Cách kê đơn thuốc lợi tiểu quai trong phù nề 2019

BMJ 2019; 364: l359 doi: 10.1136 / bmj.l359 (Xuất bản ngày 21 tháng 2 năm 2019) Trang Thực hành UNCERTAINTIES Cách kê đơn thuốc lợi tiểu quai trong phù nề Bác sĩ tim mạch xâm lấn Steven D Anisman, bác sĩ thận học lâm sàng Stephen B Erickson, bác sĩ chăm sóc chính Nancy E Morden SVMC Tim mạch, Khoa Y học tim mạch Dartmouth Hitchcock, Bennington, VT, Hoa Kỳ; Phòng khám 2Mayo, Khoa Thận và Tăng huyết áp, Rochester, MN, Hoa Kỳ; 3 Viện Dartmouth về Chính sách Y tế & Thực hành Lâm sàng, Khoa Y tế Cộng đồng và Gia đình, Trường Y Geisel tại Dartmouth, Hanover, NH, Hoa Kỳ Những điều bạn cần biết • Thuốc lợi tiểu quai đáp ứng theo kiểu tất cả hoặc không, nghĩa là không có cách nào để tăng hoặc giảm dần tác dụng lợi tiểu của các thuốc này; họ “bật” hoặc “tắt”. Đối với một cá nhân cụ thể, một liều lượng có hiệu quả hoặc không • Thuốc lợi tiểu quai được sử dụng rộng rãi cho các triệu chứng phù nề do bất kỳ nguyên nhân nào • Có rất ít hướng dẫn về việc lựa chọn loại thuốc lợi tiểu quai nào, nhưng bằng chứng có cường độ vừa phải cho thấy rằng xoắn khuẩn có thể có lợi thế hơn furosemide, bao gồm hiệu lực cao hơn, thời gian tác dụng dài hơn và có thể cải thiện triệu chứng • Liều lượng thuốc lợi tiểu quai khi cần thiết có thể giúp bệnh nhân kiểm soát tình trạng thể tích đồng thời giảm thiểu nguy cơ hạ thể tích máu và các tác dụng phụ khác của thuốc lợi tiểu quai Hộp 1: Bài báo này được tạo ra như thế nào Chúng tôi ban đầu viết bài báo này để trả lời các câu hỏi mà bác sĩ chăm sóc sức khỏe ban đầu thường đặt ra khi tìm kiếm sự hỗ trợ trong việc kiểm soát phù ở bệnh nhân suy tim Bằng chứng được thu thập trong khoảng thời gian 15 năm để trả lời các câu hỏi của bệnh nhân và bác sĩ liên quan đến việc kiểm soát phù và sử dụng thuốc lợi tiểu quai Chúng tôi đã sử dụng PubMed làm tài nguyên tìm kiếm chính; và sách văn bản đã đánh giá Các cụm từ tìm kiếm khác nhau tùy thuộc vào các truy vấn được giải quyết và bao gồm: “furosemide”, “torsemide”, “bumetanide”, “(các) thuốc lợi tiểu quai”, “lợi tiểu”, “suy tim”, “ngưỡng” dược động học ”và“ dược lực học ”. Chúng tôi đã tìm kiếm Nền tảng đăng ký các thử nghiệm lâm sàng quốc tế, 59 metaRegister of Kiểm soát Thử nghiệm, 60 và Cơ quan Đăng ký Thử nghiệm Lâm sàng Hoa Kỳ61 vào tháng 7 năm 2018 bằng cách sử dụng các cụm từ tìm kiếm “furosemide”, “torsemide” và “bumetanide.” Bằng chứng của sự không chắc chắn là gì? Thuốc lợi tiểu quai thường được kê đơn để kiểm soát các triệu chứng phù nề như sưng chân hoặc khó thở và giảm quá tải chất lỏng. Chúng được khuyến cáo rộng rãi bởi các hướng dẫn và tổ chức như Viện Y tế và Chăm sóc Quốc gia (NICE) ở Anh. Thuốc lợi tiểu quai có sẵn trong Vương quốc Anh là furosemide, bumetanide và torasemide Nhưng lựa chọn nào là tốt nhất? Dược động học của thuốc lợi tiểu quai được đặc trưng rõ ràng Các nghiên cứu và thử nghiệm trên người và động vật mô tả sự khác biệt về dược lực học giữa thuốc lợi tiểu quai Tuy nhiên, có rất ít bằng chứng so sánh trực tiếp chúng. Đặc biệt, có rất ít thông tin chất lượng thấp so sánh kết quả lâm sàng của furosemide với loại ít phổ biến hơn lựa chọn thay thế torsemide và bumetanide Bài viết này (hộp 1) phác thảo một số khác biệt về dược động học giữa các thuốc lợi tiểu quai có sẵn có thể ảnh hưởng đến việc lựa chọn thuốc lợi tiểu quai trong thực tế và tư vấn cách dùng thuốc một cách hiệu quả An toàn hoặc không có tác dụng Dược động học của thuốc lợi tiểu quai là khác thường; đối với hầu hết các loại thuốc, liều thấp hơn dẫn đến phản ứng yếu trong khi liều cao hơn tạo ra phản ứng mạnh dần dần, hoạt động giống như một “công tắc điều chỉnh độ sáng” (hình 1) Tuy nhiên, ba bài báo tổng quan toàn diện về dược lý của thuốc lợi tiểu quai chỉ ra rằng chúng đáp ứng toàn diện -hoặc không theo cách nào (bảng 1) Thuốc lợi tiểu quai hoạt động giống như một công tắc bật / tắt khi chúng đạt đến ngưỡng điều trị, không có sự thay đổi dần dần giữa “tắt hoàn toàn” và “bật hoàn toàn” (hình 2) Đối với một bệnh nhân riêng lẻ, một liều là dưới điều trị hoặc điều trị Liều để đạt đến ngưỡng điều trị Liều lớn hơn duy trì nồng độ trên ngưỡng trong thời gian dài hơn.5 Khi chức năng thận suy giảm hoặc khi protein niệu tăng, có thể cần liều lớn hơn để đạt được cùng nồng độ hiệu quả trong nội bào để kích hoạt Tác dụng “trên” Miễn là chức năng thận ổn định, liều lặp lại hiệu quả sẽ ổn định, mặc dù sự dung nạp nhẹ có thể phát triển theo thời gian.6 Thư từ gửi tới SD Anisman steven.anisman@svhealthcare.org Chỉ sử dụng cho mục đích cá nhân: Xem quyền và tái bản http://www.bmj.com/permissions Đăng ký: http://www.bmj.com/subscribe BMJ: xuất bản lần đầu là 10.1136 / bmj.l359 vào ngày 21 tháng 2 năm 2019 Tải xuống từ http : //www.bmj.com/ vào ngày 21 tháng 2 năm 2019 bởi khách Được bảo vệ bởi bản quyền PRACTICE BMJ 2019; 364: l359 doi: 10.1136 / bmj.l359 (Xuất bản ngày 21 tháng 2 năm 2019) Trang THỰC HÀNH Bằng chứng về tác động của việc thay đổi lối sống của bệnh nhân đối với suy tim và bài niệu, đặc biệt là hạn chế chất lỏng và natri, đang gây tranh cãi; bệnh nhân có thể sẽ được hưởng lợi từ một nghiên cứu nghiêm ngặt hơn để định lượng giá trị của những can thiệp như vậy đối với các kết quả quan trọng Bằng chứng về sự khác biệt giữa

BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of Practice UNCERTAINTIES How to prescribe loop diuretics in oedema Steven D Anisman invasive cardiologist , Stephen B Erickson clinical nephrologist , Nancy E Morden primary care physician SVMC Cardiology, Dartmouth Hitchcock Department of Cardiovascular Medicine, Bennington, VT, USA; 2Mayo Clinic, Division of Nephrology and Hypertension, Rochester, MN, USA; 3The Dartmouth Institute for Health Policy & Clinical Practice, The Department of Community and Family Medicine, The Geisel School of Medicine at Dartmouth, Hanover, NH, USA What you need to know • Loop diuretics respond in an all-or-none fashion, meaning there is no way to gradually increase or decrease the diuretic effect of these medications; they are either “on” or “off.” For a given individual, a dose is either effective or not • Loop diuretics are widely used for symptoms of oedema of any aetiology • There is little guidance on which loop diuretic to choose, but moderate strength evidence suggests torsemide may have advantages over furosemide, including higher potency, longer duration of action, and possibly improved symptomatic improvement • As-needed dosing of loop diuretics may help patients control their volume status while minimising the risk of hypovolaemia and other side effects of loop diuretics Box 1: How this article was created We initially wrote this article in response to questions primary care clinicians frequently posed when seeking assistance in managing oedema in patients with heart failure Evidence was gathered over a 15 year period in response to patient and physician queries regarding the management of oedema and the use of loop diuretics We used PubMed as the primary search resource; and reviewed text books Search terms varied depending on the queries addressed, and included: “furosemide,” “torsemide,” “bumetanide,” “loop diuretic(s),” “diuresis,” “heart failure,” “threshold,” “pharmacokinetics,” and “pharmacodynamics.” We searched the International Clinical Trials Registry Platform,59 the metaRegister of Controlled Trials,60 and the US Clinical Trials Register61 in July 2018 using the search terms “furosemide,” “torsemide,” and “bumetanide.” What is the evidence of the uncertainty? Loop diuretics are commonly prescribed to manage oedema symptoms such as swollen legs or breathlessness and to relieve fluid overload They are widely recommended by guidelines and organisations such as the National Institute for Health and Care Excellence (NICE) in the UK The loop diuretics available in the UK are furosemide, bumetanide, and torasemide But which option is best? The pharmacokinetics of loop diuretics are well characterised Studies and trials on humans and animals describe pharmacodynamic differences between loop diuretics However, there is limited evidence directly comparing them In particular, there is little and low quality information comparing the clinical outcomes of furosemide with the less commonly chosen alternatives torsemide and bumetanide This article (box 1) outlines some pharmacokinetic differences between available loop diuretics that may influence loop selection in practice and advises how to dose them effectively An all or nothing effect The pharmacokinetics of loop diuretics are unusual; for most drugs, lower doses result in a weak response while higher doses create a progressively stronger response, acting like a “dimmer switch” (fig 1) However, three comprehensive review articles on the pharmacology of loop diuretics indicate that they respond in an all-or-none manner (table 1) Loop diuretics behave like an on/off switch once they reach their therapeutic threshold, without a gradual change between “fully off” and “fully on” (fig 2) For an individual patient, a single dose is either subtherapeutic or therapeutic Dosing to reach the therapeutic threshold Larger doses maintain a concentration above the threshold for longer periods.5 As renal function declines, or as proteinuria rises, larger doses may be needed to achieve the same effective intratubular concentration to trigger the “on” effect As long as renal function is stable, the effective loop dose is stable, though mild tolerance can develop over time.6 Correspondence to S D Anisman steven.anisman@svhealthcare.org