Peter A. McCullough M.D.

McCullough, P. A., H. S. Mehta, C. M. Barker, D. P. Cork, C. Gunnarsson, M. P. Ryan, E. R. Baker, J. Van Houten, S. Mollenkopf and P. Verta (2019). “The Economic Impact of Mitral Regurgitation on Patients With Medically Managed Heart Failure.” Am J Cardiol 124(8): 1226-1231.

Full text of this article.

The objective of this study was to quantify the financial healthcare burden of mitral regurgitation (MR) on medically managed heart failure (HF) patients. Data from the Truven Health MarketScan Commercial Claims and Medicare Supplemental Databases were analyzed. Included patients had a minimum of 1 inpatient or 2 outpatient claims for HF with a 6-month preperiod (baseline). A 6-month postperiod (landmark) after HF index was used to capture MR diagnosis and severity. Following the landmark period, patients had to have 12 months of continuous medical and prescription drug plan enrollment with at least 2 records of HF medication refills. A therapeutic intensity score was calculated based on HF medication usage. Medically managed HF patients were separated into 3 cohorts: without MR (no MR), insignificant MR (iMR), and significant MR (sMR). Healthcare utilization and all-cause expenditures were modeled to quantify the burden of MR. All models controlled for baseline demographics, co-morbid conditions, and HF therapeutic intensity. Medically managed incident HF patients with sMR had significantly more hospital days (1.91 vs 1.72 days; p=0.0096) and annual expenditures ($23,988 vs $21,530; p < 0.0001) compared with no MR patients. No differences were identified when comparing iMR and no MR. When evaluating HF admissions, sMR patients had an estimated 50% greater HF admissions rate (0.036 vs 0.024; p < 0.0001) compared with no MR patients. Additionally, HF admits for iMR were 23% more than those with no MR (0.029 vs 0.024; p=0.0064). In conclusion, evidence of MR in retrospective claims significantly increases the healthcare impact of medically managed HF patients. Both utilization and financial burden is more pronounced when MR is clinically significant.

Husain-Syed, F., H. W. Birk, C. Ronco, T. Schormann, K. Tello, M. J. Richter, J. Wilhelm, N. Sommer, E. Steyerberg, P. Bauer, H. D. Walmrath, W. Seeger, P. A. McCullough, H. Gall and H. A. Ghofrani (2019). “Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure.” J Am Heart Assoc Nov 5;8(21). [Epub 2019 Oct 19].

Full text of this article.

Background Persistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography. Methods and Results We enrolled 205 patients with suspected or prediagnosed pulmonary hypertension (PH) undergoing right heart catheterization. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary hemodynamics, echocardiography, renal function, intra-abdominal pressure, and neurohormones and hydration status. Four spectral Doppler intrarenal venous flow patterns and a novel renal venous stasis index (RVSI) were defined. We evaluated PH-related morbidity using the Cox proportional hazards model for the composite end point of PH progression (hospitalization for worsening PH, lung transplantation, or PH-specific therapy escalation) and all-cause mortality for 1-year after discharge. The prognostic utility of RVSI and intrarenal venous flow patterns was compared using receiver operating characteristic curves. RVSI increased in a graded fashion across increasing severity of intrarenal venous flow patterns (P<0.0001) and was significantly associated with right heart and renal function, intra-abdominal pressure, and neurohormonal and hydration status. During follow-up, the morbidity/mortality end point occurred in 91 patients and was independently predicted by RVSI (RVSI in the third tertile versus referent: hazard ratio: 4.72 [95% CI, 2.10-10.59; P<0.0001]). Receiver operating characteristic curves suggested superiority of RVSI to individual intrarenal venous flow patterns in predicting outcome (areas under the curve: 0.789 and 0.761, respectively; P=0.038). Conclusions We propose RVSI as a conceptually new and integrative Doppler index of renal congestion. RVSI provides additional prognostic information to stratify PH for the propensity to develop right heart failure. Clinical Trial Registration Unique identifier: NCT03039959.

Rossing, P., G. A. Block, M. P. Chin, A. Goldsberry, H. J. L. Heerspink, P. A. McCullough, C. J. Meyer, D. Packham, P. E. Pergola, B. Spinowitz, S. M. Sprague, D. G. Warnock and G. M. Chertow (2019). “Effect of Bardoxolone Methyl on the Urine Albumin-to-Creatinine Ratio in Patients with Type 2 Diabetes and Stage 4 Chronic Kidney Disease.” Kidney Int 96(4): 1030-1036.

