Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.

BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression. METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604. FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses). INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. FUNDING: F Hoffmann-La Roche.

Cluster analysis and its application to healthcare claims data: a study of end-stage renal disease patients who initiated hemodialysis.

BACKGROUND: Cluster analysis (CA) is a frequently used applied statistical technique that helps to reveal hidden structures and "clusters" found in large data sets. However, this method has not been widely used in large healthcare claims databases where the distribution of expenditure data is commonly severely skewed. The purpose of this study was to identify cost change patterns of patients with end-stage renal disease (ESRD) who initiated hemodialysis (HD) by applying different clustering methods. METHODS: A retrospective, cross-sectional, observational study was conducted using the Truven Health MarketScan® Research Databases. Patients aged ≥18 years with ≥2 ESRD diagnoses who initiated HD between 2008 and 2010 were included. The K-means CA method and hierarchical CA with various linkage methods were applied to all-cause costs within baseline (12-months pre-HD) and follow-up periods (12-months post-HD) to identify clusters. Demographic, clinical, and cost information was extracted from both periods, and then examined by cluster. RESULTS: A total of 18,380 patients were identified. Meaningful all-cause cost clusters were generated using K-means CA and hierarchical CA with either flexible beta or Ward's methods. Based on cluster sample sizes and change of cost patterns, the K-means CA method and 4 clusters were selected: Cluster 1: Average to High (n = 113); Cluster 2: Very High to High (n = 89); Cluster 3: Average to Average (n = 16,624); or Cluster 4: Increasing Costs, High at Both Points (n = 1554). Median cost changes in the 12-month pre-HD and post-HD periods increased from $185,070 to $884,605 for Cluster 1 (Average to High), decreased from $910,930 to $157,997 for Cluster 2 (Very High to High), were relatively stable and remained low from $15,168 to $13,026 for Cluster 3 (Average to Average), and increased from $57,909 to $193,140 for Cluster 4 (Increasing Costs, High at Both Points). Relatively stable costs after starting HD were associated with more stable scores on comorbidity index scores from the pre-and post-HD periods, while increasing costs were associated with more sharply increasing comorbidity scores. CONCLUSIONS: The K-means CA method appeared to be the most appropriate in healthcare claims data with highly skewed cost information when taking into account both change of cost patterns and sample size in the smallest cluster.

Treatment patterns and costs for anti-TNFα biologic therapy in patients with psoriatic arthritis.

BACKGROUND: Real-world data regarding anti-tumor necrosis factor alpha (anti-TNFα) biologic therapy use in psoriatic arthritis (PsA) are limited; therefore, we described treatment patterns and costs of anti-TNFα therapy in PsA patients in the United States. METHODS: PsA patients (N = 990) aged ≥18 years who initiated anti-TNFα therapy were selected from MarketScan claims databases (10/1/2009 to 9/30/2010). Number of patients on first- (n = 881), second- (n = 72), or third- or greater (n = 37) line of anti-TNFα therapy, persistence, time-to-switch or modification, pharmacy and medical costs (measured per patient per month [PPPM]) for each line of therapy were observed during the 3-year follow-up. RESULTS: PsA patients receiving only one line of anti-TNFα therapy remained on first-line for ~17 months while those who switched to second- or third- or greater persisted on first-line for ~11 to 12 months, respectively. Time to first-line modification was longer for patients who switched to third- or greater line therapy (7 months) than those who did not switch or switched to second-line (range, ~2 to 4 months). Time-to-switch and time to first-line modification was progressively shorter with each line of therapy for patients who received third- or greater line. PPPM medical costs were higher for patients who did not switch ($322) than those who switched to second- ($167) or third- or greater ($217) line. PPPM pharmacy costs were greater for patients with third- or greater line therapy ($2539) than those who did not switch ($1985) or switched to second-line ($2045). CONCLUSION: While the majority of patients received only one line of anti-TNFα therapy, a subset of patients switched to multiple lines of therapy during the 3-year follow-up period. Persistence and therapy modifications differed between these patients and those receiving only one line. Overall medical costs were highest for patients who did not switch, and pharmacy costs increased as patients switched to each new line of therapy.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

The prognostic value and economic benefits of coronary angiography-derived fractional flow reserve-guided strategy in patients with coronary artery disease.