For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe BMJ: first published as 10.1136/bmj.l359 on 21 February 2019 Downloaded from http://www.bmj.com/ on 21 February 2019 by guest Protected by copyright PRACTICE BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of PRACTICE Evidence regarding the effect of patient lifestyle modification on heart failure and diuresis, particularly fluid and sodium restriction, is controversial; patients would likely benefit from a further rigorous research quantifying the value of such interventions on important outcomes Evidence of the differences between loops includes systematic reviews, a limited number of head-to-head trials, basic science studies, and pooled data sources (table 2) Pharmacology reveals some clinically valuable differences between loops What should we in the light of the uncertainty? Potential advantages of torsemide over furosemide include higher potency, longer duration of action, higher and more predictable bioavailability, lower hospital readmission rates for heart failure, aldosterone inhibition, higher functional/symptomatic improvements, lower rates of cardiac fibrosis than furosemide, less hypokalaemia, and the absence of potentially damaging low thiamine levels There is limited guidance on which diuretic to use for patients with oedema The UK NICE guidance on management of oedema in heart failure, for example, does not direct clinicians to select one loop diuretic over another Our recommendation is based on our expert opinion and derived from the well described pharmacodynamics of loop diuretics With any loop diuretic, monitor electrolytes and renal function routinely and when dose or symptom changes Bumetanide is less well studied, but a review of loop diuretic pharmacokinetics and comparative safety and efficacy suggests it may have favourable features, similar to those of torsemide, when compared with furosemide.25 Definitive evidence for differences in quality of life is not available Furosemide is the most commonly used loop diuretic in the US,26-28 despite some disadvantages relative to torsemide or bumetanide Is ongoing research likely to provide relevant evidence? Five trials are under way to examine the benefits of various diuretic strategies in the treatment of patients with heart failure (box 2) These studies will advance the science, although future research regarding the clinical implications of various approaches will still be necessary Box 2: Clinical trials that address some of the uncertainties raised in this article All trials are currently recruiting • Comparing standard of care outpatient heart failure management with a weight based torsemide regimen Clinicaltrials.gov identifier NCT03187509 • Comparing the treatment strategy of torsemide versus furosemide on clinical outcomes over 12 months in patients with heart failure who are hospitalised Clinicaltrials.gov identifier NCT03296813 • Comparing the effects of torasemide and furosemide on clinical and biochemical parameters of haemodynamic and neurohormonal compensation and myocardial remodelling in patients with chronic heart failure Clinicaltrials.gov identifier NCT01942109 • Clarifying the factors that contribute to loop-diuretic resistance, and to evaluate the benefit of adding intravenous chlorothiazide to loop-diuretic dosing Clinicaltrials.gov identifier NCT02546583 • Evaluating the safety and efficacy of loop and thiazide diuretics used in combination for patients with acute decompensated heart failure Clinicaltrials.gov identifier NCT01647932 A head-to-head study comparing responsive dosing of the different drugs within the class on clinical outcomes, including those related to patient quality of life, would be helpful for both providers and patients Outcomes could include hospitalisations for heart failure and hospital-free days at home, patient-reported quality of life assessment, and incidence of electrolyte abnormalities Ideally, studies would include important subpopulations defined by age, race, ethnicity, and common comorbidities as different patient populations may have different responses to different diuretics Results of such studies could be useful in the management of patients with oedema, particularly the large number of people with heart failure For personal use only: See rights and reprints http://www.bmj.com/permissions Select a loop diuretic Consider starting with torsemide as the loop of choice depending on local formulary; a typical starting dose is 10-20 mg in clinical practice, although some authorities recommend starting lower 29-31 which can be adjusted depending on patient response Consider bumetanide when minimising fluid infusion is critical, since intravenous formulations of bumetanide are 40 times