Full text of this article.

Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor kappaB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: -0.035 [95% confidence interval -0.031 to -0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

McCullough, P. A., H. S. Mehta, D. P. Cork, C. M. Barker, C. Gunnarsson, S. Mollenkopf, J. Van Houten and P. Verta (2019). “The healthcare burden of disease progression in medicare patients with functional mitral regurgitation.” Journal of Medical Economics 22(9): 909-916.

Full text of this article.

Objective: This retrospective database analysis estimated the incremental effect that disease progression from non-clinically significant functional mitral regurgitation (nsFMR) to clinically significant FMR (sFMR) has on clinical outcomes and costs. Methods: Medicare Fee for Service beneficiaries with nsFMR were examined, defined as those with a heart failure diagnosis prior to MR. Patients were classified as ischemic if there was a history of: CAD, AMI, PCI, or CABG. The primary outcome was time to sFMR, defined as pulmonary hypertension, atrial fibrillation, mitral valve surgery, serial echocardiography, or death, using a Cox hazard regression model. Annualized hospitalizations, inpatient hospital days, and healthcare expenditures were also modeled. Results: Patients with IHD had higher risk (Hazard Ratio = 1.22 [1.14-1.30]) for disease progression compared to patients without. The progression cohort had significantly more annual inpatient hospitalizations (non-IHD = 1.32; IHD = 1.40) than the non-progression cohort (non-IHD = 0.36; IHD = 0.34), and significantly more annual inpatient hospital days (non-IHD = 13.07; IHD = 13.52) than the non-progression cohort (non-IHD = 2.29; with IHD = 2.08). The progression cohort had over 3.5-times higher costs vs the non-progression cohort, independent of IHD (non-IHD = $12,798 vs $46,784; IHD = $12,582 vs $49,348). Conclusion: Treating FMR patients earlier in their clinical trajectory may prevent disease progression and reduce high rates of healthcare utilization and expenditures.

Rangaswami, J., S. Bangalore, B. Kaplan, K. A. Birdwell, A. C. Wiseman, P. A. McCullough and D. M. Dadhania (2019). “Cardiovascular disease care fragmentation in kidney transplantation: a call for action.” Kidney Int 96(3): 568-571.

Full text of this article.

Kidney transplantation (KT) is the treatment of choice for end-stage kidney disease, offering the highest survival benefit among all the different renal replacement therapies. Long-term renal allograft and patient survival have shown substantial improvements over time: however, death with a functioning allograft remains the leading cause of late allograft loss, with cardiovascular disease (CVD)–related deaths representing a major cause of mortality. Although recipients of KT have a lower risk of CVD as compared with the 10- to 20-fold increased risk in patients on dialysis, their risk of CVD is substantially higher than that in the general population3 (Figure 1). The transplantation milieu represents the confluence of several traditional and nontraditional cardiovascular risk factors intrinsic to the backdrop of chronic kidney disease (CKD). The entry point of a patient with advanced CKD into transplantation juxtaposes several patient- and donor-related cardiovascular risk factors including preexisting diabetes and hypertension, dialysis vintage, chronic inflammation, allograft quality, donor age, and donor vascular disease. Several post-transplant risk factors are superimposed on this background, such as the chronic effects of immunosuppression with calcineurin inhibitors and steroids, episodes of allograft rejection, new-onset diabetes post-transplantation, and left ventricular hypertrophy. Reduction in CVD-related morbidity and mortality after KT poses challenges across several interfaces: the pre–kidney transplant cardiovascular evaluation, the period of active transplant listing, and post-transplant CVD care. According to the United States Renal Data System 2017 annual report, 18,021 kidney transplant procedures were performed in the United States in 2015, out of the 83,978 wait-listed candidates on maintenance dialysis alone, with a steady increase in the cumulative number of recipients living with a functioning kidney transplant.3 This mandates the need for a coordinated effort across these interfaces to optimize long-term patient and allograft outcomes. On behalf of the Cardiovascular Work Group of the Kidney Pancreas Community of Practice of the American Society of Transplantation, we summarize key factors that may contribute to CVD care fragmentation in KT and offer suggestions for optimizing CVD care delivery in this high-risk population. (Excerpt from text, p. 568-569; no abstract available.)