Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2).

BACKGROUND: The phase III reSURFACE 1 and reSURFACE 2 (NCT01722331/NCT01729754) trials of the anti-interleukin-23p19 monoclonal antibody tildrakizumab (TIL) for psoriasis treatment are complete. OBJECTIVES: We present 5-year pooled data from reSURFACE 1 and reSURFACE 2. METHODS: reSURFACE 1 and reSURFACE 2 were double-blind, randomized, controlled studies with optional long-term extensions. Adults with moderate-to-severe chronic plaque psoriasis were randomized 2 : 2 : 1 to TIL 100 mg (TIL 100) or 200 mg (TIL 200) or placebo at weeks 0 and 4, and every 12 weeks thereafter [reSURFACE 2 included an etanercept (ETN) arm]. Efficacy outcomes included proportions of patients achieving absolute and relative improvement from baseline Psoriasis Area and Severity Index (PASI) score through week 244 in TIL responders (≥ 75% improvement from baseline PASI; PASI 75 response) continuously receiving the same dose and ETN partial responders and nonresponders (PASI < 75 response) switched to TIL 200 at week 28. Safety was assessed from adverse events (AEs) in all patients as treated. RESULTS: Efficacy analyses included 329 and 227 week 28 responders to TIL 100 and TIL 200, respectively, and 121 ETN partial responders/nonresponders switched to TIL 200 at week 28. Of TIL 100 or TIL 200 responders and ETN partial responders/nonresponders entering the extensions, 235/302, 176/213 and 85/107, respectively, were evaluated at week 244, and 88·7%, 92·5% and 81·3%, respectively, achieved PASI 75 response. Exposure-adjusted rates of serious AEs were 6·3 and 6·0 patients with events per 100 patient-years of TIL 100 and TIL 200, respectively. CONCLUSIONS: TIL treatment provided sustained disease control over 5 years in week 28 TIL responders and ETN partial responders/nonresponders, with a reassuring safety profile.

Efficacy of tildrakizumab by patient demographic and disease characteristics across a phase 2b and 2 phase 3 trials in patients with moderate-to-severe chronic plaque psoriasis.

BACKGROUND: Tildrakizumab is a high-affinity, anti-interleukin-23p19 monoclonal antibody approved for treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the effects of patient demographic and disease characteristics on tildrakizumab efficacy using phase 2b/3 trial data. METHODS: Data from patients who received placebo, or tildrakizumab 100 or 200 mg, in P05495 [NCT01225731], reSURFACE 1 [NCT01722331] and reSURFACE 2 [NCT01729754] were analysed. Patient subgroups were defined by age, sex, race, weight, self-reported psoriatic arthritis, failure of ≥1 traditional systemic treatment and prior biologic use. Percentage of Psoriasis Area and Severity Index (PASI) 75 and 90 responders at Week 12 were compared across treatment arms in each subgroup. Absolute PASI at Weeks 0 and 12 was also determined for each subgroup. RESULTS: Among patients randomized in P05495 (N = 355), reSURFACE 1 (N = 772) and 2 (N = 1090), percentage of PASI 75 and 90 responders were significantly greater for each tildrakizumab dose vs. placebo (P < 0.0001). PASI 75 and 90 responder percentages were numerically greater in patients <65 years of age, bodyweight ≤90 kg, without psoriatic arthritis and with no prior biologic exposure (only PASI 90), vs. their counterparts in corresponding subgroups. There were no clear or consistent differences in efficacy between the other subgroups. Absolute PASI scores were generally similar across subgroups. CONCLUSIONS: Small numerical differences in tildrakizumab efficacy were observed between subgroups defined by patient age and weight, presence of psoriatic arthritis and prior biologic use. These differences were not clinically meaningful; however, analyses of long-term data may be of value. Tildrakizumab efficacy did not differ with respect to patient sex or race, or number of prior failed conventional systemic treatments. Overall, these results suggest tildrakizumab may be appropriate for treatment of moderate-to-severe plaque psoriasis in patients with a range of demographic and disease characteristics.

Transumbilical balloon angioplasty of subclavian artery thrombosis in a neonate.

We present a case of arterial thrombosis of the upper extremity in a 1-day-old neonate. The initial response to thrombolytic and anticoagulant therapy alone was unsuccessful. Distal flow to the extremity was reestablished by combined percutaneous transluminal angioplasty of the subclavian artery using transumbilical access followed by resumption of the thrombolytic and anticoagulant regimen. Cathet. Cardiovasc. Intervent. 49:56-60, 2000.