more concentrated than the equivalent furosemide dose (box 3).32 Ethacrynic acid, which has high potential for ototoxicity, is usually reserved for patients with a documented allergy to diuretics containing sulfa (box 4) Box 3: Equivalent doses of loop diuretics 80 mg PO furosemide ≈ 40 mg IV furosemide ≈ 40 mg PO or IV torsemide ≈ mg PO or IV bumetanide ≈ 100 mg PO or IV ethacrynic acid diuretics Box 4: Common myths about loop diuretics Myth Avoid oral diuretics in oedematous patients, because absorption is compromised Fact Absorption may be slower with oedema, but the overall dose absorbed and the diuretic effect is essentially the same with or without intestinal oedema2 Myth Do not use loop diuretics in patients with a sulfa allergy Fact All loop diuretics except ethacrynic acid contain a sulfa moiety However, many patients with allergies to sulfonamide antibiotics are not allergic to loops.33 Thus antibiotic sulfa allergy should not be considered an absolute contraindication to loop diuretics Myth Intravenous drip is more effective than bolus dosing for severe oedema Fact The largest trial comparing bolus dosing with continuous infusion in heart failure showed no difference in any measured outcome.34 A meta-analysis of 10 trials drew the same conclusion.35 One review suggested infusion may be beneficial despite lack of evidence36 Myth Stop diuresis if creatinine is rising Fact Some increase in blood urea nitrogen/urea and creatinine may be unavoidable, or even an indication of effective diuresis An observational substudy of the ESCAPE trial found aggressive diuresis causing haemoconcentration positively correlated with a statistically significant 180 day mortality benefit37 Determine if the dose is working To determine if the chosen loop dose is working, ask about the patient’s response to the diuretic: “When you take the medication, what you notice regarding how much you urinate? How long does that effect last?” If the dose is therapeutic, frequent urination should occur in the 4-6 hours immediately following ingestion; the urine volume can be as high as 2000-4000 mL during that period.2 38 Within that 4-6 Subscribe: http://www.bmj.com/subscribe BMJ: first published as 10.1136/bmj.l359 on 21 February 2019 Downloaded from http://www.bmj.com/ on 21 February 2019 by guest Protected by copyright Loop diuretics accumulate in the renal tubule via tubular secretion The drug’s intratubular concentrations (not serum concentrations) determine if the therapeutic threshold is reached.7-9 Glomerular filtration rate and/or proteinuria generally indicate the likelihood of achieving effective intratubular concentrations at common doses BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of PRACTICE hour window, torsemide has the longest duration of action, bumetanide the shortest, and furosemide is intermediate.2 If there is no short term increase in urine output, or if patients report polyuria unrelated to dosing (“I pee all day and all night”), the dose is likely to be subtherapeutic and should be increased until the diuretic threshold is reached Diuresis caused by a loop diuretic (frequent urination for 4-6 hours) is distinct from the frequent urination caused by hypervolaemia, where excess fluid chronically fills the intravascular space and causes continuous polyuria, often worse at night when lying down Nocturia typically indicates ineffective daytime diuresis, not excessive diuretic response.41 42 As needed, dry weight dosing of loop diuretics After an effective regimen is started, hypervolaemia will resolve and the patient will move towards euvolaemia Diuretics continued consistently, after euvolaemia is achieved, can cause hypovolaemia Once euvolaemia is achieved using the patient’s therapeutic dose, we suggest using an as-needed dose of diuretic based on dry weight Avoid common dosing errors (box 5) Box 5: Common errors in loop diuretic use • Prescribing multiple, different daily doses (“Take 40 mg in the morning and 20 mg at night”) Instead, find a dose that works, and use only that dose; avoid subtherapeutic doses • Prescribing variable doses (“Take 20 mg a day, make that 40 mg if you’re very oedematous”) Instead find a dose that works, and use only that dose • Increasing doses that are already effective (“You’re still oedematous, even though that 40 mg dose is working Take 80 mg for a few days”) Once the switch is on, you can’t turn it up • Using subtherapeutic doses to achieve “gentle diuresis” or to “save the kidneys.” (“That 40 mg dose isn’t doing anything, take it twice daily.”) Keeping a switch in the off position has no effect, and is essentially a placebo Based on the evidence in table 2, an understanding of the pharmacokinetics of loop diuretics, and our