作者: Tabriziani, Hossein ; Nester, Carla ; Cook, Terence H. ; Trachtman, Howard ; Remuzzi, Giuseppe ; Meier, Matthias ; Feldman, David L. ; van de Kar, Nicole ; Decker, Dima A. ; Thompson, Aliza ; Wang, Yaqin ; Licht, Christoph ; Wong, Edwin ; Mathur, Mohit ; Balogun, Seyi ; Portillo, Cesia ; Praga, Manuel ; Lim, Mark ; Gooch, Ann ; Johnson, Sally ; Caravaca-Fontán, Fernando ; Smith, Richard J. ; Aslam, Shakil ; Fremeaux-Bacchi, Veronique ; Gale, Daniel P. ; Mistry, Kirtida ; Bomback, Andrew S. ; Selvarajah, Viknesh ; Pickering, Matthew C.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to (1) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and (2) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points—(1) proteinuria, (2) eGFR, and (3) histopathology—and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials.

2022-11-08·Circulation

Abstract 9381: Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes

作者: Januzzi, James L ; Cristino, Joaquim ; Hu, Xingdi ; Tsimikas, Sam ; Haidermota, Sara ; Miksenas, Hannah ; Gilliland, Thomas C ; Mohebi, Reza ; Browne, Auris ; Plutzky, Jorge ; Natarajan, Pradeep ; Liu, Yuxi ; Wong, Megan

Introduction: Lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) are independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs together predict coronary artery disease (CAD) severity and outcomes is unclear. We measured Lp(a) isoform-independent particle number and OxPLs associated with apolipoprotein(a) [OxPL-apo(a)] and apolipoprotein-B (OxPL-apoB) among participants in CASABLANCA (ClinicalTrials.gov NCT00842868), a contemporary cath-based registry, and assessed angiographic CAD at baseline and CV events in follow-up. Methods: In 1098 participants undergoing baseline coronary angiography, logistic regression estimated odds of any CAD (≥1 severe coronary stenosis) or multi-vessel CAD (≥2 severe coronary stenoses). Cox proportional hazards regression estimated risk of major adverse cardiovascular events (MACE: non-fatal MI, non-fatal stroke, CV death, or coronary revascularization) over median 4.2 years. Models were adjusted for age, sex, medical history, cholesterol, smoking, and statin use. Results: Median [IQR] Lp(a) was 26.45 nmol/L [11.39-89.49]. Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R≥0.91 for all pairwise combinations). Biomarkers were not associated with any CAD, but Lp(a) and OxPL-apoB were associated with multi-vessel CAD. All biomarkers were associated with CV events. Odds of multi-vessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI 1.03-1.18, P=0.006), 1.18 (95% CI 1.03-1.34, P=0.01), and 1.07 (95% CI 0.99-1.16, P=0.07), respectively ( Figure, A ). Hazard ratios for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI 1.03-1.14, P=0.001), 1.15 (95% CI 1.05-1.26, P=0.004), and 1.07 (95% CI 1.01-1.14, P=0.02), respectively ( Figure, B ). Conclusions: Lp(a) and OxPL-apoB are associated with multi-vessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident CV events.

2021-04-01·The American Journal of Cardiology3区 · 医学

Relation of First and Total Recurrent Atherosclerotic Cardiovascular Disease Events to Increased Lipoprotein(a) Levels Among Statin Treated Adults With Cardiovascular Disease

3区 · 医学

Article

作者: Sung, Jennifer ; Zhao, Yanglu ; Browne, Auris ; Wong, Nathan D

The relation between elevated lipoprotein(a) and total atherosclerotic cardiovascular disease (ASCVD) residual risk in persons with known cardiovascular disease on statin therapy is not well-established. We examined first and total recurrent ASCVD event risk in statin-treated adults with prior ASCVD. We studied 3,359 adults (mean age 63.6 years, 85.1% male) with prior ASCVD on statin therapy from the AIM-HIGH clinical trial cohort. The first and total ASCVD event rates were calculated by lipoprotein(a) [Lp(a)] categories. Cox regression and Prentice, Williams and Peterson (PWP) models provided hazard ratios (HRs) for ASCVD events over a mean follow-up of 3.3 years, adjusted for age, gender, trial treatment, LDL-C, and other risk factors. A total of 747 events occurred during follow-up, among which 544 were first events. First and total ASCVD event rates were greater with higher Lp(a) levels. Compared with Lp(a)<15 mg/dL, HRs (95% CIs) for subsequent total ASCVD events among Lp(a) levels of 15-<30, 30-<50, 50-<70, and ≥70 mg/dL were 1.04 (0.82 to 1.32), 1.15 (0.88 to 1.49), 1.27 (1.00 to 1.63) and 1.51 (1.25 to 1.84). Moreover, a continuous relation for total events was observed (HR=1.08 [1.04 to 1.12] per 20 mg/dL greater Lp(a). Findings for first ASCVD events and in those with LDL-C ≥70 mg/dL versus <70 mg/dL and with and without diabetes were similar. The risk of first and total ASCVD events is increased with Lp(a) levels of ≥70 mg/dL and ≥50 mg/dL, respectively, among adults with known CVD on statin therapy.

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