Transcatheter closure of a patent foramen ovale following mitral valve replacement.

We report the successful closure of a postoperative patent foramen ovale in a patient who underwent coronary artery bypass grafting and mitral valve replacement for severe mitral insufficiency. The postoperative course was complicated by severe hypoxemia due to a large patent foramen ovale. The patient underwent transcatheter closure with the Das Angel Wings transcatheter occluder (Microvena Corporation, White Bear Lake, MN) with immediate improvement.

Effect of myocardial hypertrophy on systolic and diastolic function in children: insights from the force-frequency and relaxation-frequency relationships.

OBJECTIVE: The objective of this study was to evaluate the effect of myocardial hypertrophy on systolic and diastolic properties of the left ventricle in children. BACKGROUND: In children with myocardial hypertrophy, ejection phase indices are invariably increased. However, indices of force-generation, e.g., end-systolic elastance and invasive indices of diastolic properties, have been studied infrequently in children with myocardial hypertrophy. METHODS: We studied 10 children with congenital aortic stenosis or coarctation of aorta and nine control patients. Systolic properties were assessed from shortening fraction, end-systolic fiber elastance (Ef(es)) measured at resting heart rates, and force-frequency relationship measured at heart rates increasing from 110 to 160 beats per minute. Diastolic properties were assessed from time constant of relaxation (tau) at matched heart rates, chamber stiffness constant, myocardial stiffness constant, and relaxation-frequency relationship measured at gradually increasing heart rates. RESULTS: Ef(es) remained unchanged by myocardial hypertrophy, however, tau was prolonged (tauL: 27.3+/-2.3 vs. 21.8+/-2.2 ms, p < 0.001; and tauD: 43.2+/-3.1 vs. 34.3+/-3.3 ms, p < 0.001). Both chamber and myocardial stiffness constants remained unchanged. Incremental increases in heart rate produced incremental improvement in both contraction and relaxation. Slopes of force-frequency and relaxation-frequency relationships remained unchanged in the experimental group. However, the relaxation-frequency relationship manifested a parallel shift upward. CONCLUSIONS: In conscious, sedated children with myocardial hypertrophy, systolic function assessed by an index of force generation remains unchanged. However, relaxation is prolonged but passive diastolic properties remain unaffected. The combined effect of hypertrophy and heart rate does not alter the force-frequency and relaxation-frequency relationships.

Coarctation of the aorta following coil occlusion of a patent ductus arteriosus.

A case is described in which coarctation of the aorta develops following coil occlusion of a patent ductus arteriosus with a single Gianturco coil. This finding has yet to be reported in children undergoing this procedure and demonstrates the possibility of its occurrence and brings into question the need for and the duration of antibiotic prophylaxis following coil deployment.

Is echocardiography or magnetic resonance imaging superior for precoarctation angioplasty evaluation?

We compared the dimensions of the aorta obtained by two-dimensional transthoracic echocardiography (echo) (median, 2.5 mo preangioplasty) and magnetic resonance imaging (MRI) (median, 4.2 mo preangioplasty) to those obtained by angiography (cath) in 13 patients (age, 7.7 +/- 1.6 yr; mean +/- SEM) who underwent evaluation for coarctation balloon angioplasty between April 1993-January 1996. Echo measurements were obtained from the suprasternal and subcostal sagittal planes, MRI measurements from axial and sagittal oblique views, and cath measurements from the straight lateral or oblique views. Measurements of the diameters of the aortic isthmus, coarctation, descending aorta at the diaphragm, and isthmus length were made by all three modalities. Presence of aorto-aortic collaterals was determined, and the coarctation length was delineated. Investigators were blinded to other measurement data prior to statistical analysis. Data analysis by repeated analysis of variance (ANOVA) and Student-Newman-Keuls testing revealed no statistically significant difference between systolic pressure gradient by clinical examination (32.2 +/- 5.9 mm Hg), peak instantaneous Doppler evaluation (37.5 +/- 2.9 mm Hg), or preangioplasty systolic pressure gradient (32.1 +/- 3.3 mm Hg). With the exception of measurements of the descending aorta (echo, 11.7 +/- 0.9 mm vs. MRI, 13.3 +/- 0.8 mm vs. cath, 14.0 +/- 1.3 mm; P = 0.04), there was no statistically significant difference in dimensions of the aortic isthmus (9.2 +/- 0.6 mm vs. 10.5 +/- 0.9 mm vs. 10.8 +/- 0.9 mm), coarctation site diameter (4.8 +/- 0.6 mm vs. 5.6 +/- 0.9 mm vs. 5.3 +/- 0.8 mm), or isthmus length (12.4 +/- 2.1 mm vs. 12.1 +/- 2.2 mm vs. 10.9 +/- 1.7 mm). The correlation coefficients derived from comparisons of MRI vs. cath to echo vs. cath were similar for all dimensions except for isthmus length (P < 0.01). MRI demonstrated aorto-aortic collaterals more frequently than echo, while echocardiography better demonstrated cardiac function and intracardiac anomalies. Both modalities detected the single patient with a long segment coarctation. We conclude that echocardiography and MRI provide similar definition of the coarcted thoracic aorta, and either test may be individually advantageous in specific clinical situations.