practice experience, we recommend “as-needed dosing.” This potentially reduces several problems, including the risks of over- and under-diuresis Use of diuretics can be triggered by weight gain or by specific symptoms Weight gain can serve as an early indicator of fluid retention Daily weighing is recommended in most guidelines, including the Scottish,43 American,44 and European guidelines on managing heart failure,45 although to date no trials have shown that daily weights improve outcomes.46 This approach is effective for most patients, but does require them to self-manage: checking their weight daily and making medication decisions based on that weight Patients who have the ability and desire to follow a weight or symptom based dosing regimen, or those who have adequate support in making these decisions, should be selected Follow up in clinic or by phone to assess symptom resolution for safe implementation of this strategy Visible oedema or shortness of breath can be used as triggers for treatment; this may be useful in patients who develop symptomatic oedema without previous weight gain.47 48 For personal use only: See rights and reprints http://www.bmj.com/permissions Since loop diuretics cause a predictable but binary response, their effect cannot be titrated gradually up or down On their own, other diuretic classes (including thiazide, thiazide like, and potassium sparing) are less potent than loops They are a good choice when patients need “gentle” diuresis for relatively mild hypervolemia or oedema For example, thiazides may cause only 25% of the urine output expected from a loop diuretic.49 Potassium sparing diuretics on their own are only 3% as effective as loop diuretics.50 Causing more diuresis When a loop alone proves insufficient, adding a thiazide or potassium sparing diuretic can increase the effect of the loop diuretic by blocking reabsorption beyond the loop of Henle in the nephron Alternatively, patients can take a second therapeutic dose of loop diuretic or more hours after the first to achieve additional diuresis.2 Consider limiting fluid and sodium intake, although the evidence for these recommendations is weak51 52 and controversial.53 54 The kidneys aggressively retain sodium (termed “sodium avidity”) following the 4-6 hour diuretic phase Sodium ingested after a loop diuretic is used can noticeably decrease the diuretic effect.3 Drugs that reduce the effect of loop diuretics Angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB),55 56 and non-steroidal anti-inflammatory (NSAID) medications57 can reduce the effect of loop diuretics These drugs all reduce glomerular filtration rate through various mechanisms; ACE-I and ARB dilate the efferent arteriole, which reduces the pressure head on the glomerulus, while NSAIDs constrict the afferent arteriole, also reducing blood flow to the glomerulus NSAIDs also directly increase the risk of oedema, via inhibition of prostaglandin E2 synthesis and the associated increased sodium reabsorption.58 What patients need to know about as-needed dosing Ask the patient to weigh him/herself daily, and to take an effective loop diuretic dose if the weight is higher than the target If the weight is at or below target, no loop diuretic is taken For example, “Take 20 mg of torsemide if your weight is 93 kg (205 lb) or above; if it is 92 kg (203 lb) or less, take no torsemide.” Base target weights on patient wellbeing—if the patient reports no notable swelling, nor difficulty breathing in any position, and there is no weakness or dizziness to suggest dehydration, that is a clinically reasonable “dry weight” and should be used as an aid for deciding when to take these medications If daily weights are not possible, consider using an alternative trigger for use of an appropriate dose Examples might include visible swelling (typically in the legs and/or feet), shortness of breath, or difficulty breathing while lying down Doses other than the prescribed dose should not be taken (ie, not take less or more than the prescribed dose; there is only one best dose) Education into practice • How you think your patients would manage as-needed dry weight dosing? What support or information could you offer them to help with this approach? • Project: how many of your patients with heart failure are on variable doses of loop diuretics as outlined in this article? • How you assess whether a diuretic is working? For example, you assess the therapeutic threshold through urine output when commencing loop diuretics? Subscribe: http://www.bmj.com/subscribe BMJ: first published as 10.1136/bmj.l359 on 21 February 2019 Downloaded from http://www.bmj.com/ on 21 February 2019 by guest Protected by copyright A higher dose of loop diuretic, above