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

How to prescribe loop diuretics in oedema

1 SVMC Cardiology, Dartmouth Hitchcock Department of Cardiovascular Medicine, Bennington, VT, USA; 2 Mayo Clinic, Division of Nephrology and

Hypertension, Rochester, MN, USA; 3 The 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

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

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 Register 61 in July 2018 using the search terms “furosemide,” “torsemide,” and “bumetanide.”

What is the evidence of the uncertainty?

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

PRACTICE

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

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

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

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,

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

What should we do in the light of the uncertainty?

Select a loop diuretic

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

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 ≈

1 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 oedema 2

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 evidence 36

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 benefit 37

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 do 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

hour window, torsemide has the longest duration of action,

bumetanide the shortest, and furosemide is intermediate.2

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

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

What to do when more or less diuresis is needed

Causing less diuresis

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 6 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, do not take less or more than the prescribed dose; there is only one best dose).

Education into practice

• How do 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 do you assess whether a diuretic is working? For example, do you

assess the therapeutic threshold through urine output when commencing loop diuretics?

How patients were involved in the creation of this article

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.

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

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-failure-beyond-the-basics

Competing interestsThe BMJ has judged that there are no disqualifying financial

ties to commercial companies The authors declare the following other interests:

none.

Further details of The BMJ policy on financial interests is here: https://www.bmj.

com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Contributor Statement and Guarantor: Steven Anisman planned the paper,

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

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.

Steven Anisman is the guarantor and accepts full responsibility for the contents of

the paper.

Provenance and peer review: Commissioned, based on an idea from the author;

externally peer reviewed.

1 Brater DC Diuretic therapy N Engl J Med 1998;339:387-95.

10.1056/NEJM199808063390607 9691107

2 Brater DC Update in diuretic therapy: clinical pharmacology Semin Nephrol

2011;31:483-94 10.1016/j.semnephrol.2011.09.003 22099505

3 Ellison DH, Felker GM Diuretic treatment in heart failure N Engl J Med 2017;377:1964-75.

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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

Findings Type

Study

The logarithmic dose-response curves (p 485) indicate a sigmoid curve with an almost vertical rise, and horizontal response below and above threshold dose Review article, including basic science of the pharmacology

of diuretics Brater 1998 1

The logarithmic dose-response curves for loop diuretics (p 389) recapitulate the 1998

paper Review article on the basic science of the pharmacology

of diuretics Brater 2011 2

Pharmacokinetic focus is on the threshold effect and ceiling doses, as well as sodium 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

Review article of basic science of diuretics in heart failure.

Including loops Ellison 2017 3

Table 2 | Summary of evidence comparing loop diuretics

Clinical

Comment Description and finding

Drugs studied Date Type of study Name

For this population of oedema patients, the study authors conclude torsemide may confer

a mortality benefit over furosemide.

Mechanisms of mortality benefit are not well understood, but may result from aldosterone inhibition associated with torsemide Study

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<0.05, relative risk 51.5% (confidence interval not reported)

Mortality in a torsemide group was lower than that in a furosemide group, in the treatment

of heart failure

Torsemide, furosemide 2002

Non-randomised, open-label TORIC 10

included low risk population which did not receive what would become standard-of-care optimal medical treatment; interpret cautiously for different populations

This trial showed substantial improvement in fatigue and dyspnoea scores in multiple time frames, as well as a reduction in number of hospital days for heart failure, again favouring torsemide over furosemide

Reduced HF or cardiac readmissions have implications for providers in the US (they are

234 patients with heart failure were randomised to torsemide vs furosemide Showed a statistically significant reduction in hospital readmission for cardiovascular causes at one year favouring torsemide (torsemide 17%; furosemide 32%, P=0.03, confidence interval not reported) Torsemide, compared with furosemide, may reduce days in hospital for patients with heart

Torsemide, furosemide 2001

Open label trial of

234 patients with chronic heart failure randomised to torsemide vs furosemide

Open-label randomised trial

of torsemide compared with

furosemide therapy for

patients with heart failure 11

an outcome used to determine quality), and time out of the hospital is an important factor for patients Fatigue is an important factor in patient quality of life

failure, and readmission rates for heart failure and cardiovascular disease

Patient-relevant factors should be given weight when selecting a medication

237 primary care patients with NYHA II-IV HF,

on ACE inhibitors, were randomised to furosemide or torsemide Torsemide showed improvement in NYHA class, tolerability, improvement in daily restrictions, and urge to urinate when compared with furosemide Various measures of quality of life favour torsemide over furosemide

Torsemide, furosemide 2003

Prospective, randomised, unblinded

Torasemide vs furosemide

in primary care patients with

chronic heart failure NYHA

II to IV—efficacy and quality

of life 12

In reviewing heart failure trials intended to study other questions, this author concluded that torsemide and furosemide may not have meaningful differences in outcomes However, the re-analysis of the ASCEND-HF trial includes

a useful review summarising the potential

Post hoc re-analyses of previous trials and cohorts, includes review of mortality and other advantages