Objective: This study aims to investigate the prognostic value and economic benefit of coronary angiography-derived fractional flow reserve (caFFR) guided percutaneous coronary intervention (PCI) in patients with coronary artery disease. Methods: All patients with coronary artery disease (CAD) who underwent coronary angiography in our center between April 2021 and November 2021 were retrospectively enrolled and divided into the caFFR guidance group (n = 160) and angiography guidance group (n = 211). A threshold of caFFR≤0.8 was used for revascularization. Otherwise, delayed PCI was preferred. The patients were prospectively followed up by telephone or outpatient service at six months for major adverse cardiovascular events (MACE) of all-cause death, myocardial infarction or target vessel revascularization, stent thrombosis, and stroke. All in-hospital expenses were recorded, including initial hospitalization and re-hospitalization related to MACE. Results: There was no significant difference in the baseline characteristics between the two groups. There were 2 (1.2%) patients in the caFFR guidance group and 5 (2.4%) patients in the angiography guidance group with MACE events during the following six months. Compared with angiography guidance, caFFR guidance reduced the revascularization rate (63.7% vs. 84.4%, p = 0.000), the average length of stents implanted (0.52 ± 0.88 vs. 1.1 ± 1.4, P < 0.001). The cost of consumables in the caFFR guidance group was significantly lower than that in the angiography guidance group (33257 ± 19595 CNY vs. 38341 ± 16485 CNY, P < 0.05). Conclusion: Compared with coronary angiography guidance, caFFR guidance is of great significance in reducing revascularization and cost, which has significant health and economic benefits.

Prospective multicenter randomized trial comparing physician versus patient transfer for primary percutaneous coronary intervention in acute ST-segment elevation myocardial infarction.

BACKGROUND: Primary percutaneous coronary intervention (PCI) has been identified as the first therapeutic option for patients with acute ST-segment elevation myocardial infarction (STEMI). The strategy of transferring patient to a PCI center was recently recommended for those with acute STEMI who were present to PCI incapable hospitals, which include lack of facilities or experienced operators. In China, some local hospitals have been equipped with PCI facilities, but they have no interventional physicians qualified for performing primary PCI. This study was conducted to assess the feasibility, safety and efficacy of the strategy of transferring physician to a PCI-equipped hospital to perform primary PCI for patients with acute STEMI. METHODS: Three hundred and thirty-four consecutive STEMI patients with symptom presentation = 12 hours in five local hospitals from November 2005 to November 2007 were randomized to receive primary PCI by either physician transfer (physician transfer group, n=165) or patient transfer (patient transfer group, n=169) strategy. Door-to-balloon time, in-hospital and 30-day major adverse cardiac events (MACE, including death, non-fatal re-infarction, and target vessel revascularization) were compared between the two groups. RESULTS: Baseline characteristics between the two groups were comparable. Thrombolysis in myocardial infarction (TIMI) 3 flow was revealed in more patients in the physician transfer group at initial angiography (17.6% vs 10.1%, P<0.05). The success rate of primary PCI (96.3% vs 95.4%, P>0.05) and length of hospital stay were similar between the two groups ((15+/-4) days vs (14+/-3) days, P>0.05). In the physician transfer group, door-to-balloon time was significantly shortened ((95+/-20) minutes vs (147+/-29) minutes, P<0.0001) and more patients received primary PCI with door-to-balloon time less than 90 minutes (21.2% vs 7.7%, P<0.001). During hospitalization, MACE occurred in 6.7% and 11.2% of patients in the physician and patient transfer groups, respectively (P=0.14). At 30-day clinical follow-up, the occurrence rates of death, non-fatal re-infarction, and target vessel revascularization (TVR) were 3.6% vs 5.9%, 4.2% vs 8.9%, and 1.2% vs 2.4% in the physician and patient transfer groups, respectively (all P>0.05). The cumulative composite of MACE was significantly reduced (8.9% vs 17.2%, P=0.03) and MACE free survival (91.0% vs 82.9%, P<0.05) was significantly improved in the physician transfer group at 30 days. CONCLUSION: The strategy of transferring physician to local hospital to perform primary PCI for patients with acute STEMI is feasible, safe and efficient in reducing the door-to-balloon time and 30-day MACE rate.

