Early cardiac response is possible in stage IIIb cardiac AL amyloidosis and is associated with prolonged survival.

Patients with immunoglobulin light chain (AL) amyloidosis and stage IIIb cardiac involvement have a dismal outcome despite the introduction of novel treatments. However, a rapid hematologic response translates in better survival. We evaluated the impact of early cardiac response and its depth on outcome in 249 patients with newly diagnosed stage IIIb cardiac AL amyloidosis. Hematologic and cardiac responses were evaluated by intent to treat. After a median follow-up of 52 months, 219 (84%) patients died, and median survival was 4.2 months. The 30- and 90-day hematologic response rates were 22% (at least very good partial response [VGPR] in 9%) and 24% (at least VGPR in 15%), respectively. Early hematologic response resulted in better survival. At 90 days, 21 (8%) patients achieved a cardiac response (cardiac very good partial response [cardiac VGPR] in 12 cases and cardiac partial response [cardiac PR] in 9). At the 90-day landmark analysis, cardiac response resulted in longer survival (median, 54 months), also in those patients who have achieved at least VGPR (median, 62 vs 26 months, P = .011). Patients with cardiac VGPR had a longer survival than those with cardiac PR (median, 92 vs 24 months; P = .027), whereas patients without cardiac response had a poor survival (median, 6 months). A baseline difference of involved/uninvolved free light chains > 50 mg/L (odds ratio [OR], 0.21, P = .024) and a bone marrow plasma cell infiltrate > 10% (OR, 0.23, P = .040) were negative predictors of 90-day cardiac response. Early cardiac responses are rare but possible in stage IIIb AL amyloidosis and translate to longer survival.

Diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy: a multicentre network study.

AIM: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival. METHODS AND RESULTS: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival. CONCLUSIONS: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself.

Meta-Analysis Comparing Potent Oral P2Y12 Inhibitors versus Clopidogrel in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

BACKGROUND: In patients with atrial fibrillation (AF) receiving percutaneous coronary intervention (PCI), current guidelines recommend against combining potent oral P2Y12 inhibitors (i.e. ticagrelor or prasugrel) with oral anticoagulant (OAC) therapy, but the evidence is limited. OBJECTIVE: The aim of this meta-analysis was to compare the efficacy and safety of potent oral P2Y12 inhibitors with clopidogrel in patients receiving OAC therapy for AF after a recent PCI. METHODS: Electronic databases were searched for randomized controlled trials (RCT) reporting outcomes according to the P2Y12 inhibitor used. Major or clinically relevant non-major bleeding were the safety endpoints, while the efficacy outcomes were major adverse cardiovascular events (MACE). The potent oral P2Y12 inhibitors prasugrel and ticagrelor were compared with clopidogrel. A subgroup analysis was conducted to evaluate the differences between patients treated with dual antithrombotic therapy (DAT) versus triple antithrombotic therapy (TAT). RESULTS: Four RCTs that included 10,057 patients were included in this analysis. Potent oral P2Y12 inhibitors were associated with a significant increase in major or clinically relevant non-major bleeding compared with clopidogrel (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.06-1.59, p = 0.01; number needed to harm 18, 95% CI 12-36). This finding was consistent regardless of the concomitant antithrombotic therapy (DAT vs. TAT; p = 0.69). The risk of MACE did not differ between potent oral P2Y12 inhibitors and clopidogrel (RR 1.02, 95% CI 0.57-1.82). CONCLUSIONS: In patients receiving OAC therapy for AF after a recent PCI, potent oral P2Y12 inhibitors increase the risk of clinically relevant bleeding compared with clopidogrel, with no evident benefit in terms of MACE reduction.

Direct oral Xa inhibitors versus warfarin in patients with cancer and atrial fibrillation: a meta-analysis.

AIMS: Patients with cancer are at higher risk of atrial fibrillation, thromboembolic complications and bleeding events compared with the general population. The aim of the present meta-analysis was to compare the efficacy and safety of direct oral Xa inhibitor anticoagulants versus warfarin in patients with cancer and atrial fibrillation. METHODS: We searched electronic databases for randomized controlled trials comparing direct oral Xa inhibitor anticoagulants and warfarin in cancer patients. The primary efficacy outcome was stroke or systemic embolism. The primary safety outcome was major bleeding. A subgroup analysis was performed to explore the outcome differences between patients with active cancer or history of cancer. RESULTS: Three trials with a total of 3029 cancer patients were included in the analysis. There was no statistically significant difference in the risk of stroke or systemic embolism [risk ratio (RR) 0.76; 95% confidence interval (CI) 0.52-1.10] between the two therapeutic strategies. Direct oral Xa inhibitors significantly reduced the incidence of major bleeding compared with warfarin (RR 0.79; 95% CI 0.63-0.99; P = 0.04; number needed to treat = 113). These results were consistent both in patients with active cancer and in those with history of cancer. CONCLUSION: In patients with cancer and atrial fibrillation, direct oral Xa inhibitors have a similar efficacy and may be safer compared with warfarin. These results are consistent both in patients with active cancer and history of cancer.

Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study.

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD). Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity. Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot's score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

Determination of perfluorooctanoic acid and perfluorooctanesulfonate in human tissues by liquid chromatography/single quadrupole mass spectrometry.

A method is described that permits the measurement of the levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in human liver, kidney, adipose tissue, brain, basal ganglia, hypophysis, thyroid, gonads, pancreas, lung, skeletal muscle and blood, even in subjects not occupationally exposed to these compounds. The purification of samples involved the use of trifunctional (tC18) and strong anion-exchange (SAX) solid-phase extraction cartridges, and the analysis utilized a high-performance liquid chromatograph coupled to a single quadrupole mass spectrometer (LC/MS). The analyses were conducted on a mixed-bed reversed-phase column by gradient runs using 3 mM ammonium acetate/methanol mixtures at different proportions as the mobile phase. The detector was used in electrospray negative ion mode by recording simultaneously the ions m/z 413.0 (PFOA) and 499.0 (PFOS). Perfluorononanoic acid (PFNA), added to the samples before the purification, was used as the internal standard (ion monitored = m/z 463.6). The recovery rates of the extraction procedure ranged from 79.6 to 95.6% (CV% 1.7-7.4%) for PFOA, from 79.7 to 100.8% (CV% = 1.2-7.1) for PFOS, and from 89.1 to 102.3% (CV% = 0.9-5.2 %) for PFNA. The calibration curves were linear up to at least 400 ng of analytes per gram of tissue. The detection limits (signal-to-noise ratio = 3) were 0.1 ng/g for both PFOA and PFOS measured in all tissues except adipose tissue, where the limits were about 0.2 ng/g. The content of analytes in tissues varied from 0.3 to 3.8 ng/g (respectively: basal ganglia and lung) for PFOA, and from 1.0 to 13.6 ng/g (respectively: skeletal muscle and liver) for the linear isomer of PFOS. The method is suitable to evaluate the content of PFOA and PFOS in different tissues taken from the general population exposed to very low concentrations of these pollutants.