the threshold, will not lead to greater diuresis.39 40 If the dose is below the patient’s therapeutic threshold, urine output will not change substantially in response to the drug.38 What to when more or less diuresis is needed Causing less diuresis BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of PRACTICE How patients were involved in the creation of this article 16 17 18 Additional educational resources Diuretics and Heart Failure, by Eitan Friedman A Medscape membership is required, although the initial sections are available to non-members http://emedicine.medscape.com/article/2145340-overview Diuretic Therapy, by D Craig Brater A NEJM membership is required http://www.nejm.org/doi/full/10.1056/NEJM199808063390607 Use of Diuretics in Patients with Heart Failure, by Colucci and Sterns An UpToDate membership is required https://www.uptodate.com/contents/ use-of-diuretics-in-patients-with-heart-failure 19 20 21 22 23 24 25 Information for patients Sources of Sodium in your Diet, by the USA Centers for Disease Control http://www.cdc.gov/salt/pdfs/sources_of_sodium.pdf Heart Failure—Beyond the Basics, by Wilson Colucci An UpToDate membership is required https://www.uptodate.com/contents/heart-failurebeyond-the-basics 26 27 28 29 30 31 Competing interestsThe BMJ has judged that there are no disqualifying financial 32 ties to commercial companies The authors declare the following other interests: none 33 Further details of The BMJ policy on financial interests is here: https://www.bmj com/about-bmj/resources-authors/forms-policies-and-checklists/declaration- 34 competing-interests Contributor Statement and Guarantor: Steven Anisman planned the paper, 35 conducted the literature review, drafted early and late versions of the paper He led the team through all phases of the work and is guarantor of the work Stephen 36 Erickson served as a consultant on nephrology and diuresis topics; he edited drafts of the paper Nancy Morden supported the literature review process and writing 37 Steven Anisman is the guarantor and accepts full responsibility for the contents of the paper 38 Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed 39 40 41 10 11 12 13 14 Brater DC Diuretic therapy N Engl J Med 1998;339:387-95 10.1056/NEJM199808063390607 9691107 Brater DC Update in diuretic therapy: clinical pharmacology Semin Nephrol 2011;31:483-94 10.1016/j.semnephrol.2011.09.003 22099505 Ellison DH, Felker GM Diuretic treatment in heart failure N Engl J Med 2017;377:1964-75 10.1056/NEJMra1703100 29141174 Farinde A Dose response relationships http://www.merckmanuals.com/professional/ clinical-pharmacology/pharmacodynamics/dose-response-relationships Brater TC Personal communication April 20, 2016 Brater DC Resistance to loop diuretics Why it happens and what to about it Drugs 1985;30:427-43 10.2165/00003495-198530050-00003 3905337 Odlind B, Beermann B Renal tubular secretion and effects of furosemide Clin Pharmacol Ther 1980;27:784-90 10.1038/clpt.1980.111 7379446 Brater DC, Leinfelder J, Anderson SA Clinical pharmacology of torasemide, a new loop diuretic Clin Pharmacol Ther 1987;42:187-92 10.1038/clpt.1987.131 3608350 Shankar SS, Brater DC Loop diuretics: from the Na-K-2Cl transporter to clinical use Am J Physiol Renal Physiol 2003;284:F11-21 10.1152/ajprenal.00119.2002 12473535 Cosín J, Díez JTORIC investigators Torasemide in chronic heart failure: results of the TORIC study Eur J Heart Fail 2002;4:507-13 10.1016/S1388-9842(02)00122-8 12167392 Murray MD, Deer MM, Ferguson JA, etal Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure Am J Med 2001;111:513-20 10.1016/S0002-9343(01)00903-2 11705426 Müller K, Gamba G, Jaquet F, Hess B Torasemide vs furosemide in primary care patients with chronic heart failure NYHA II to IV-efficacy and quality of life Eur J Heart Fail 2003;5:793-801 10.1016/S1388-9842(03)00150-8 14675858 Mentz RJ, Hasselblad V, DeVore AD, etal Torsemide versus furosemide in patients with acute heart failure (from the ASCEND-HF Trial) Am J Cardiol 2016;117:404-11 10.1016/j.amjcard.2015.10.059 26704029 Mentz RJ, Velazquez EJ, Metra M, etal Comparative effectiveness of torsemide versus furosemide in heart failure patients: insights from the PROTECT trial Future Cardiol 2015;11:585-95 10.2217/fca.15.56 26403536 For personal use only: See rights and reprints http://www.bmj.com/permissions 42 43 44 45 46 47 48 49 50 51 Mentz RJ, Buggey J, Fiuzat M, etal Torsemide versus furosemide in heart failure patients: insights from Duke University Hospital J Cardiovasc Pharmacol 2015;65:438-43 10.1097/FJC.0000000000000212 25945862 López B, Querejeta R, González A, Sánchez E, Larman M, Díez J Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure J Am Coll Cardiol 2004;43:2028-35 