4% (one patient). Postoperative complications included re-operation for bleeding (7%), renal failure (21%), tracheostomy (14%), sternal wound infection (7%), atrial fibrillation (25%) and permanent pacemaker implantation (7%). Kaplan-Meier survival at median follow-up of 359 (148-744) days was 81% (one further death of non-cardiac aetiology). Quality-of-life assessment at follow-up also yielded satisfactory results. CONCLUSIONS: MDT assessment of high-risk aortic stenosis in the era of TAVI has increased the number of referrals. Conventional open surgery remains a valid option for these patients, with acceptable in-hospital mortality and early/midterm outcomes but high in-hospital morbidity.

How to manage the left subclavian artery during endovascular stenting of the thoracic aorta.

We performed a systematic review of the literature to establish whether revascularisation of the left subclavian territory is necessary when this artery is covered by a stent. We retrieved data from 99 studies incorporating 4906 patients. Incidences of left-arm ischaemia (0.0% vs 9.2%, p=0.002) and stroke (4.7% vs 7.2%, p<0.001) were significantly less following revascularisation, although mortality (10.5% vs 3.4%, p=0.032) and endoleak incidence (25.8% vs 12.6%, p=0.008) were increased. No significant differences in spinal-cord ischaemia were seen. Revascularisation may reduce downstream ischaemic complications but can cause significant risk. Indications must be carefully considered on an individual patient basis.

How to manage the left subclavian artery during endovascular stenting for thoracic aortic dissection? An assessment of the evidence.

BACKGROUND: Despite the publication of recent guidelines for management of the left subclavian artery (LSA) during endovascular stenting procedures of the thoracic aorta, specific management for those presenting with dissection remains unclear. This systematic review attempts to address this issue. METHODS: Systematic assessment of the published data on thoracic aorta dissection was performed identifying 46 studies, which incorporated 1,275 patients. Primary outcomes included the prevalence of left arm ischemia, stroke, spinal cord ischemia, endoleak, stent migration, and mortality. Outcomes were compared between patients with and without LSA coverage and revascularization incorporating factors such as the number of stents used, length of aorta covered, urgency of intervention, and type of dissection (acute or chronic). Statistical pooling techniques, χ(2) tests, and Fisher's exact testing were used for group comparisons. RESULTS: As compared with other outcomes, LSA coverage without revascularization in the presence of aortic dissection is much more likely to be complicated by left arm ischemia (prevalence increased from 0.0% to 4.0% [p = 0.021]), stroke (prevalence increased from 1.4% to 9.0% [p = 0.009]), and endoleak (prevalence increased from 4.0% to 29.3% [p = 0.001]). However, revascularization was not shown to reverse these effects. Longer aortic coverage (≥ 150 mm) was associated with an increased prevalence of spinal cord ischemia (from 1.3% to 12.5% [p = 0.011]) and mortality (from 1.3% to 15.6% [p = 0.003]). CONCLUSION: In patients undergoing endovascular stenting for thoracic aortic dissection, in cases where LSA coverage is necessary, revascularization should be considered before the procedure to avoid complications such as left arm ischemia, stroke, and endoleak, and where feasible, an appropriate preoperative assessment should be carried out.

A rare case of suture material obstructing the closure mechanism of a prosthetic aortic valve: a case report.

Prosthetic aortic valve dysfunction presenting as aortic regurgitation is a complication of mechanical valve replacement. We describe a case of late valve dysfunction caused by an annular suture of excessive length obstructing the closure mechanism of a bileaflet prosthetic valve.We present this rare cause of valve dysfunction in an 80-year-old male patient who presented with haemolysis and dyspnoea. At the time of operation it was found that a long vertically positioned annular valve suture was interfering with the normal closure mechanism of one of the prosthetic leaflets causing eccentric regurgitation jets. These findings were misdiagnosed as paravalvular leaks on the preoperative transoesophageal echo. No paravalvular leak was identified intraoperatively. After removal of the responsible suture normal prosthetic valve function was restored.Whilst early aortic valve dysfunction caused by suture material has previously been reported, this is the first report of suture material causing late dysfunction.