Peter A. McCullough M.D.

Cedars, A., K. M. Tecson, A. N. Zaidi, A. Lorts and P. A. McCullough (2019). “Impact of Durable Ventricular Assist Device Support on Outcomes of Patients with Congenital Heart Disease Waiting for Heart Transplant.” ASAIO J Jul 15. [Epub ahead of print].

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The number of congenital heart disease (CHD) patients with heart failure is expanding. These patients have a high probability of dying, while awaiting heart transplant. The potential for durable ventricular assist devices (VAD) to improve waiting list survival in CHD is unknown. We conducted an analysis of the Scientific Registry of Transplant Recipients database for the primary outcome of death or delisting due to clinical worsening, while listed for heart transplant. We compared CHD patients with non-CHD patients matched for listing status. Multivariable models were constructed to account for confounding variables. Congenital heart disease patients were less likely to have a VAD and were more likely to experience the primary outcome of death or delisting due to clinical worsening compared to non-CHD patients. Ventricular assist devices decreased the probability of experiencing the primary outcome for non-CHD but not for CHD patients with a final listing status of 1A. Ventricular assist devices increased the probability of experiencing the primary outcome among CHD patients for those with a final listing status of 1B with no impact in non-CHD patients. Among non-CHD patients who died or were delisted, the time to the primary outcome was delayed by VAD, with a similar trend in CHD. Except for patients with a final listing status of 1B, VAD does not adversely affect waiting list outcomes in CHD patients listed for heart transplant. Ventricular assist devices may prolong waiting list survival among high-risk CHD patients.

Vasudevan, A., J. W. Choi, G. A. Feghali, S. R. Lander, L. Jialiang, J. M. Schussler, R. C. Stoler, R. C. Vallabhan, C. E. Velasco and P. A. McCullough (2019). “Event dependence in the analysis of cardiovascular readmissions postpercutaneous coronary intervention.” J Investig Med 67(6): 943-949.

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Recurrent hospitalizations are common in longitudinal studies; however, many forms of cumulative event analyses assume recurrent events are independent. We explore the presence of event dependence when readmissions are spaced apart by at least 30 and 60 days. We set up a comparative framework with the assumption that patients with emergency percutaneous coronary intervention (PCI) will be at higher risk for recurrent cardiovascular readmissions than those with elective procedures. A retrospective study of patients who underwent PCI (January 2008-December 2012) with their follow-up information obtained from a regional database for hospitalization was conducted. Conditional gap time (CG), frailty gamma (FG) and conditional frailty models (CFM) were constructed to evaluate the dependence of events. Relative bias (%RB) in point estimates using CFM as the reference was calculated for comparison of the models. Among 4380 patients, emergent cases were at higher risk as compared with elective cases for recurrent events in different statistical models and time-spaced data sets, but the magnitude of HRs varied across the models (adjusted HR [95% CI]: all readmissions [unstructured data]-CG 1.16 [1.09 to 1.22], FG 1.45 [1.33 to 1.57], CFM 1.24 [1.16 to 1.32]; 30-day spaced-CG1.14 [1.08 to 1.21], FG 1.28 [1.17 to 1.39], CFM 1.17 [1.10 to 1.26]; and 60-day spaced-CG 1.14 [1.07 to 1.22], FG 1.23 [1.13 to 1.34] CFM 1.18 [1.09 to 1.26]). For all of the time-spaced readmissions, we found that the values of %RB were closer to the conditional models, suggesting that event dependence dominated the data despite attempts to create independence by increasing the space in time between admissions. Our analysis showed that independent of the intercurrent event duration, prior events have an influence on future events. Hence, event dependence should be accounted for when analyzing recurrent events and challenges contemporary methods for such analysis.

Vasudevan, A., J. W. Choi, G. A. Feghali, A. Y. Kluger, S. R. Lander, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, R. C. Stoler, R. C. Vallabhan, C. E. Velasco, A. Yoon and P. A. McCullough (2019). “First and recurrent events after percutaneous coronary intervention: implications for survival analyses.” Scand Cardiovasc J Jul 25: 1-6. [Epub ahead of print].

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Objectives. Using composite endpoints and/or only first events in clinical research result in information loss and alternative statistical methods which incorporate recurrent event data exist. We compared information-loss under traditional analyses to alternative models. Design. We conducted a retrospective analysis of patients who underwent percutaneous coronary intervention (Jan2010-Dec2014) and constructed Cox models for a composite endpoint (readmission/death), a shared frailty model for recurrent events, and a joint frailty (JF) model to simultaneously account for recurrent and terminal events and evaluated the impact of heart failure (HF) on the outcome. Results. Among 4901 patients, 2047(41.8%) experienced a readmission or death within 1 year. Of those with recurrent events, 60% had >/=1 readmission and 6% had >4; a total of 121(2.5%) patients died during follow-up. The presence of HF conferred an adjusted Hazard ratio (HR) of 1.32 (95% CI: 1.18-1.47, p < .001) for the risk of composite endpoint (Cox model), 1.44 (95% CI: 1.36-1.52, p < .001) in the frailty model, and 1.34 (95% CI:1.22-1.46, p < .001) in the JF model. However, HF was not associated with death (HR 0.87, 95% CI: 0.52-1.48, p = .61) in the JF model. Conclusions. Using a composite endpoint and/or only the first event yields substantial loss of information, as many individuals endure >1 event. JF models reduce bias by simultaneously providing event-specific HRs for recurrent and terminal events.

Spinowitz, B. S., S. Fishbane, P. E. Pergola, S. D. Roger, E. V. Lerma, J. Butler, S. von Haehling, S. H. Adler, J. Zhao, B. Singh, P. T. Lavin, P. A. McCullough, M. Kosiborod and D. K. Packham (2019). “Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study.” Clin J Am Soc Nephrol 14(6): 798-809.

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Background and objectives: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate–associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. Design, setting, participants, & measurements: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24–72 hours until normokalemic (potassium =3.5–5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5–5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. Results: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3–12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor–naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0–3.4 mmol/L, respectively. Conclusions: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

Rizk, D. V., A. L. Silva, P. E. Pergola, R. Toto, D. G. Warnock, M. P. Chin, A. Goldsberry, M. O’Grady, C. J. Meyer and P. A. McCullough (2019). “Effects of Bardoxolone Methyl on Magnesium in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.” Cardiorenal Med Jun 6: 1-10. [Epub ahead of print].

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BACKGROUND: Treatment with bardoxolone methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. METHODS: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. RESULTS: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (-0.17 mEq/L, 95% CI -0.18 to -0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. CONCLUSIONS: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.