Milton Packer M.D.

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 (2019). “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 21(5): 577-587.

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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.

Balmforth, C., J. Simpson, L. Shen, P. S. Jhund, M. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. Shi, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2019). “Outcomes and Effect of Treatment According to Etiology in HFrEF: An Analysis of PARADIGM-HF.” JACC Heart Fail May 3. [Epub ahead of print].

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OBJECTIVES: The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. BACKGROUND: Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy. METHODS: We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide. RESULTS: Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum-related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11). CONCLUSIONS: Just under half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255).

Packer, M. (2019). “What Have We Learned From Randomized Controlled Trials of Catheter Ablation for Atrial Fibrillation in Patients With Chronic Heart Failure?” Circ Arrhythm Electrophysiol 12(4): e007222.

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Six trials have evaluated the effects of catheter ablation for atrial fibrillation (AF) in chronic heart failure (HF) (Table). Four compared catheter ablation to medical therapy directed at rate-control. These studies primarily enrolled patients with long-standing AF, and the control groups received atrioventricular nodal blocking drugs. In contrast, 2 trials compared catheter ablation to medical therapy primarily directed at rhythm control. These studies generally enrolled patients with paroxysmal or nonpermanent AF, and the control groups received membrane-active antiarrhythmic drugs . . . The totality of evidence suggests that catheter ablation for AF may have benefits on EF and functional capacity in chronic HF. However, the trials have been small and largely focused on patients with minimal or mild HF and only modest impairment of left ventricle function. In patients with meaningful degrees of HF and low EF, little efficacy has been observed, and the complication rate has been high. Because of the sparse number of events, the large number of patients with excluded or missing data, the lack of balance at randomization, and the use of comparator groups who were treated with cardiotoxic antiarrhythmic drugs to achieve rhythm control, it is not possible to suggest that a benefit of catheter ablation on morbidity and mortality has been demonstrated. Although the results of the 6 randomized trials of catheter ablation have been combined in numerous meta-analyses, summary estimates cannot overcome the inherent limitations of the component trials. Importantly, the available evidence from the 6 trials was not persuasive to the writers of the most recent guideline, which provided its weakest possible positive recommendation for the use of catheter ablation in patients with AF and chronic HF. . . Therefore, additional randomized controlled trials are needed to understand the range of potential responses to this procedure. (Excerpt from text, p. 1, 2-3; no abstract available.)

Packer, M. (2019). “Electrophysiological interventions in the treatment of chronic heart failure: a comparison of the strength of evidence supporting cardiac resynchronization for electrical conduction delay and catheter ablation for atrial fibrillation.” Eur J Heart Fail 21(4): 398-401.

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In patients with a meaningful electrical conduction delay, the evidentiary support for the benefits of cardiac resynchronization is robust and strikingly consistent and is based on a large number and broad range of patients (n ≅ 10 000) enrolled in definitely‐powered trials. Many of these were specifically designed to evaluate the effects of treatment on morbidity and mortality, and they demonstrated meaningful reductions in the risk of death and hospitalizations for heart failure. In contrast, in patients with atrial fibrillation, the available trials of catheter ablation are small and have reported only sparse data. Reports of favourable effects on exercise tolerance and quality of life are difficult to interpret because of the open‐label design of the studies; changes in ejection fraction have been assessed by unreliable methods and have been inconsistent; and the reported decreases in morbidity and mortality have been observed in trials that had significant methodological limitations and/or used potentially cardiotoxic membrane‐active agents as a comparator. In addition, it is noteworthy that cardiac resynchronization follows a standardized approach, whereas the technique for catheter ablation varies considerably by physician. If catheter ablation is to be adopted as an appropriate therapy for large numbers of patients with chronic heart failure, it is important to develop a persuasive evidentiary base that approaches that of cardiac resynchronization therapy or pharmacological treatments for heart failure. This is particularly true, given its invasive nature and its considerable expense. (Excerpt from text, p. 400; no abstract available.)

Myhre, P. L., M. Vaduganathan, B. Claggett, M. Packer, A. S. Desai, J. L. Rouleau, M. R. Zile, K. Swedberg, M. Lefkowitz, V. Shi, J. J. V. McMurray and S. D. Solomon (2019). “B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial.” J Am Coll Cardiol 73(11): 1264-1272.

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BACKGROUND: Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. OBJECTIVES: The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. METHODS: BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. RESULTS: Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). CONCLUSIONS: Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).