T h e ne w engl a nd jour na l o f medicine
New Agents for Hyperkalemia
To the Editor: In the study by Weir et al. (Jan. 15 issue),1 the low baline rate of u of loop diuretics (32% of patients) is noteworthy and might limit the clinical applicability of their finding that patiromer was effective in reducing hyperkalemia in patients with chronic kidney dia receiving renin–angiotensin–aldosterone system (RAAS) inhibitors. The African American Study of Kidney Dia and Hypertension
(AASK) enrolled 1094 black patients with chronic kidney dia that was attributed to hyperten-sion. In AASK, approximately 40% of the partici-pants were randomly assigned to RAAS blockade. During 3.0 to 6.4 years of follow-up, only 80 hyper-kalemic events in 51 patients (<5%) were identi-fied.2 Notably, 75% of the patients were receiving a concomitant loop diuretic, and such diuretic u was associated with a decrea of 59% in the risk of hyperkalemia. The AASK findings suggest that including a loop diuretic in therapy for pa-tients with chronic kidney dia who are treat-ed with a RAAS inhibitor might diminish the potential need for patiromer to prevent hyper-kalemia. A subgroup analysis stratified accord-ing to loop-diuretic u would be informative to help us understand whether patiromer has any additional benefit in patients already receiving loop diuretics.
Robert A. Phillips, M.D., Ph.D.Houston Methodist Houston, TX
Lawrence J. Appel, M.D., M.P.H.
Johns Hopkins University
pervertBaltimore, MD Joy M. Weinberg, M.D.Albert Einstein College of Medicine Bronx, NY
No potential conflict of interest relevant to this letter was re-ported.
1. Weir MR, B akris GL, B ushinsky DA, et al. Patiromer in
patients with kidney dia and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;372:211-21.2. Weinberg J, Appel L, Bakris G, et al. Risk of hyperkalemia in
nondiabetic patients with chronic kidney dia receiving anti-hypertensive therapy. Arch Intern Med 2009;169:1587-94.DOI: 10.1056/NEJMc1501933
To the Editor: Weir et al. describe a group of patients with rum potassium levels ranging from 5.1 mmol per liter to less than 6.5 mmol per liter (moderate-to-vere hyperkalemia), stage 3 or 4 chronic kidney dia, and stable u of RAAS inhibitors. Patients were excluded if they had potassium-related electrocardiographic changes or other specified rious medical con-ditions. They began receiving an experimental treatment and were nt home with follow-up laboratory testing 3 days later. Their u of RAAS inhibitors was not modified. The study design was approved after ethics review at all study centers.Evidence is scarce about the treatment of patients such as the with moderate-to-vere hyperkalemia. Can the authors clarify why they felt safe nding the patients home with a
T h e ne w engl a nd jour na l o f medicine
potassium level as high as 6.4 mmol per liter without a specific established treatment? Thomas E. Finucane, M.D.
Johns Hopkins Bayview Medical Center
Baltimore, MD
tfinucan@jhmi.edu
No potential conflict of interest relevant to this letter was re-ported.
DOI: 10.1056/NEJMc1501933
To the Editor: In the two articles and one edito-rial1 on treatments for hyperkalemia (patiromer in the study by Weir et al. and sodium zirconium cyclosilicate [ZS-9] in the study by Packham et al.2), I was surprid that the authors did not mention fludrocortisone. In my experience, fludrocortisone works well as a long-term therapy by increasing urinary potassium excretion (kali-uresis). It also only costs 40 cents at the starting do of 0.1 mg daily. The main side effect of this synthetic mineralocorticoid i
s sodium retention, with subquent edema. However, this side effect allows for increasing the diuretic do, which further increas potassium elimination through the kidney.
Arkady Synhavsky, M.D.
Kidney Specialists of Minnesota
轮廓度
Saint Paul, MN
The views expresd in this letter are tho of the correspon-dent and do not necessarily reprent the views of Kidney Spe-cialists of Minnesota.