Hemodynamic and clinical effects of oral levodopa in children with congestive heart failure.

OBJECTIVES: This study was undertaken to evaluate the safety, efficacy and pharmacodynamic variables of oral levodopa in pediatric patients with congestive heart failure refractory to standard therapy. BACKGROUND: Therapeutic options for children with congestive cardiomyopathies are limited to digoxin, diuretic agents and angiotensin-converting enzyme inhibitors. Previous work in adults with congestive heart failure has shown a short-term effectiveness of levodopa and improvement of cardiac function. METHODS: Baseline two-dimensional and M-mode echocardiography, surface electrocardiography, Holter monitoring and exercise testing, when applicable, were performed. Levodopa was administered in a dose escalation scale from 8 mg/kg body weight per dose to 20 mg/kg per dose over 3 days with concomitant metoclopramide and pyridoxine. Catecholamine levels at initiation of the trial and throughout dose escalation were measured, with echocardiographic and electrocardiographic correlation. After 24-h drug washout, cardiac catheterization was performed both before and after administration of levodopa. RESULTS: Between February 1992 and December 1995, nine children (age 10 +/- 1.7 years, weight 27.8 +/- 4.3 kg) were enrolled in this study. At cardiac catheterization, serum dopamine levels rose from 108.5 +/- 59.2 pg/ml to 1,375.8 +/- 567.9 pg/ml (p = 0.03) at 100 +/- 14.8 min after levodopa administration without a significant change in serum norepinephrine or epinephrine levels. Paralleling these increases, there were significant changes in the cardiac index (1.7 +/- 0.3 to 3.2 +/- 0.7 liters/min per m2), stroke volume index (16.1 +/- 3.2 to 31.2 +/- 7.0 ml/m2 per min), oxygen consumption (138.6 +/- 24.4 to 188.3 +/- 30.8 ml/min per m2) and systemic vascular resistance (36.8 +/- 8 to 21.9 +/- 5.5 indexed Wood's units; all p < 0.01). There was a significant reversal of the daily fluid volume output/input ratio from 0.8 +/- 0.1 to 1.2 +/- 0.1 (p < 0.01). Levodopa administration was complicated by hypertension or tachycardia, or both, requiring a dose reduction in three patients, and by significant gastrointestinal distress in one. There was sustained symptomatic improvement a median of 19.5 months after drug initiation in seven of the patients. CONCLUSIONS: These preliminary data support the hemodynamic value of oral levodopa in the treatment of severe congestive heart failure in children.

Hepatic venous malformation after modified Fontan procedure with partial hepatic vein exclusion.

Partial hepatic vein exclusion, as an alternative to baffle fenestration, has been performed as a modification of the Fontan procedure. We report a case of severe cyanosis resulting from massive right-to-left shunting via a hepatic vascular malformation that developed in a patient after a modified Fontan procedure with partial hepatic vein exclusion.

Predictors of successful pulmonary balloon valvuloplasty: 10-year experience.

