Mayo Clinic Proceedings August 2018 Issue Summary

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1 Greetings, I am Dr Karl Nath, the Editor-in-Chief of Mayo Clinic Proceedings, and I am pleased to welcome you to the multimedia summary for the journal s August 2018 issue. There are 4 articles this month that have been selected as our Editor s Choice or Highlights articles. Our Editor's Choice is an Original Article examining the relationships among plasma aldosterone levels, the use of antihypertensive medications, clinical profiles, and plasma atrial natriuretic peptide levels in hypertensive individuals from a general community. Aldosterone promotes increased intravascular volume and elevation in blood pressure; and, in pathophysiologic amounts, it may cause organ damage in the heart, kidneys, and vasculature. The counterregulatory hormone, atrial natriuretic peptide, promotes natriuresis and lowers blood pressure. This article is authored by Dr Valentina Cannone from the University of Parma in Parma, Italy, and colleagues from Mayo Clinic in Rochester, Minnesota, and other institutions. The authors studied a well-characterized, randomly selected, adult community-based cohort using the Rochester Epidemiology Project in Olmsted County, Minnesota. The cohort consisted of individuals 45 years and older at risk for cardiovascular, kidney, and metabolic disease, and comprised 1550 subjects seen between August 1997 and September All subjects had plasma aldosterone and atrial natriuretic peptide levels measured, and their use of antihypertensive medications clearly documented. Of the 1550 subjects, approximately two thirds were normotensive and one third was hypertensive. Hypertensive subjects were older and had higher plasma atrial natriuretic peptide and aldosterone levels than those without hypertension. Aldosterone levels progressively increased as the number of antihypertensive medications increased. In hypertensive participants, the mean systolic blood pressure was above 120 mmhg systolic blood pressure, the new hypertension threshold based on the Systolic Blood Pressure Intervention Trial, the SPRINT trial. Importantly, use of increasing numbers of antihypertensive medications was associated with an increase in atrial natriuretic peptide level, higher body mass index, lower HDL cholesterol level, higher triglyceride level, lower glomerular filtration rate, and higher insulin and glucose levels; the number of anti-hypertensive medications was also associated with increased prevalence of obesity, chronic kidney disease, diabetes mellitus, cardiovascular diseases, and use of lipid-lowering agents. The most commonly used antihypertensive agents were diuretics and the most common combination was

2 diuretics and a beta blocker. Only 6 participants were taking mineralocorticoid receptor antagonists. These findings have several important implications in human hypertension. The study showed elevation of circulating aldosterone level in hypertensive individuals randomly selected from the general population, and, importantly, that this elevation is progressively higher with increasing number of anti-hypertensive medications. The prevalence of cardiovascular, renal, and metabolic disease was highest in hypertensive participants with the highest levels of aldosterone. Moreover, in the hypertension group, greater aldosterone levels were associated with lower circulating atrial natriuretic peptide levels. The authors conclude that additional studies are warranted to examine further the significance of plasma aldosterone and atrial natriuretic peptide levels in human hypertension, and to define whether antagonizing aldosterone and/or compensating for the relative deficiency of atrial natriuretic peptide may be effective strategies in the treatment of hypertension. The article is accompanied by an editorial by Dr Giovanni Davogustto and colleagues from Vanderbilt University in Nashville, Tennessee. These authors broadly discuss the contribution of the studies by Cannone and colleagues to the field of hypertension, the latter representing one of the most common chronic disorder worldwide. As emphasized by Davogustto et al, the studies of Cannone et al support the notion that anti-hypertensive therapies may be selected to target the major pathophysiologic change driving elevation in blood pressure: specifically, the use of mineralocorticoid receptor antagonist in patients with high aldosterone levels; and the use of agents that either elevate levels of, or promote the effects of atrial natriuretic peptide, in patients with relative deficiency of atrial natriuretic peptide. Our first Highlight is an Original Article that examined whether the level of kidney function and its rate of decline in the immediate predialysis period among veterans transitioning to end-stage renal disease associates with postdialysis mortality and hospitalization. It is authored by Ms Melissa Soohoo and colleagues from the University of California Irvine Medical Center in California, and other national institutions. More than 120,000 persons transition to end-stage renal disease each year in the United States, and are managed mainly by hemodialysis. Mortality rates for dialysis patients are especially high in the first few months after initiation of hemodialysis. Dialysis is generally initiated when chronic kidney disease has