Healthcare Resource Use and Direct Costs in Patients with Ankylosing Spondylitis and Psoriatic Arthritis in a Large US Cohort.

OBJECTIVE: Direct costs of ankylosing spondylitis (AS) and psoriatic arthritis (PsA) have not been well characterized in the United States. This study assessed healthcare resource use and direct cost of AS and PsA, and identified predictors of all-cause medical and pharmacy costs. METHODS: Adults aged ≥ 18 with a diagnosis of AS and PsA were identified in the MarketScan databases between October 1, 2011, and September 30, 2012. Patients were continuously enrolled with medical and pharmacy benefits for 12 months before and after the index date (first diagnosis). Baseline demographics and comorbidities were identified. Direct costs included hospitalizations, emergency room and office visits, and pharmacy costs. Multivariable regression was used to determine whether baseline covariates were associated with direct costs. RESULTS: Patients with AS were younger and mostly men compared with patients with PsA. Hypertension and hyperlipidemia were the most common comorbidities in both cohorts. A higher percentage of patients with PsA used biologics and nonbiologic disease-modifying drugs (61.1% and 52.4%, respectively) compared with patients with AS (52.5% and 21.8%, respectively). Office visits were the most commonly used resource by patients with AS and PsA (∼11 visits). Annual direct medical costs [all US dollars, mean (SD)] for patients with AS and PsA were $6514 ($32,982) and $5108 ($22,258), respectively. Prescription drug costs were higher for patients with PsA [$14,174 ($15,821)] compared with patients with AS [$11,214 ($14,249)]. Multivariable regression analysis showed higher all-cause direct costs were associated with biologic use, age, and increased comorbidities in patients with AS or PsA (all p < 0.05). CONCLUSION: Biologic use, age, and comorbidities were major determinants of all-cause direct costs in patients with AS and PsA.

Clinical symptoms and self-reported disease severity among patients with psoriasis - Implications for psoriasis management.

BACKGROUND: Pain, itching, burning and irritation are common symptoms of psoriasis but have not been well characterized by overall psoriasis severity. METHODS: Using 2012 syndicated psoriasis patient survey data, 1050 subjects were classified into mild (n = 610) and moderate-to-severe (n = 440) psoriasis severity groups based on self-reporting. Demographics, comorbid medical conditions and patient-reported key symptoms (i.e. flare-up frequency, psoriasis-related pain, itching, burning, hurting, irritation) were compared between groups. Multiple regressions were employed to examine the impact of overall psoriasis severity on each key symptom, controlling for demographics and comorbidities. RESULTS: Mild patients were older; more than 20% in both groups had joint pain and depression. Over 35 and 68% of the moderate-to-severe patients reported severe pain between or during flare-ups, respectively, and over 79% reported frequent bothersome itching. Controlling for between-group differences, moderate-to-severe patients had worse pain, were more likely to have continual flare-ups (odds ratio = 3.0) and flare-ups more than once monthly (odds ratio = 3.0), and reported more bothersome symptoms than patients with mild disease (all p < 0.05). CONCLUSION: The presence and level of particular symptoms increase with self-reported disease severity in patients with psoriasis. Careful investigation of symptoms in tandem with clinical observation is important for effective psoriasis management.

Absence of gender disparity in short-term clinical outcomes in patients with acute ST-segment elevation myocardial infarction undergoing sirolimus-eluting stent based primary coronary intervention: a report from Shanghai Acute Coronary Event (SACE) Registry.