10.1016/j.jacc.2003.12.052 15172408 Kasama S, Toyama T, Hatori T, etal Effects of torasemide on cardiac sympathetic nerve activity and left ventricular remodelling in patients with congestive heart failure Heart 2006;92:1434-40 10.1136/hrt.2005.079764 16621879 Yamato M, Sasaki T, Honda K, etal Effects of torasemide on left ventricular function and neurohumoral factors in patients with chronic heart failure Circ J 2003;67:384-90 10.1253/circj.67.384 12736474 Broekhuysen J, Deger F, Douchamps J, Ducarne H, Herchuelz A Torasemide, a new potent diuretic Double-blind comparison with furosemide Eur J Clin Pharmacol 1986;31(Suppl):29-34 10.1007/BF00541464 3536530 Buggey J, Mentz RJ, Pitt B, etal A reappraisal of loop diuretic choice in heart failure patients Am Heart J 2015;169:323-33 10.1016/j.ahj.2014.12.009 25728721 Lesne M Comparison of the pharmacokinetics and pharmacodynamics of torasemide and furosemide in healthy volunteers Arzneimittelforschung 1988;38(1A):160-3.3370062 Vadivelan M, Dabhi AS Torsemide: a new loop diuretic Int J Clin Pract 2013;24:385-8 Katta N, Balla S, Alpert MA Does long-term furosemide therapy cause thiamine deficiency in patients with heart failure? A focused review Am J Med 2016;129:753.e7-11 10.1016/j.amjmed.2016.01.037 26899752 Ellison DH, Fleker DM Diuretic treatment in heart failure Correspondence N Engl J Med 2018;378:683-510.1056/NEJMc1716477 Wargo KA, Banta WM A comprehensive review of the loop diuretics: should furosemide be first line?Ann Pharmacother 2009;43:1836-47 10.1345/aph.1M177 19843838 Kwa M Medicine by numbers: 131 million Furosemide was the 13th most-prescribed medication in the US, and the only diuretic in the top 16 http://www.clinicalcorrelations org/?p=4888 IMS Institute for Healthcare Informatics The Use of Medicines in the United States; Review of 2011 https://kaiserhealthnews.files.wordpress.com/2012/10/ihii_medicines_in_u.s_ report_2011.pdf Centers for Medicare & Medicaid Services https://www.cms.gov/newsroom/ mediareleasedatabase/fact-sheets/2016-fact-sheets-items/2016-08-18.html Epocrates Torsemide https://online.epocrates.com/u/101603/torsemide/Adult+Dosing UpToDate Torsemide https://www.uptodate.com/contents/torsemide-drug-information National Institute for Health and Care Excellence Torasemide https://bnf.nice.org.uk/ drug/torasemide.html Nappi JM A retrospective evaluation of the efficacy of intravenous bumetanide and comparison of potency with furosemide Pharm Pract (Granada) 2013;11:44-50 10.4321/S1886-36552013000100008 24155849 Strom BL, Schinnar R, Apter AJ, etal Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics N Engl J Med 2003;349:1628-35 10.1056/NEJMoa022963 14573734 Felker GM, Lee KL, Bull DA, etal NHLBI Heart Failure Clinical Research Network Diuretic strategies in patients with acute decompensated heart failure N Engl J Med 2011;364:797-805 10.1056/NEJMoa1005419 21366472 Wu M-Y, Chang N-C, Su C-L, etal Loop diuretic strategies in patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials J Crit Care 2014;29:2-9 10.1016/j.jcrc.2013.10.009 24331943 Ellison DH, Felker GM Diuretic treatment in heart failure N Engl J Med 2017;377:1964-75 10.1056/NEJMra1703100 29141174 Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival Circulation 2010;122:265-72 10.1161/CIRCULATIONAHA.109.933275 20606118 Oh SW, Han SY Loop diuretics in clinical practice Electrolyte Blood Press 2015;13:17-21 10.5049/EBP.2015.13.1.17 26240596 Craig Brater D Personal communication April 20, 2016 Brater DC Diuretic therapy N Engl J Med 1998;339:387-95 10.1056/NEJM199808063390607 9691107 Phelps KR Clinical Methods: The history, physical, and laboratory examinations 3rd edition Ch 29: Edema Walker HK, Hall WD, Hurst JW editors Boston: Butterworths; 1990 Kujubu DA, Aboseif SR Evaluation of nocturia in the elderly Perm J 2007;11:37-9 10.7812/TPP/06-098 21472053 Scottish Intercollegiate Guidelines Network (SIGN) Management of chronic heart failure Edinburgh: SIGN; 2016 (SIGN publication no 147) http://www.sign.ac.uk Section 4.2.3 Yancy CW, Jessup M, Bozkurt B, etal 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America J Am Coll Cardiol 2017;70:776-803 10.1016/j.jacc.2017.04.025 28461007 Ponikowski P, Voors AA, Anker SD, etal Authors/Task Force MembersDocument Reviewers 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC Eur J Heart Fail 2016;18:891-975 10.1002/ejhf.592 27207191 Lyngå P, Persson H, Hägg-Martinell A, etal Weight monitoring in patients with severe heart failure (WISH) A randomized controlled trial Eur J Heart Fail 2012;14:438-44 10.1093/eurjhf/hfs023 22371525 Burchell AE, Sobotka PA, Hart EC, Nightingale AK, Dunlap ME Chemohypersensitivity and autonomic modulation of venous capacitance in the pathophysiology