No potential conflict of interest relevant to this letter was re-ported.
1. Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J Med 2015;372:275-7.
2. Packham DK, Rasmusn HS, Lavin PT, et al. Sodium zirco-nium cyclosilicate in hyperkalemia. N Engl J Med 2015;372:222-31.
guineapigDOI: 10.1056/NEJMc1501933
To the Editor: Weir et al. and Packham et al. state that sodium polystyrene sulfonate is associ-ated with colonic necrosis, is indicated only in acute ttings, and is inappropriate as an active control. However, the authors incorrectly cite the results of our large, retrospective cohort study of the incidence of colonic necrosis associated with sodium polystyrene sulfonate as supporting the association between the u of sodium polysty-rene sulfonate and this complication.1 In our study, the inpatient u of oral sodium polysty-rene sulfonate with sorbitol was not significantly associated with colonic necrosis (relative risk, 2.10; 95% confidence interval, 0.68 to 6.48; P =0.20). Clinicians u sodium polystyrene sulfonate on a long-term basis in outpatients. In our study, 17% of the 1860 outpatient prescriptions for sodium polystyrene sulfonate appeared to be for long-term therapy.1 Chernin et al. described suc-cessful long-term u of this drug in a small number of patients with congestive heart fail-ure.2 A recently concluded trial evaluated the effects of daily sodium polystyrene sulfonate in outpatients for 7 days (v number, NCT02065076).
Individual patient therapy should be lected on the basis of efficacy, side-effect profile, and cost considerations. Unless a patient has unac-ceptable side effects, sodium polystyrene sulfo-nate may be preferred to more costly options.3 With heightened national interest in compara-tive clinical-effecti
veness rearch and patient-centered outcomes, sodium polystyrene sulfo-nate should be an active control in future clinical trials of patiromer and ZS-9.
Christina M. Yuan, M.D.
Dustin J. Little, M.D.国民教育毕业生
Robert Nee, M.D.
Walter Reed National Military Medical Center
Bethesda, MD
The views expresd in this letter are tho of the correspon-dents and do not necessarily reflect the official policy of the Department of the Army, the Department of the Navy, the Depart-ment of Defen, or the United States government.
No potential conflict of interest relevant to this letter was re-ported.
1. Watson MA, Baker TP, Nguyen A, et al. Association of pre-scription of oral sodium polystyrene sulfonate with sorbitol in an inpatient tting with colonic necrosis: a retrospective cohort study. Am J Kidney Dis 2012;60:409-16.
2. Chernin G, Gal-Oz A, Ben-Assa E, et al. Secondary preven-tion of hyperkalemia with sodium polystyrene sulfonate in car-diac and kidney patients on renin-angiotensin-aldosterone sys-tem inhibition therapy. Clin Cardiol 2012;35:32-6.
3. Little DJ, Nee R, Abbott KC, Watson MA, Yuan CM. Cost-utility analysis of sodium polystyrene sulfonate vs. potential alternatives for chronic hyperkalemia. Clin Nephrol 2014;81: 259-68.
DOI: 10.1056/NEJMc1501933
opportunity怎么读Dr. Weir and colleagues reply: We agree with Phillips et al. that loop diuretics can be ud to prevent hyperkalemia and control volume in p atients with advanced chronic kidney dia.
B ecau the agents can induce intravascular volume depletion and increa the risk of gout,
correspondence
they are not ideal when the primary purpo is long-term lowering of the rum potassium level. Patients with chronic kidney dia who ingest potassium-rich foods can overcome the capacity of a diuretic to control hyperkalemia.1 B oth AASK2 and our study enrolled patients with ad-vanced chronic kidney dia. However, the pa-tients in our study were older, frequently had diabetes (57% of patients), and had hyperkale-mia while they were receiving maximal or, more frequently, submaximal RAAS inhibitor therapy (56% of patients). Overall, 54% of the patients were receiving diuretics (loop in 32% and thia-zide in 29%), and 9% were receiving mineralo-corticoid antagonists. Although the frequency of hyperkalemia was low in AASK, adver effects such as dizziness (50.1%), light-headedness (49.2%), and syncope (6.7%) were obrved in pa-tients treated with ramipril,2 possibly condary to diuretic therapy.
