Cardiology

Packer, M. (2019). “Methodological and Clinical Heterogeneity and Extraction Errors in Meta-Analyses of Catheter Ablation for Atrial Fibrillation in Heart Failure.” J Am Heart Assoc Nov 5: 8(21). [Epub 2019 Oct 18].

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Background Meta-analyses are expected to follow a standardized process, and thus, they have become highly formulaic, although there is little evidence that such regimentation yields high-quality results. Methods and Results This article describes the results of a critical examination of 14 published meta-analyses of catheter ablation for atrial fibrillation in heart failure that were based on a nearly identical core set of 4 to 6 primary trials. Methodological issues included (1) the neglect of primary data or the failure to report any primary data; (2) the inaccurate recording of the number of randomized patients; (3) the lack of attention to data missingness or baseline imbalances; (4) the failure to contact investigators of primary trials for additional data; (5) the incorrect extraction of data, the misidentification of events, and the assignment of events to the wrong treatment groups; (6) the calculation of summary estimates based on demonstrably heterogenous data, methods of differing reliability, or unrelated end points; and (7) the development of conclusions based on sparse numbers of events or overly reliant on the results of 1 dominant trial. Conclusions These findings reinforce existing concerns about the methodological validity of meta-analyses and their current status in the hierarchy of medical evidence, and they raise new questions about the process by which meta-analyses undergo peer review by medical journals.

Packer, M. (2019). “Methodological and Clinical Heterogeneity and Extraction Errors in Meta-Analyses of Catheter Ablation for Atrial Fibrillation in Heart Failure.” J Am Heart Assoc Nov 5: 8(21). [Epub 2019 Oct 18].

Full text of this article.

Background Meta-analyses are expected to follow a standardized process, and thus, they have become highly formulaic, although there is little evidence that such regimentation yields high-quality results. Methods and Results This article describes the results of a critical examination of 14 published meta-analyses of catheter ablation for atrial fibrillation in heart failure that were based on a nearly identical core set of 4 to 6 primary trials. Methodological issues included (1) the neglect of primary data or the failure to report any primary data; (2) the inaccurate recording of the number of randomized patients; (3) the lack of attention to data missingness or baseline imbalances; (4) the failure to contact investigators of primary trials for additional data; (5) the incorrect extraction of data, the misidentification of events, and the assignment of events to the wrong treatment groups; (6) the calculation of summary estimates based on demonstrably heterogenous data, methods of differing reliability, or unrelated end points; and (7) the development of conclusions based on sparse numbers of events or overly reliant on the results of 1 dominant trial. Conclusions These findings reinforce existing concerns about the methodological validity of meta-analyses and their current status in the hierarchy of medical evidence, and they raise new questions about the process by which meta-analyses undergo peer review by medical journals.

Packer, M. (2019). “Heightened risk of intensive rate control in patients with atrial fibrillation who are obese or have type 2 diabetes: A critical review and re-evaluation.” J Cardiovasc Electrophysiol Oct 18. [Epub ahead of print].

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Atrial fibrillation (AF) is common in patients with obesity and diabetes; the arrhythmia (if long-standing) is typically managed by rate control and anticoagulation. However, the coexistence of these two metabolic disorders complicates therapeutic options for rate control. The likely pathogenesis of AF in these patients is an expansion of epicardial adipose tissue whose inflammation is transmitted to the left atrium causing electromechanical remodeling. However, this same process is also transmitted to the left ventricle (LV), impairing its distensibility and its ability to tolerate volume, leading to heart failure with preserved ejection fraction. Unfortunately, the latter diagnosis (although commonly present in patients with AF and a coexistent metabolic disorder) is often ignored. To achieve rate control, physicians prescribe intensive treatment with atrioventricular (AV) nodal-blocking drugs, often at doses that are titrated to blunt exercise as well as resting heart rate responses. However, strict rate control (target rate, <80/min) is associated with somewhat worse outcomes than lenient rate control (target rate, <110/min). Furthermore, any rate slowing that facilitates diastolic filling may aggravate filling pressures that are already disproportionately increased because the LV is stiff and overfilled as a result of cardiac inflammation. Rate slowing in AF with beta blockers may not achieve the benefit expected from the blockade of adrenergically mediated cardiotoxicity, and some AV nodal-blocking drugs (digoxin and dronedarone) can increase the risk of death in patients with AF. Finally, cardiac fibrosis in obesity and diabetes may affect the conduction system, which can predispose to serious bradyarrhythmias if patients are prescribed AV nodal-blocking drugs.

Packer, M. (2019). “Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction in Patients With Nonalcoholic Fatty Liver Disease.” Am J Med Oct 14. [Epub ahead of print].

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The most common causes of chronic liver disease in the developed world -nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) – are the hepatic manifestations of an insulin-resistant state that is linked to visceral adiposity and systemic inflammation. NAFLD and NASH lead to an expansion of epicardial adipose tissue and the release of proinflammatory adipocytokines that cause microcirculatory dysfunction and fibrosis of the adjoining myocardium, resulting in atrial fibrillation as well as heart failure with a preserved ejection fraction (HFpEF). Inflammatory changes in the left atrium lead to electroanatomical remodeling; thus, NAFLD and NASH markedly increase the risk of atrial fibrillation. Simultaneously, patients with NAFLD or NASH commonly show diastolic dysfunction or latent HFpEF. Interventions include (1) weight loss by caloric restriction, bariatric surgery or intensive exercise; and (2) drugs that ameliorate fat-mediated inflammation in both the liver and heart (e.g., statins, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and pioglitazone). Patients with NAFLD or NASH commonly have an inflammation-related atrial and ventricular myopathy, which may contribute to symptoms and long-term outcomes.

Packer, M. (2019). “Are healthcare systems now ready to adopt sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in chronic heart failure? The culmination of a 20-year journey.” Eur Heart J 40(40): 3353-3355.

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As one of the two principal investigators of the PARADIGM-HF trial, I was dismayed when obstacles were placed in the path of physicians who sought to prescribe neprilysin inhibition to patients with chronic heart failure. As a matter of personal choice, I have had no financial relationship with the manufacturer of sacubitril/valsartan (Novartis) since the publication of the primary papers, and I have not been involved in any efforts to market or give sponsored presentations on behalf of the drug. However, at the same time, I have been an ardent supporter of the findings of the trial, which represented my second chance (after the disappointment of the OVERTURE trial) to finally demonstrate that neprilysin inhibitors can meaningfully potentiate the survival benefits of conventional antagonists of the renin–angiotensin system in patients with heart failure. If the PIONEER-HF trial allows all cardiologists to embrace that conclusion, I am very pleased. If the biomarker data published in this issue are motivating to practitioners to increase their appropriate prescribing of sacubitril/valsartan, I am delighted to hear that. If physicians, healthcare systems, and the manufacturer are prepared to work collaboratively to facilitate affordable unrestricted access to a life-saving treatment for heart failure, I doubt that patients will complain. (Excerpt from text of this editorial, p. 3355; no abstract available. Refers to “Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.” New England Journal of Medicine 381(17): 1609-1620.)