Cardiology

Packer, M. (2018). “Questioning the obvious: does dyspnoea really matter in heart failure?” Eur Heart J Jun 22. [Epub ahead of print].

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Dyspnoea is the cardinal manifestation of heart failure and remains its most perplexing feature. Those afflicted with chronic heart failure typically report both symptoms of dyspnoea and exercise intolerance, but does dyspnoea actually limit activities of daily living? It is maddeningly difficult to know if patients with heart failure stop exercising because they are short of breath or because they are limited for some other reason and incidentally report dyspnoea as an accompanying symptom. Although it may seem obvious that dyspnoea impairs quality of life in heart failure, it is time to question the obvious. Our thinking about dyspnoea in heart failure has long been heavily influenced by observations in patients with acute heart failure, particularly those who present with acute pulmonary oedema. This syndrome is characterized by abrupt and marked increases in cardiac filling and pulmonary venous pressures, which are accompanied by overwhelming dyspnoea at rest. Classically, patients exhibited pink frothy sputum upon coughing, the result of the transudation of fluid from the pulmonary capillaries into the alveoli. The presentation was so dramatic that it seemed reasonable to surmise that oxygen transport was impaired, and that the resulting hypoxaemia was responsible for the sensation of dyspnoea. However, most patients with acute heart failure following myocardial injury are not hypoxaemic, even though they are generally dyspnoeic. (Excerpt from the text of this editorial, p. 1; no abstract available.)

Packer, M. (2018). “Is the Popularity of Dipeptidyl-Peptidase-4 Inhibitors Justified? Insights From Mechanistic Studies and Clinical Trials.” Am J Med 131(7): e287- e289.

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Because of their ease of use and patient acceptability, dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly prescribed to lower blood glucose in type 2 diabetes, typically, together with metformin. DPP-4 inhibitors do not require parenteral administration, and unlike other incretin-based agents, they have few gastrointestinal adverse effects. When compared with older antidiabetic drugs, DPP-4 inhibitors do not cause weight gain and are unlikely to trigger episodes of hypoglycemia.1 In contrast to sodium-glucose transporter 2 (SGLT2) inhibitors, they do not lead to genitourinary infections. Collectively, these features contribute to the popularity of DPP-4 inhibitors in the management of diabetes. Yet, aside from the symptomatic benefits of controlling blood glucose, antidiabetic drugs should prevent macrovascular and microvascular events. So we should ask: is the prominent place of DPP-4 inhibitors supported by a favorable effect of these drugs on the course of type 2 diabetes? (Excerpt from text of this commentary, p. e287; no abstract available.)

Packer, M. (2018). “Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: A novel approach based on large-scale trials with active comparators.” Int J Cardiol 261: 130-133.

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BACKGROUND: Current guidelines for the treatment of heart failure strongly recommend the use of inhibitors of the renin-angiotensin system and sympathetic nervous system in all patients with a reduced ejection fraction who can tolerate these drugs. Yet, there is no consensus about the efficacy of low doses of these drugs or the likely shape of the dose-response relationship for these agents. METHODS: Inferences were made by examining the effects of drugs in placebo-controlled trials before the protocol-specified opportunity for uptitration and by reassessing the results of large-scale trials with active comparators that inadvertently produced different intensities of neurohormonal blockade. RESULTS: In the case of inhibitors of the renin-angiotensin system, low starting doses appear to be effective in many patients, and 3-5 fold increases in dose do not have a mortality advantage over low doses. By contrast, in the case of beta-adrenergic blockers, although low starting doses appear effective in improving outcomes, achievement of target doses may yield substantial incremental mortality benefits, even such doses are accompanied by only small additional decreases in heart rate. CONCLUSION: When treating patients with heart failure to reduce mortality, the totality of evidence supports a relatively flat dose-response relationship for inhibitors of the renin-angiotensin system but a steep dose-response relationship for beta-adrenergic receptor blockers.

Packer, M. (2018). “Higher mortality rate in patients with heart failure who are taking commonly prescribed antidiabetic medications and achieve recommended levels of glycaemic control.” Diabetes Obes Metab 20(7): 1766-1769.

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Current guidelines for diabetes recommend that physicians attain a glycated haemoglobin (HbA1c) concentration less than or equal to 7.0%, but this target may not be applicable to those with heart failure. Fourteen studies in patients with chronic heart failure that examined the relationship between the level of HbA1c and risk of death specified whether HbA1c was influenced by treatment with antidiabetic medications. In patients with heart failure not receiving glucose-lowering drugs, the mortality rate was not higher among those with an HbA1c concentration <7.0%. By contrast, in patients who were treated with insulin, sulphonylureas and thiazolidinediones, an inverse or U-shaped relationship between HbA1c and the risk of death was generally observed, and mortality was lowest in patients with both heart failure and diabetes if the level of HbA1c was >7.0%. These studies suggest that patients with both heart failure and diabetes are at increased risk of death if they are prescribed certain glucose-lowering drugs to achieve levels of HbA1c <7.0%.

Packer, M. (2018). “Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications.” Eur J Heart Fail 20(7): 1100-1105.

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Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.