We appreciate Finucane’s concern. Our study design was developed under a special protocol asssment with the Food and Drug Administra-tion and was approved after a review of the rum potassium respon to patiromer and its safety profile in two pha 1 and four pha 2 studies, including a prespecified interim analysis of the 52-week pha 2b study in patients with rum potassium levels between 5.0 mmol per liter and 6.0 mmol per liter. In our study, protocol-specified inclusion and exclusion criteria were designed to eliminate high-risk patients with hyperkalemia, and
all the patients were instructed to consume a low-potassium diet. The mean rum potassium level was less than 5.5 mmol per liter 2 days after the start of treatment (the time of the first post-baline asssment) in patients with moder-ate-to-vere hyperkalemia. Significant early de-creas in rum potassium levels were reported at 7 hours in patients with moderate-to-vere hyperkalemia who were receiving patiromer in a pha 1 study.3 Our experience suggests that patiromer is safe and effective in protocol-defined populations, including tho with moderate-to-vere hyperkalemia receiving long-term RAAS inhibitor therapy.
Fludrocortisone has been ud to treat chronic hyperkalemia. The drug should be ud with caution in patients with heart failure, renal in-sufficiency, or hypertension, and long-term u may be further limited by side effects rem-bling symptoms of Cushing’s dia.4
be honestIn respon to Yuan et al.: our study was not designed to provide health economic-outcome data. We elected not to u sodium polystyrene sulfonate as a comparator, given the recognized warnings, precautions, and sodium load associ-ated with therapy,5 along with the lack of results from prospective long-term trials.
Matthew R. Weir, M.D.
University of Maryland School of Medicine
Baltimore, MD
mweir@medicine.umaryland.edu
George L. Bakris, M.D.
University of Chicago Medicine
Chicago, IL
Bertram Pitt, M.D.
University of Michigan
Ann Arbor, MI
Since publication of their article, the authors report no fur-ther potential conflict of interest.
1. Lazich I, Bakris GL. Prediction and management of hyper-kalemia across the spectrum of chronic kidney dia. Semin Nephrol 2014;34:333-9.
2. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pres-sure lowering and antihypertensive drug class on progression of hypertensive kidney dia: results from the AASK trial. JAMA 2002;288:2421-31. [Erratum, JAMA 2006;295:2726.]
3. Bushinsky DA, Bakris GL, Williams G, et al. Patiromer in-duced a rapid ont of action and sustained K+ lowering through-out the dosing period in CKD patients with hyperkalemia. J Am Soc Nephrol 2014;25:669A. abstract.
4. Florinef. Montreal: Paladin Labs (package inrt) ( /pdf_files/monograph_florinef.pdf).
5. Kayexalate. Bridgewater, NJ: Sanofi-Aventis (package inrt) (www.v/drugsatfda_docs/label/2011/ 011287s023lbl.pdf).
DOI: 10.1056/NEJMc1501933existence
Dr. Packham and colleagues reply: There are veral reasons that sodium polystyrene sulfo-nate and fludrocortisone are inappropriate thera-peutic options for patients with chronic hyperka-lemia or as comparators for ZS-9 in clinical trials. First, with regard to the safety of sodium polystyrene sulfon
ate, its association with colon-ic necrosis is well established, as shown by the package inrt warning, which rais concern with respect to an undesirable, potentially fatal outcome.1 Furthermore, other rious gastroin-testinal side effects are associated with sodium polystyrene sulfonate and sorbitol, making that agent an unsuitable control.2
Second, the taste, consistency, and color of sodium polystyrene sulfonate are easily identifiable, making it impossible to rve as a masked treat-ment paired with ZS-9, a white, inorganic, tasteless oral suspension. To date, studies of ZS-9 have been
relationship
T h e ne w engl a nd jour na l o f medicine
the only double-blind, placebo-controlled trials involving patients with hyperkalemia.
