There is uncertainty regarding the clinical effects of discontinuation of drugs for heart failure after long-term use. The withdrawal of long-term treatment can follow 1 of 4 distinct patterns: 1) loss of on-treatment effect with no observed changes following discontinuation (eg, prazosin); 2) attenuation or loss of on-treatment effect with rebound clinical worsening following discontinuation (eg, nitroprusside); 3) persistence of deleterious on-treatment effect followed by clinical worsening after discontinuation (eg, milrinone and flosequinan); and 4) persistence of favorable on-treatment effect followed by clinical worsening after discontinuation (eg, digoxin and sodium-glucose cotransporter 2 inhibitors). Persuasive evidence for persistence of efficacy has been demonstrated for the use of digoxin, diuretic agents, sodium-glucose cotransporter 2 inhibitors, and (to a limited extent) for angiotensin-converting enzyme inhibitors. Available evidence for worsening of clinical status following the withdrawal of neurohormonal antagonists largely consists of observational studies. However, their findings are difficult to interpret because of considerable confounding related to the fact that drugs were withdrawn for clinical reasons, which represented a more important contributor to the poor outcome of these patients than the withdrawal of an effective drug. Nevertheless, the totality of available evidence points to a meaningful clinical deterioration within a few weeks following the withdrawal for most drugs that have been evaluated for the treatment of heart failure. These findings suggests that that our current emphasis on the implementation of foundational drugs needs to include an equally important emphasis to avoid even short-term gaps in treatment.

2018-01-01·JACC. Heart failure

Flosequinan

Letter

作者: Weinrauch, Larry A.

ABSTRACT The Weismann barrier postulates that genetic information passes only from the germline to the soma and not in reverse, thus providing an obstacle to the inheritance of acquired traits. Certain organisms such as planaria – flatworms that can reproduce through asymmetric fission – avoid the limitations of this barrier, thus blurring the distinction between the processes of inheritance and development. In this paper, we re-evaluate canonical ideas about the interaction between developmental, genetic and evolutionary processes through the lens of planaria. Biased distribution of epigenetic effects in asymmetrically produced parts of a regenerating organism could increase variation and therefore affect the species9 evolution. The maintenance and fixing of somatic experiences, encoded via stable biochemical or physiological states, may contribute to evolutionary processes in the absence of classically defined generations. We discuss different mechanisms that could induce asymmetry between the two organisms that eventually develop from the regenerating parts, including one particularly fascinating source – the potential capacity of the brain to produce long-lasting epigenetic changes.

2017-06-01·JACC. Heart failure1区 · 医学

Long-Term Effects of Flosequinan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure

1区 · 医学

Article

作者: Bertram Pitt ; Jean Lucien Rouleau ; Lloyd Fisher ; Karl Swedberg ; Milton Packer ; David L. DeMets

OBJECTIVES:

The purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure.

BACKGROUND:

Flosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use.

METHODS:

Following a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction ≤35% to receive long-term treatment with placebo or flosequinan (75 or 100 mg/day) in addition to their usual therapy. The primary outcome was all-cause mortality.

RESULTS:

The trial was terminated after a recommendation of the Data and Safety Monitoring Board, because during an average of 10 months of follow-up, 192 patients died in the placebo group and 255 patients died in the flosequinan group (hazard ratio: 1.39, 95% confidence interval: 1.15 to 1.67; p = 0.0006). Flosequinan also increased the risk of disease progression, which was paralleled by drug-related increases in heart rate and neurohormonal activation. However, during the first month, patients in the flosequinan group were more likely to report an improvement in well-being and less likely to experience worsening heart failure. Similarly, during the month following drug withdrawal at the end of the trial, patients withdrawn from flosequinan were more likely than those withdrawn from placebo to report symptoms of or to require treatment for worsening heart failure.

CONCLUSIONS:

Although flosequinan produced meaningful symptomatic benefits during short- and long-term treatment, the drug increased the risk of death in patients with severe chronic heart failure.

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