BACKGROUND: Randomized, controlled trials have demonstrated the superiority of sirolimus-eluting stent (SES) implantation during primary percutaneous coronary intervention (PCI), as opposed to bare-metal stents, in patients with ST-elevation myocardial infarction (STEMI). This study aimed to test the hypothesis that clinical benefits of SES treatment were independent of gender in this setting. METHODS: A total of 2042 patients with STEMI undergoing SES-based primary PCI were prospectively enrolled into Shanghai Acute Coronary Event (SACE) registry (1574 men and 468 women). Baseline demographics, angiographic and PCI features, and in-hospital and 30-day major adverse cardiac events (MACE) were analyzed as a function of gender. RESULTS: Compared with men, women were older and more frequently had hypertension, diabetes, and hypercholesterolemia. Use of platelet glycoprotein IIb/IIIa receptor inhibitor (GPI, 65.5% vs. 62.2%, P = 0.10) and procedural success rate (95.0% vs. 94.2%, P = 0.52) were similar in both genders. In-hospital death and MACE occurred in 3.8% and 7.6%, and 4.5% and 8.1% in the male and female patients, respectively (all P > 0.05). At 30-day follow-up, survival (94.3% vs. 93.8%, P = 0.66) and MACE-free survival (90.2% vs. 89.3%, P = 0.52) did not significantly differ between men and women. After adjustment for differences in patient demographics, angiographic and procedural features, there were no significant difference in either in-hospital (OR = 0.77, 95%CI of 0.48 to 1.22, P = 0.30) or 30-day mortality (OR = 1.28, 95%CI of 0.73 to 2.23, P = 0.38) between women and men. CONCLUSION: Despite more advanced age and clustering of risk factors in women, female patients with STEMI treated by SES-based primary PCI had similar in-hospital and short-term clinical outcomes as their male counterparts.

Impact of different clinical pathways on outcomes of patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: the RAPID-AMI study.

BACKGROUND: Current guidelines support primary percutaneous coronary intervention (primary PCI) as the first treatment of choice (as opposed to thrombolytic therapy) for patients with acute ST-segment elevation myocardial infarction (STEMI) especially when delivered within 12 hours of symptom onset. We aimed to evaluate the impact of different clinical pathways on reduction of reperfusion delay and subsequent improvement in outcomes in patients with STEMI. METHODS: From November 2005 to November 2007, 546 consecutive patients with definite STEMI, who upon arrival at the emergency room were triaged to undergo primary PCI, were included. Of them, 271 patients were brought directly to catheterization laboratory (rapid group), and 275 patients were admitted to the coronary care unit (CCU) or cardiac ward first, and then transferred to the catheterization laboratory (non-rapid group). Primary endpoint was door-to-balloon (D2B) time, and secondary endpoints included infarct size assessed by peak CK-MB level and rates of major cardiac adverse events (MACE) including death, reinfarction, or target-vessel revascularization during hospitalization and at 30-day clinical follow-up. RESULTS: Baseline clinical characteristics, angiographic features and procedural success rates were comparable between the two groups, except that more patients received glycoprotein IIb/IIIa receptor inhibitors before angiography (84.0% and 77.1, P = 0.042) and had TIMI 3 flow in the culprit vessel at initial angiogram (17.1% and 9.2%, P = 0.007) in the non-rapid group. The D2B time was shortened ((108 +/- 44) minutes and (138 +/- 31) minutes, P < 0.0001), and number of patients with D2B time < 90 minutes was greater (22.6% and 10.9%, P < 0.0001) in the rapid group. The advantages associated with rapid intra-hospital transfer were enhanced if the patients presented to the hospital at regular hours. Peak CK-MB level was significantly reduced in the rapid group. In-hospital mortality (4.1% and 5.8%) and cumulative MACE rate (7.0% and 9.8%) did not significantly differ between rapid and non-rapid groups. At 30 days, cumulative death- and MACE-free survival rates were improved in the rapid group (94.5% and 89.5%, P = 0.035; 90.1% and 84.0%, P = 0.034, respectively). CONCLUSIONS: Clinical pathway with bypass of CCU/cardiac ward admission was associated with rapid reperfusion, smaller infarct size, and improved short-term survival for patients with STEMI undergoing primary PCI. In the future, it is essential to reduce the time delay for patients presenting at off-hours.