of acute decompensated heart failure Curr Heart Fail Rep 2013;10:139-46 10.1007/s11897-013-0135-y 23504401 Dunlap ME, Sobotka PA Fluid re-distribution rather than accumulation causes most cases of decompensated heart failure J Am Coll Cardiol 2013;62:165-6 10.1016/j.jacc.2013.02.081 23603694 Mycek MJ, Harvey RA, Champe PC Pharmacology, 2nd ed Lippincott Philadelphia PA, 1997:223-33 Rose BD Diuretics Kidney Int 1991;39:336-52 10.1038/ki.1991.43 2002648 Philipson H, Ekman I, Forslund HB, et al Salt and fluid restriction is effective in patients with chronic heart failure Eur Heart Fail 2013;15:1304-10 Subscribe: http://www.bmj.com/subscribe BMJ: first published as 10.1136/bmj.l359 on 21 February 2019 Downloaded from http://www.bmj.com/ on 21 February 2019 by guest Protected by copyright The article was shared with a panel of patients with heart failure, each of whom had extensive experience with diuretics for the treatment of oedema Their feedback helped to guide subsequent revisions, particularly practical issues regarding patient involvement with as-needed dosing and writing of the “What patients need to know” box Their input guided some of the specific phrases suggested for communicating with patients 15 BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of PRACTICE 52 53 55 56 Lennie TA, Song EK, Wu JR, et al Three gram sodium intake is associated with longer event-free survival only in patients with advanced heart failure J Card Fail 2011;17:325-30 Aliti GB, Rabelo ER, Clausell N, Rohde LE, Biolo A, Beck-da-Silva L Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial JAMA Intern Med 2013;173:1058-64 10.1001/jamainternmed.2013.552 23689381 Doukky R, Avery E, Mangla A, etal Impact of dietary sodium restriction on heart failure outcomes JACC Heart Fail 2016;4:24-35 10.1016/j.jchf.2015.08.007 26738949 Motwani JG, Fenwick MK, Morton JJ, Struthers AD Furosemide-induced natriuresis is augmented by ultra-low-dose captopril but not by standard doses of captopril in chronic heart failure Circulation 1992;86:439-45 10.1161/01.CIR.86.2.439 1638713 McLay JS, McMurray JJ, Bridges AB, Fraser CG, Struthers AD Acute effects of captopril on the renal actions of furosemide in patients with chronic heart failure Am Heart J 1993;126:879-86 10.1016/0002-8703(93)90702-B 8213445 For personal use only: See rights and reprints http://www.bmj.com/permissions 57 58 59 60 61 Nies AS Renal effects of nonsteroidal anti-inflammatory drugs Agents Actions Suppl 1988;24:95-106.3142236 Wolfe F, Zhao S, Pettitt D Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal antiinflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care J Rheumatol 2004;31:1143-51.15170928 International Clinical Trials Registry Platform http://apps.who.int/trialsearch/ metaRegister of Controlled Trials http://www.isrctn.com/page/mrct US Clinical Trials Register https://clinicaltrials.gov/ Published by the BMJ Publishing Group Limited For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/ permissions Subscribe: http://www.bmj.com/subscribe BMJ: first published as 10.1136/bmj.l359 on 21 February 2019 Downloaded from http://www.bmj.com/ on 21 February 2019 by guest Protected by copyright 54 BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of PRACTICE Tables Study Type Findings Brater 1998 Review article, including basic science of the pharmacology of diuretics The logarithmic dose-response curves (p 485) indicate a sigmoid curve with an almost vertical rise, and horizontal response below and above threshold dose Brater 20112 Review article on the basic science of the pharmacology of diuretics The logarithmic dose-response curves for loop diuretics (p 389) recapitulate the 1998 paper Ellison 20173 Review article of basic science of diuretics in heart failure Pharmacokinetic focus is on the threshold effect and ceiling doses, as well as sodium Including loops avidity, diuretic resistance, nephron remodelling, and diuretic tolerance The dose-response graph (p 1967) is less severe than Brater’s but communicates the same principle For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe BMJ: first published as 10.1136/bmj.l359 on 21 February 2019 Downloaded from http://www.bmj.com/ on 21 February 2019 by guest Protected by copyright Table 1| Summary of evidence for all-or-none dose-response curve BMJ 2019;364:l359 doi: 10.1136/bmj.l359 (Published 21 February 2019) Page of PRACTICE Table 2| Summary of evidence comparing loop diuretics Type of study TORIC10 Non-randomised, 2002 Torsemide, open-label furosemide 1377 patient study in 231 centres in Spain compared torsemide with other diuretics in patients with moderate heart failure Twelve month mortality was 2.2% in the torsemide group vs 4.5% in the furosemide group, P