3 progressed to stage V, the latter defined by a glomerular filtration rate less than 15 ml/min. However, there is considerable variability regarding the timing of the initiation of dialysis as the decision is made not just on the reduced glomerular filtration rate (below 15 ml/min), but also on clinical symptoms and findings, co-morbidities, and relevant laboratory tests. This study examined whether there is an association between outcomes for veterans who transition to end-stage renal disease and the level of glomerular filtration rate and rate of loss of kidney function just prior to such transition. Soohoo et al retrospectively analyzed data from the Transition-of-Carein-CKD study, which investigated veterans transitioning to end-stage renal disease between October 2007 and March The source population comprised more than 85,000 veterans identified from the USRDS, and following exclusion of patients with missing data, data from approximately 20,000 patients were analyzed. The mean age of the cohort was 66 years, and the cohort included 2% females and 34% black Americans. The median estimated glomerular filtration rate at transition and slope for the decline in renal function were approximately 10 ml/min and 11 ml/min per year, respectively. 26% of patients transitioned to end-stage renal disease with a low estimated glomerular filtration rate and slow slope and were more likely to have pre end-stage renal disease nephrology and dietician care, and had a lower prevalence of diabetes, depression, and chronic obstructive pulmonary disease. The presence of congestive heart failure consistently had the highest odds of transitioning with a high estimated glomerular filtration rate across all models. The authors observed that in veteran patients transitioning to end-stage renal disease, transitioning with a low estimated glomerular filtration rate and slow functional decline were associated with a lower risk of 12-month all-cause and cardiovascular mortality and hospitalization, and this relationship was independent of laboratory markers. Conversely, patients with a relatively high estimated glomerular filtration rate and a fast functional decline had the highest risk of all-cause and cardiovascular mortality and hospitalization rates compared with those with a low glomerular filtration rate and slow decline. This adverse effect of earlier initiation of dialysis (based on estimated glomerular filtration rate) may reflect the more rapid loss of residual kidney function in this subgroup or earlier exposure to the proinflammatory and procachexia effects that may occur with hemodialysis. These present results support the notion that an early transition to dialysis may not be as beneficial as

4 is often thought. The authors suggest that trials examining a more conservative and delayed approach in initiating dialysis are warranted. The second Highlight is an Original Article that assessed the independent and combined associations of long-term changes in depressive symptoms and estimated cardiorespiratory fitness with all-cause mortality. It is authored by Ms Trude Carlsen and colleagues from the Norwegian University of Science and Technology, in Trondheim, Norway, and colleagues from other international institutions. Studies investigating the relationship between depressive symptoms and mortality rarely consider the possible influence of cardiorespiratory fitness. In this study, the authors determined the independent associations of changes in depressive symptoms and estimated cardiorespiratory fitness with all-cause mortality in middle-aged and older adults using the Nord-Trøndelag Health Study, the HUNT study, a population-based health study undertaken in Nord- Trøndelag, Norway, in three waves. The participants in the present study attended both the second and third waves, HUNT 2, from August 1995 through June 1997, and HUNT 3, from October 2006 through June Estimated cardiorespiratory fitness was calculated using a validated nonexercise prediction model, and depressive symptoms were assessed by a Norwegian translation of the Hospital Anxiety and Depression Scale. Marital status, alcohol consumption, smoking habits, disease status/history, and systolic blood pressure, were obtained, and the outcome variable was all-cause mortality. The mean age of the 15,217 participants was 63 years, and 52% were women. During the follow-up period of 7 years, 7.6% died of all causes. Those who increased and maintained high estimated cardiorespiratory fitness had lower all-cause mortality risk than did those with persistently low estimated cardiorespiratory fitness, a finding consistent with prior studies. A major conclusion from the present study is that maintaining low or improving depressive symptoms and high estimated cardiorespiratory fitness are, independently, associated with a decreased all-cause mortality risk. The lowest mortality risk was observed with persistently high estimated cardiorespiratory fitness combined with decreased or persistently low depressive symptoms. Maintaining high estimated cardiorespiratory fitness and at the same time having high or increasing depressive symptoms were not associated with reduced all-cause mortality risk. These results emphasize the effect of reducing depressive symptoms and maintaining high cardiorespiratory fitness on longterm mortality risk in this patient population.

