Milton Packer M.D.

Rorth, R., P. S. Jhund, S. L. Kristensen, A. S. Desai, L. Kober, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2018). “The prognostic value of troponin T and N-terminal pro B-type natriuretic peptide, alone and in combination, in heart failure patients with and without diabetes.” Eur J Heart Fail Dec 10. [Epub ahead of print].

Full text of this article.

AIMS: We examined the prognostic importance of N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin T (TnT) in heart failure patients with and without diabetes. METHODS AND RESULTS: We measured NT-proBNP and TnT in the biomarker substudy of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Of 1907 patients, 759 (40%) had diabetes. Median TnT in patients with diabetes was 18 (interquartile range 11-27) ng/L and 13 (9-21) ng/L in those without (P < 0.001). The TnT frequency-distribution curve was shifted to the right in patients with diabetes, compared to those without diabetes. By contrast, NT-proBNP did not differ between patients with and without diabetes. Diabetes and each biomarker were predictive of worse outcomes. Thus, patients with diabetes, an elevated TnT and a NT-proBNP level in the highest tertile (9% of all patients) had an absolute risk of cardiovascular death or heart failure hospitalization of 265 per 1000 person-years, compared to a rate of 42 per 1000 person-years in those without diabetes, a TnT < 18 ng/L and a NT-proBNP in the lowest tertile (16% of all patients). TnT remained an independent predictor of adverse outcomes in multivariable analyses including NT-proBNP. CONCLUSION: TnT is elevated to a greater extent in heart failure patients with diabetes compared to those without (whereas NT-proBNP is not). TnT and NT-proBNP are additive in predicting risk and when combined help identify diabetes patients at extremely high absolute risk.

Packer, M. (2018). “The conundrum of patients with obesity, exercise intolerance, elevated ventricular filling pressures and a measured ejection fraction in the normal range.” Eur J Heart Fail Dec 18. [Epub ahead of print].

Full text of this article.

Patients with obesity, a reduced exercise capacity, increased cardiac filling pressures and a measured left ventricular ejection fraction in the normal range do not have a homogeneous disorder, but instead, exhibit one of three phenotypes. First, many obese people exhibit sodium retention, plasma volume expansion and cardiac enlargement, and some are likely to have heart failure that is related to hypervolaemia, even though cardiac index and circulating levels of natriuretic peptides are not meaningfully increased. Second, in some middle-aged men and women (particularly those with minimal co-morbidities), levels of natriuretic peptides increase markedly and can lower systemic vascular resistance, thus leading to high-output heart failure (HOHF) and glomerular hyperfiltration. Third, older obese people, particularly women with multiple co-morbidities, exhibit the syndrome of heart failure with a preserved ejection fraction (HFpEF). Despite degrees of plasma volume expansion similar to HOHF, these patients exhibit only modestly increased ventricular dimensions and circulating levels of natriuretic peptides (despite a high prevalence of atrial fibrillation), and glomerular function is characteristically impaired. A conceptual framework is proposed to distinguish among the three phenotypes seen in obese patients with exercise intolerance, increased ventricular filling pressures and a measured left ventricular ejection fraction in the normal range, since they may respond differently to therapeutic interventions. Efforts are needed to enhance the recognition of heart failure in obese people and to ensure that clinical trials that are designed to study patients with HFpEF actually enrol those who have the disease.

Grayburn, P. A., A. Sannino and M. Packer (2018). “Proportionate and Disproportionate Functional Mitral Regurgitation: A New Conceptual Framework That Reconciles the Results of the MITRA-FR and COAPT Trials.” JACC Cardiovasc Imaging Dec 6. [Epub ahead of print].

Full text of this article.

Traditional approaches to the characterization of secondary or functional mitral regurgitation (MR) have largely ignored the critical importance of the left ventricle (LV). We propose that patients with secondary MR represent a heterogenous group, which can be usefully subdivided based on understanding that the effective regurgitant orifice area (EROA) is dependent on left ventricular end-diastolic volume (LVEDV). According to the Gorlin hydraulic orifice equation, patients with heart failure, an LV ejection fraction of 30%, an LVEDV of 220 to 250 ml, and a regurgitant fraction of 50% would be expected to have an EROA of approximately 0.3 cm(2) independent of specific tethering abnormalities of the mitral valve leaflets. The MR in these patients is proportionate to the degree of LV dilatation and can respond to drugs and devices that reduce LVEDV. In contrast, patients with EROA of 0.3 to 0.4 cm(2) but with LVEDV of only 160 to 200 ml exhibit degrees of MR that are disproportionately higher than predicted by LVEDV. These patients appear to preferentially benefit from interventions directed at the mitral valve. Our proposed conceptual framework explains the apparently discordant results from 2 recent randomized controlled trials of mitral valve repair. The MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial enrolled patients who had MR that was proportionate to the degree of LV dilatation, and during long-term follow-up, the LVEDV and clinical outcomes of these patients did not differ from medically-treated control subjects. In comparison, the patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial had an EROA approximately 30% higher but LV volumes that were approximately 30% smaller, indicative of disproportionate MR. In these patients, transcatheter mitral valve repair reduced the risk of death and hospitalization for heart failure, and these benefits were paralleled by a meaningful decrease in LVEDV. Thus, characterization of MR as proportionate or disproportionate to LVEDV appears to be critical to the selection of an optimal treatment for patients with chronic heart failure and systolic dysfunction.