Torsemide, furosemide 2016

2015 2015

Review, re-analysis Torsemide versus

furosemide in patients with

acute heart failure (from the

ASCEND-HF Trial) 13

Comparative effectiveness

of torsemide versus

mortality and other outcome advantages of torsemide over furosemide

furosemide in heart failure

patients: insights from the

PROTECT trial 14

Torsemide versus

furosemide in heart failure

patients: insights from Duke

University Hospital 15

Basic science

Decreased fibrosis and collagen deposition have been correlated with improved outcomes

in heart failure patients

36 patients with moderate to severe heart failure were randomised to torsemide or bio-equivalent dose of furosemide, with endomyocardial biopsy at baseline and 8 months

Torsemide may correlate with reduced cardiac fibrosis compared with furosemide

Torsemide, furosemide 2004

Open label, randomised Effects of loop diuretics on

myocardial fibrosis and

collagen type I turnover in

chronic heart failure 16

Although clinical outcomes were not studied, these parameters are all measures of reduced ventricular remodelling, as well as improved cardiac function These benefits did not accrue

to patients receiving furosemide

40 patients with non-ischaemic cardiomyopathy with heart failure were randomised to torsemide vs furosemide Only patients receiving torsemide had improvements in multiple parameters (delayed heart to mediastinum count ratio, delayed total

Torsemide, furosemide 2006

Randomised Effects of torasemide on

cardiac sympathetic nerve

activity and left ventricular

remodelling in patients with

congestive heart failure 17

defect score, LV end diastolic volume, LV end systolic volume) There was also a non-significant improvement in LV ejection fraction with torsemide

Aldosterone inhibition has been correlated with multiple positive outcomes in heart failure,

50 patients with moderate heart failure were randomised to furosemide or bioequivalent Torsemide,

furosemide 2003

Randomised Effects of torasemide on left

ventricular function and

including mortality benefits and reduction in dose of torsemide for 6 months Multiple

neurohumoral factors in

hypokalaemia This study showed torsemide parameters, including aldosterone levels, were

recorded at baseline and at completion Torsemide may inhibit aldosterone, an effect not seen in furosemide

patients with chronic heart

diastolic diameter, left ventricle mass index, decreased brain natriuretic peptide, and increased serum renin and aldosterone, suggesting aldosterone receptor blockade.

These effects were not seen in the group treated with furosemide

Torsemide created increased diuresis and natriuresis, with less kaliuresis, when compared with furosemide

An analysis of 18 patients with oedema, taking furosemide or torsemide over a 5 day period.

Multiple analyses were performed Torsemide may cause less hypokalaemia, relative to the degree of diuresis, than furosemide

Torsemide, furosemide 1986

Double blind Torasemide, a new potent

diuretic Double-blind

comparison with

furosemide 19

Cost is a factor many patients consider when making medication decisions Similar pricing indicates that cost should not be a major factor

in compliance (compared with furosemide).

This article also offers an overview of the relative merits of the two diuretics

Costs of furosemide and torsemide are often similar

Torsemide, furosemide 2015

Review

A reappraisal of loop diuretic

choice in heart failure

patients 20

Predictable biological and clinical effects are preferred when planning treatment This is particularly true when we ask patients to actively make therapeutic decisions

Furosemide has variable bioavailability, between 10% and 100% of the ingested dose.

Torsemide and bumetanide are 90-100%

bioavailable, making them more predictable

Various diuretics of multiple classes

2011 Review

Update in diuretic therapy:

clinical pharmacology 2

Predictable biological and clinical effects are preferred when planning treatment This is particularly true when we ask patients to actively make therapeutic decisions Hypokalaemia is a dangerous adverse effect

of loop diuretics, and close monitoring is

The biological effects of torsemide and a bioequivalent dose of furosemide were studied

in 6 healthy subjects; bioavailability was one outcome There was wide variability in the bioavailability of furosemide, and consistently high bioavailability of torsemide

Also, this study found that torsemide may cause less hypokalaemia than furosemide,

Torsemide, furosemide 1998

Within-subject variability Comparison of the

pharmacokinetics and

pharmacodynamics of

torasemide and furosemide

in healthy volunteers 21

needed to prevent this potentially lethal complication Medication choices that reduce this risk are preferable.

This finding is also supported in Vadivelan

2013 22

perhaps because torsemide has no proximal tubule action

Hepatic clearance “prevents the accumulation

of torsemide in patients with renal insufficiency”

Torsemide is cleared hepatically; furosemide

is cleared renally Torsemide,

furosemide 2013

Review Torsemide: a new loop

diuretic 22

Low thiamine levels are associated with lower LVEF and worsening symptoms of HF These low levels have been reported in furosemide and other diuretics (not with spironolactone).

No studies have evaluated this problem with torsemide Katta suggests that thiamine loss

Furosemide leads to low thiamine levels, which can worsen heart failure The effect of other loops on thiamine has not been studied.

There is relevant additional information in Elllison 2018, including expert opinion 24

Furosemide 2016

Review Does long term furosemide

therapy cause thiamine

deficiency in patients with

heart failure? A focused

review 23

is proportional to urinary flow, which means this same effect may occur with torsemide; study

is needed.

Fig 1 Common (linear) dose-response curve seen in many drugs (but not loop diuretics) Adapted from Merck Manual4

Fig 2 Dose-response curve (logarithmic) for loop diuretics For a given individual, any dose above the therapeutic threshold

will result in maximal diuresis Adapted from Brater 19981 and Brater 20112