Peter A. McCullough M.D.

McCullough, P. A. (2018). “Editorial: Robertsonian Perspectives on Atherosclerosis: The Power of Direct Observation.” Am J Cardiol 121(11): 1441.

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The contributions of William C. Roberts, MD, to the field of cardiovascular disease have been immense and he has already made a lasting impact of the history of medicine. His study in this issue of Journal discloses highlights from 50 years of studying atherosclerosis in the most intimate manner—by direct examination. Anatomic pathology and histology allow an investigator to create clean lines of inference by asking and answering questions within the bounds of what is observable. This avoids extrapolation beyond the range of the data and is less likely to lead to forms of bias and ultimately reduces the chances of rendering false conclusions. Using direct observation over a very long period of time with a disciplined methodical approach also leads to the discovery of “principles.” When sufficiently strong, these principles can be the basis of future hypothesis testing, clinical strategies for diagnosis, prognosis, and ultimately patient management. In the present study, Roberts addresses 15 questions related to atherosclerosis and its management from which several important principles can be appreciated . . . In cardiovascular medicine, Dr. William C. Roberts, MD, is truly a luminary and we are indebted to his long-standing service. His methods of observation and discipline in defining clinical conditions have kept conclusions within the range of the data, and the resultant impact on our field has been not only vast, but foundational. (Excerpt from Commentary on Quantitative extent of atherosclerotic plaque in major epicardial coronary arteries in patients with fatal coronary heart disease, in coronary endarterectomy specimens in patients with non-fatal coronary artery disease, in aorta-coronary saphenous venous conduits, and means to prevent plaques: a review after studying the coronary arteries for 50 years, W. C. Roberts, Am J Cardiol, 121 (2018).)

Cherney, D. Z. I., Y. Lytvyn and P. A. McCullough (2018). “Cardiovascular Risk Reduction in Patients With Chronic Kidney Disease: Potential for Targeting Inflammation With Canakinumab.” J Am Coll Cardiol 71(21): 2415-2418. May 29 [epub ahead of print].

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Ridker et al., in a post hoc analysis of CANTOS, report that in patients with moderate CKD (estimated GFR <60 ml/min/1.73 m2), and a high overall rate of CV events, canakinumab reduced the risk of major adverse cardiovascular events. In addition to demonstrating CV benefit, this analysis is of interest because canakinumab was safe and well tolerated in patients with CKD. Although the precise mechanisms responsible for CV protection with canakinumab are not yet clear, the largest benefit was observed in patients with a robust anti-inflammatory response to the first dose, a finding strongly suggesting that reducing inflammation played a role in CV protection. Comparable effects were also observed in patients with baseline albuminuria and in those with diabetes. Thus, the CV benefit observed with IL-1β inhibition in this cohort of patients with earlier stages of CKD may also set the stage for future research in patients with diabetes or more advanced renal disease including stages 3B and 4, who tend to exhibit exaggerated proinflammatory states . . . This post hoc analysis of CANTOS provides strong evidence for CV—but not renal—protection in response to suppressing inflammatory pathways in patients with moderate CKD. To elucidate fully the potential for renal protection with canakinumab, enriched CKD cohorts including patients with significant renal function impairment and proteinuria will likely be required. The lack of any signal, either positive or negative, in CANTOS around renal endpoints suggests that although this agent is generally safe, studies with canakinumab that specifically target CKD risk factors should not yet be prioritized. Nevertheless, dedicated studies are needed to determine whether canakinumab is protective in other high-risk groups and to explore the role of other novel anti-inflammatory agents on markers of CKD progression. (Excerpt from text of this commentary, p. 2416, 2418; no abstract available.)

McCullough, P. A., C. M. Ballantyne, S. K. Sanganalmath, G. Langslet, S. J. Baum, P. K. Shah, A. Koren, J. Mandel and M. H. Davidson (2018). “Efficacy and Safety of Alirocumab in High-Risk Patients With Clinical Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from 5 Placebo-Controlled ODYSSEY Trials).” Am J Cardiol 121(8): 940-948.

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Patients with previous atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk of future cardiovascular events. Despite maximally tolerated doses of statins, many patients still have elevated low-density lipoprotein cholesterol (LDL-C) levels. We evaluated the efficacy and safety of alirocumab in patients with ASCVD and/or HeFH on a maximally tolerated dose of statin (rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg, or simvastatin 80 mg, or lower doses with an investigator-approved reason) +/- other lipid-lowering therapies from 5 placebo-controlled phase 3 trials (52 to 78 weeks). Patients with (n = 2,449) and without (n = 1,050) ASCVD were pooled from the FH I, FH II, HIGH FH, LONG TERM, and COMBO I trials. Patients with HeFH with (n = 575) and without ASCVD (n = 682) were pooled from all trials except COMBO I. High-intensity statins were utilized in 55.7% to 59.0% and in 72.4% to 87.6% of the ASCVD and the HeFH groups, respectively. Efficacy end points included LDL-C percent change from baseline to week 24 stratified by alirocumab dose. Mean baseline demographics and lipid levels were comparable in alirocumab- and placebo-treated patients. LDL-C reductions from baseline at week 24 ranged from 46.6% to 51.3% for alirocumab 75/150 mg and from 54.1% to 61.9% for alirocumab 150 mg in ASCVD and HeFH groups and were sustained for up to 78 weeks. LDL-C reductions with alirocumab were independent of ASCVD and/or HeFH status (interaction p value >0.05). Concordant results were observed for other lipids analyzed. The overall safety in the subgroups analyzed was similar in both treatment arms. Injection-site reactions were observed more frequently with alirocumab versus placebo.

Haase, V. H., G. M. Chertow, G. A. Block, P. E. Pergola, E. M. deGoma, Z. Khawaja, A. Sharma, B. J. Maroni and P. A. McCullough (2018). “Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.” Nephrol Dial Transplant. Apr 16. [Epub ahead of print].

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Background: Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods: In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation). Results: Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions: Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.