Third, the lack of controlled trials showing definitive efficacy of sodium polystyrene sulfo-nate for acute or chronic hyperkalemia is trou-bling,2 as is the highly variable respon to this drug. Given the lack of demonstrated efficacy in controlled trials, there are practical limitations powering a study for efficacy with the u of sodium polystyrene sulfonate as a comparator. Fludrocortisone, too, is not an appropriate comparator. First, although fludrocortisone treat-ment may increa urinary potassium excretion, it is also a synthetic mineralocorticoid with aldo-sterone-like effects and thus w
ould defy the purpo of RAAS inhibition, which is common therapy for patients with chronic kidney dia and heart failure. Moreover, aldosterone ana-logues have inconsistent effects among patients with cardiovascular dia and can lead to a worning of hypertension. Second, to our knowl-edge, there has yet to be a rigorous clinical trial showing the efficacy and safety of fludrocorti-sone in the treatment of hyperkalemia across various dia states. Third, fludrocortisone is not approved for u in treating hyperkalemia.3 In an era of evidence-bad medicine, caution should be exercid when using drugs off label.
ZS-9 is not absorbed, which eliminates the risk of potential systemic effects. In two large, pha 3 trials involving more than 1000 patients, ZS-9 was found to have excellent efficacy, side-effect profile, predictability, rapidity, and safety. ZS-9 may provide a much-needed, effective treat-ment for hyperkalemia, although the need for long-term studies is acknowledged; such studies are under way.
David K. Packham, M.B., B.S., M.D.
University of Melbourne
Melbourne, VIC, Australia
au
Henrik S. Rasmusn, M.D., Ph.D. Bhupinder Singh, M.D.
ZS Pharma
上海儿童英语哪个好Coppell, TX
Medical writing support was provided by Xelay Acumen. Since publication of their article, the authors report no fur-ther potential conflict of interest.
1. Kayexalate. Bridgewater, NJ: Sanofi-Aventis (package inrt) (www.v/drugsatfda_docs/label/2011/ 011287s023lbl.pdf).
2. Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effec-tive? J Am Soc Nephrol 2010;21:733-5.
3. Florinef. Montreal: Paladin Labs (package inrt) ( /pdf_files/monograph_florinef.pdf).
DOI: 10.1056/NEJMc1501933
Trends in Opioid Analgesic Abu and Mortality
in the United States
To the Editor: Dart et al. (Jan. 15 issue)1 conclude that the United States may be making progress in controlling the abu of opioid analgesics. How-ever, they understate the increasing problem of opioid-associated deaths, especially tho related to heroin.
First, the death rates in Figure 3 of the article appear low, suggesting that only approximately 43 people and 18 people died from heroin and prescription opioids, respectively, during 2012. On the basis of data from the Centers for Dia Control and Prevention, Warner et al.2 estimated that there were 5925 heroin-associated deaths and 16,007 opioid analgesic–associated deaths during 2012. More important, however, is that the gravity of the current epidemic of opioid over-do is minimized by the statement of Dart et al. that the rates of death associated with heroin and prescription opioids are inverly related. Figure 3 of the article shows stable rates of death associated with prescription opioids from 2011 to 2013, while heroin-associated death rates were rising dramatically. We must acknowledge the growing nature of this epidemic, expand access to effective overdo treatments, and redouble our efforts toward education and prevention. David J. McCann, Ph.D.
Phil Skolnick, Ph.D., D.Sc.
National Institute on Drug Abu
Bethesda, MD
世博会美国馆
v
No potential conflict of interest relevant to this letter was re-ported.
1. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid anal-gesic abu and mortality in the United States. N Engl J Med 2015;372:241-8.