At our institution, 55 infants and children (ages 0.3-21 yr, median 2.5 yr) underwent pulmonary balloon valvuloplasty between August 1983 and May 1993. Systolic pressure gradients fell acutely following balloon valvuloplasty from 63.5 +/- 24.8 mmHg (mean +/- standard deviation) to 26.7 +/- 12.9 mmHg (P < 0.001) with a decrease in systolic pressure ratio from 0.81 +/- 0.25 to 0.42 +/- 0.12 (P < 0.0001). Fifty of the 55 patients had long-term echocardiographic evaluation performed > 2 yr following balloon valvuloplasty. Thirty-four of the 50 patients (Group A; 68%) were classified as having successful (residual systolic gradients < 25 mmHg, ventricular systolic pressure ratios < 0.6) long-term outcomes. Their peak systolic gradients fell acutely from 58.8 +/- 16.6 mmHg to 22.7 +/- 11.2 mmHg (P < 0.001). At 4.6 +/- 2.3 yr postvalvuloplasty, peak instantaneous pressure gradients were 17.8 +/- 5.7 mmHg (P = ns vs. acute postvalvuloplasty). Fifteen of the 50 patients (Group B; 30%) had unsuccessful (residual systolic gradients > or = 25 mmHg and/or ventricular systolic pressure ratios > 0.6) long-term outcomes. Their peak instantaneous systolic gradients fell acutely from 76.5 +/- 33.1 mmHg to 36.6 +/- 11.4 mmHg (P < 0.05). At 3.8 +/- 1.7 yr postvalvuloplasty, peak instantaneous pressure gradients were 35.1 +/- 9.1 mmHg (P = ns vs. acute postvalvuloplasty). One 3-yr-old patient (Group C, 2%) required repeat balloon valvuloplasty on two separate occasions for recurrent stenosis. There was no significant prevalvuloplasty difference between Groups A and B with regard to age, weight, or Z scores of the pulmonary annuli or balloon/annulus ratio; however, patients in Group A had significantly lower prevalvuloplasty gradients and lower systolic pressure ratios than patients in Group B. Total systolic gradient reduction between patients with successful and unsuccessful outcomes was not significantly different (Group A: 36.1 +/- 16.6 mmHg; Group B: 41 +/- 22.3 mmHg). At long-term follow-up, patients in Group A had fewer symptoms and a significantly lower rate of electrocardiographic right ventricular hypertrophy than Group B patients. Successful outcomes defined by our criteria following balloon valvuloplasty were achieved in 68% of patients with greatest long-term success in patients with prevalvuloplasty systolic gradients < 60 mmHg and systolic pressure ratios < 0.8. Intervention at lesser systolic gradients (40-60 mmHg) appears indicated to achieve lower long-term gradients and fewer symptoms as total systolic gradient reduction by this technique is limited.

Stent redilation in canine models of congenital heart disease: pulmonary artery stenosis and coarctation of the aorta.

In a canine puppy model, pulmonary artery stenosis was created by banding the left pulmonary artery to 30-40% of its original diameter. Animals underwent right heart catheterization and angiography 1-2 mo later, and Palmaz P308 stents were implanted. Stent redilation was performed 3-5 mo later. One mo postredilation, the animals were restudied and sacrificed. Coarctations of the aorta were created by transverse aortic incision and longitudinal repair. P308 stent implantation was performed 2-3 mo later. Stent redilation was performed after 6-10 mo, and the animals were restudied and sacrificed 1-2 mo later. Stent implantation was performed in 6 puppies with pulmonary artery stenosis, as 2 animals developed postoperative pulmonary arterial hypoplasia, precluding stenting. The stenosis diameter increased from 4.8 +/- 0.5 mm to 7.4 +/- 0.6 mm (mean +/- SE) following stenting (P = 0.005), and increased further to 9.2 +/- 0.7 mm following redilation (P < 0.001). There were no significant vessel tears or ruptures. Coarctation stenting was performed in 8 animals. The coarctation was dilated from 5.8 +/- 0.9 mm to 9.8 +/- 0.6 mm (P < 0.001), and to 13.5 +/- 0.5 mm at redilation (P = 0.002). Redilation could not be performed in 1 animal. Aortic rupture and death occurred in 2 of 7 animals at redilation. Stent implantation and redilation in experimental pulmonary artery stenosis appears safe and effective. Though stent implantation for coarctation of the aorta appears safe, there was a 28% aortic rupture rate at stent redilation in this model.

Balloon angioplasty for native coarctation of the aorta.

Balloon angioplasty of native coarctations of the aorta is one of the most controversial facets of the pediatric interventional cardiologist's practice. We have evaluated the history and experimental rationale of this technology. Presently accepted techniques are outlined and controversies intrinsic in performance of this procedure are discussed. Acute, short-term, and long-term results are reviewed with particular emphasis on differences in success of the procedure as related to patient age. Common and significant complications are discussed and in some cases compared to analogous surgical complications. Newer technologies and approaches to interventional therapy for coarctation of the aorta are also discussed.