Dewan, P., P. S. Jhund, L. Shen, M. C. Petrie, W. T. Abraham, M. Atif Ali, C. H. Chen, A. S. Desai, K. Dickstein, J. Huang, S. Kiatchoosakun, K. S. Kim, L. Kober, W. T. Lai, Y. Liao, U. M. Mogensen, B. H. Oh, M. Packer, J. L. Rouleau, V. Shi, A. S. Sibulo, Jr., S. D. Solomon, P. Sritara, K. Swedberg, H. Tsutsui, M. R. Zile and J. J. V. McMurray (2018). “Heart failure with reduced ejection fraction: comparison of patient characteristics and clinical outcomes within Asia and between Asia, Europe and the Americas.” Eur J Heart Fail Dec 10. [Epub ahead of print].

Full text of this article.

AIMS: Nearly 60% of the world’s population lives in Asia but little is known about the characteristics and outcomes of Asian patients with heart failure with reduced ejection fraction (HFrEF) compared to other areas of the world. METHODS AND RESULTS: We pooled two, large, global trials, with similar design, in 13 174 patients with HFrEF (patient distribution: China 833, India 1390, Japan 209, Korea 223, Philippines 223, Taiwan 199 and Thailand 95, Western Europe 3521, Eastern Europe 4758, North America 613, and Latin America 1110). Asian patients were younger (55.0-63.9 years) than in Western Europe (67.9 years) and North America (66.6 years). Diuretics and devices were used less, and digoxin used more, in Asia. Mineralocorticoid receptor antagonist use was higher in China (66.3%), the Philippines (64.1%) and Latin America (62.8%) compared to Europe and North America (range 32.8% to 49.6%). The rate of cardiovascular death/heart failure hospitalization was higher in Asia (e.g. Taiwan 17.2, China 14.9 per 100 patient-years) than in Western Europe (10.4) and North America (12.8). However, the adjusted risk of cardiovascular death was higher in many Asian countries than in Western Europe (except Japan) and the risk of heart failure hospitalization was lower in India and in the Philippines than in Western Europe, but significantly higher in China, Japan, and Taiwan. CONCLUSION: Patient characteristics and outcomes vary between Asia and other regions and between Asian countries. These variations may reflect several factors, including geography, climate and environment, diet and lifestyle, health care systems, genetics and socioeconomic influences.

Ramires, F. J. A., F. Martinez, E. A. Gomez, C. Demacq, C. R. Gimpelewicz, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2018). “Commentary: Post hoc analyses of SHIFT and PARADIGM-HF highlight the importance of chronic Chagas’ cardiomyopathy.” ESC Heart Fail Oct 9. [Epub ahead of print].

Full text of this article.

We read with interest the report by Bocchi and colleagues of their post hoc analysis of the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), examining the effect of study drug in the 38 patients with chronic chagasic cardiomyopathy (CCC). The authors reported that study drug lowered heart rate and improved New York Heart Association class. The sample size was too small to allow estimation of the effect of treatment on mortality or hospitalization. However, this analysis did suggest that patients with CCC experienced high event rates, despite excellent background therapy. We examined outcomes in patients with CCC in the Prospective comparison of Angiotensin Receptor Neprilysin Inhibitor with Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) and the Aliskiren trial to Minimize OutcomeS in Patients with Heart failure (ATMOSPHERE). These trials included 195 CCC patients from among a total of 2552 recruited in Latin America. Despite being younger and having less co‐morbidity, the CCC patients had higher hospitalization and mortality rates, compared with other aetiologies, despite similarly good treatment. We also conducted an exploratory post hoc analysis of the effect of sacubitril/valsartan (formerly known as LCZ696) in CCC patients in PARADIGM‐HF. Of a total of 113 patients, 58 were randomized to sacubitril/valsartan and 55 to enalapril. The two treatment groups were similar in terms of demographics, co‐morbidity, and heart failure (HF) severity. Patients with CCC treated with sacubitril/valsartan, as compared with enalapril, had a lower risk of experiencing cardiovascular death or HF hospitalization, the primary composite endpoint, and each of its components (Figure). The point estimate for risk reduction was comparable with or greater than that seen with the drug vs. enalapril in the entire study population. This analysis is underpowered and should be interpreted with caution. CCC is a major health issue in Latin America and is now recognized in the USA and Europe, reflecting contemporary migration patterns.5-8 Indeed, a recent study from Brazil concluded that the population attributable mortality risk from CCC increased between 2002/2004 and 2012/2014.9 Future trials should consider recruiting larger numbers of patients with CCC to allow adequately powered subgroup analysis and even trials specifically in CCC would be justified, given the magnitude of this problem. Until that time, patients with CCC should be treated empirically with therapies recommended by guidelines, on the assumption that treatments for patients with reduced ejection fraction are effective, irrespective of aetiology. (Text of letter concerning Bocchi. 2018. Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial.)