5 The third Highlight is an Original Article that investigated the risk of adverse clinical outcomes in a real-world cohort of patients with atrial fibrillation treated with vitamin K antagonists. This study involved patients from the Murcia Atrial Fibrillation Project whose outcomes were compared with subject outcomes in the warfarin arm of the randomized clinical trial, AMADEUS. It is authored by José Miguel Rivera-Caravaca and colleagues from the Hospital General Universitario Morales Mesegue in Murcia, Spain, and other institutions. Vitamin K antagonists, mainly warfarin, are the most commonly prescribed oral anticoagulants. Despite the emergence of oral anticoagulants other than vitamin K antagonist, vitamin K antagonists are commonly the first option for thromboprophylaxis in atrial fibrillation. The strongest evidence for the efficacy and safety of vitamin K antagonists is derived from randomized clinical trials. Patients in randomized clinical trials, however, are usually highly selected with strict inclusion and exclusion criteria, and are carefully followedup; real-world patients are often older, with many associated comorbidities that may result in a population that is challenging to appropriately manage. Indeed, in historical randomized clinical trials, less than 10% of patients screened were eventually randomized to study treatments; this has raised questions regarding the translatability of data from randomized clinical trials to everyday clinical practice. In the present study, the authors used propensity score matching to investigate the incidence and risk of adverse clinical outcomes in a real-world cohort of patients. Their cohort was composed of outpatients with paroxysmal, persistent, or permanent nonvalvular atrial fibrillation stable on vitamin K antagonists during the previous 6 months. Patients were recruited from May 2007 to December 2007 in the anticoagulation clinic of a tertiary hospital in Murcia, Spain. The authors included patients from the AMADEUS trial for comparison. The AMADEUS trial was a multicenter, randomized, open-label study with blinded assessment of outcomes that compared fixed-dose idraparinux with anticoagulation with dose-adjusted vitamin K antagonist in patients with nonvalvular atrial fibrillation. Primary end points included major bleeding events, ischemic strokes, and all-cause mortality, while secondary end points included intracranial hemorrhage, myocardial infarction, and cardiovascular mortality.

6 The study included more than 3600 patients, with 59% men, and with a mean age of 72 years, with approximately one-third consisting of real-world patients from the Murcia Atrial Fibrillation Project, and two-thirds representing patients from the AMADEUS trial. The mean time in therapeutic range of the pooled cohort was 65%, and the mean CHA2DS2-VASc and HAS-BLED scores were 3.7 and 2.1, respectively. Patients were followed-up for a median of 365 days. The study showed the presence of considerable heterogeneity in both populations. However, the real world patients with atrial fibrillation treated with vitamin K antagonist were at a higher risk for major bleeding, ischemic stroke, and all-cause mortality. These findings support circumspection that has been voiced regarding the translatability of findings from randomized clinical trials to the management of patients in the real world, in this case, patients with atrial fibrillation treated with vitamin K antagonists. The authors note, however, that these results should be interpreted with caution and are not necessarily generalizable to other differing contexts. You can access these Highlights and Editor s Choice articles free of charge during the entire month of August. When you visit our Mayo Clinic Proceedings website at you will see other free content and articles published online ahead of print. You can also find links to our social media by clicking the buttons at the top of the home page to follow us on Facebook, Twitter, and YouTube. On our YouTube channel, you will find author interviews, 60-second video article summaries, and our Mayo Clinic Proceedings Fireside Chat recordings, which are available from our website on the home page, as well as through itunes. You will also find our Pioneers and Legends video interview featuring Dr Donald Scholz; and finally, our website lists many news stories that are based on articles published in Mayo Clinic Proceedings. As always, we greatly thank you for your interest in, and support of, Mayo Clinic Proceedings. We hope you found this presentation from the content of our website valuable. Our journal s mission is, To promote the best interests of patients by advancing the knowledge and professionalism of the physician community. If you are interested in more information about us, our homepage is There you will find access to information for our social media content, such as additional videos on our YouTube Channel: or journal updates on Facebook: You can also follow us on

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Mayo Clinic Proceedings September 2018 Issue Summary

Mayo Clinic Proceedings September 2018 Issue Summary Greetings, I am Dr Karl Nath, the Editor-in-Chief of Mayo Clinic Proceedings, and I am pleased to welcome you to the multimedia summary for the journal s September 2018 issue. There are 4 articles this