Acetazolamide in Acute Decompensated Heart Failure with Volume Overload

Aug 26, 2023

Acetazolamide in Acute Decompensated Heart Failure with Volume Overload

One of the most important news items during this year’s European Society of Cardiology meeting was unrelated to a new drug or technology. The ADVOR trial demonstrated that IV acetazolamide significantly improved decongestion in patients with acute on chronic decompensated heart failure. We welcome Dr. Wilfried Mullens, the principal investigator of this trial, to discuss the rationale for the trial and explain its results.

Acetazolamide in Acute Decompensated\rHeart Failure with Volume Overload:
https://acrobat.adobe.com/link/track?…

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Content

2.1 -> foreign

4.04 -> good afternoon at noon everybody thanks

6.66 -> for joining us um we've got an exciting

8.76 -> uh visitor today

10.92 -> um today we are happy to welcome Dr

12.78 -> Wilfried Mullins and I'd like to take a

15.299 -> moment to uh introduce him uh Dr Mullins

18.359 -> received his degree in cardiology as

19.92 -> well as cardiac rehabilitation in

21.779 -> Belgium in 2005.

23.88 -> he then graduated as advanced fellow in

26.82 -> heart failure and transplant in 2007 as

29.88 -> well as a fellow in electrical therapies

31.56 -> for heart failure in 2008 at the

33.48 -> Cleveland Clinic

34.68 -> uh he received his doctor philosophy or

37.739 -> PhD at Technical University Eindhoven in

39.719 -> the Netherlands in 2009 and currently as

42.36 -> a staff cardiologist in the I'm going to

44.78 -> butcher this name probably but his

46.86 -> Hospital East Lindbergh in Belgium and

50.1 -> also is an associate professor in the

52.32 -> school of medicine and Life Sciences at

54.48 -> the University of hasselt in Belgium

57.42 -> uh Dr Mullins is a heart failure

59.1 -> clinician with a strong commitment to

60.48 -> translational research translating new

63.059 -> mechanistic insights into answering

64.92 -> questions of clinical interests his main

67.439 -> research topics are cardiac

69 -> resynchronization therapy as well as the

71.52 -> cardio renal interactions with and he's

73.32 -> published more than 270 peer-reviewed

75.42 -> Publications

76.68 -> uh he's been the president of the

78.06 -> Belgian working group on heart failure

79.68 -> and serving as a board member of the

81.24 -> European heart failure Association

83.52 -> so without further Ado uh Dr Mullins

85.92 -> thank you again for taking the time to

87.36 -> join us and uh we look forward to

89.28 -> hearing you speak

91.08 -> and good afternoon everybody it's

92.82 -> already evening here in Belgium but

94.74 -> thank you for the introduction

96.72 -> um for the invitation and also hi to

99.36 -> Jeff and Irene which I get to know

103.079 -> already for a couple of years so I'm

105.54 -> going to talk a little bit about at four

107.04 -> but um try to introduce at for a little

109.439 -> bit and I'm a hard Floor specialist I

111.6 -> think just like many of you but

113.82 -> sometimes I think I should have been a

115.32 -> nephrologist

117.06 -> um or do a lot of research in my centers

119.7 -> of course not me who's doing this I'm

122.1 -> fortunate that I have a lot of really

124.14 -> excellent PhD fellows who join me over

126.899 -> the last decade and most of the times we

128.7 -> have two PhD fellows who are really

130.92 -> really active to try to investigate

134.76 -> um everything that Michael just alluded

136.92 -> to with regards to cardiovino

138.599 -> interactions and resynchronization

140.879 -> therapy

142.08 -> so I don't have to tell you that

143.94 -> congestion is a risk factor for

147.3 -> hospitalization and all-cause mortality

149.16 -> but I think most of our colleagues don't

151.14 -> take this for granted that the risk is

153.54 -> up to 20 percent of two years in

155.52 -> ambulatory patients and goes up to 60

158.04 -> percent of one year especially if we

160.8 -> send our patients home with ongoing

162.72 -> congestion

163.92 -> that's why we put in our HFA guidelines

166.56 -> but also you did it in hfsa guidelines

168.84 -> that congestion needs to be treated

170.7 -> aggressively identified early on to

174.06 -> prevent further adverse outcomes

177.959 -> and I think one of the first people who

180.54 -> actually noticed this was Greg phonero I

182.819 -> don't think he ever published this data

184.44 -> this was from an abstract where he

186.66 -> showed that a reduction in left-sided

188.34 -> feeling pressures was more important

190.14 -> than an improvement in cardiac outputs

192.48 -> in patients who came into the hospital

194.519 -> with low cardiac outputs

197.04 -> if you look at the kidney the kidney

199.68 -> gets tremendous amount of blood almost

201.78 -> one meter per minute so it's not a

204.659 -> surprise that also the kidney depends on

207.78 -> Central hemodynamics we but also other

210.659 -> people just like Jeff have shown that

212.879 -> also for the kidney perspective reducing

216.42 -> central venous pressure so filling

218.7 -> pressures for the kidney is more

220.92 -> important than improving forward flow to

223.44 -> the kidney and so if you have an

225.06 -> elevated central venous pressure this is

227.4 -> really associated with worsening renal

229.56 -> function and patients are admitted with

231.18 -> heart failure but it's also associated

233.4 -> with more sodium and water retention

236.959 -> we done an animal experiment a couple of

239.76 -> years ago where we did The Selective

241.799 -> partial ligation of the vena cava

244.5 -> inferior in Reds was a pretty difficult

247.14 -> experiment to be honest because we had

249.42 -> to intubate these rats and it's not so

251.04 -> easy to intubate a rats but anyway if

253.439 -> you do that and you increase the central

255.72 -> venous pressure just selectively in the

258.299 -> abdomen not touching even the heart you

261.299 -> see that already after a couple of weeks

263.46 -> that there are irreversible changes to

265.74 -> the glomeruli of these Reds so elevated

268.8 -> Central Venus pressure is really a bad

270.9 -> thing to happen for your kidneys

273.9 -> one slide about chronic heart failure

276.36 -> and bear in mind that you lose about one

278.759 -> ml per G of R per year once you reach

281.699 -> the age of 50 this goes up to 2.5 ml if

285.36 -> you have heart failure and up to five if

287.58 -> you have diabetes which is uncontrolled

289.8 -> that is why we have to do our utmost

292.08 -> best to stop this deterioration and for

295.5 -> chronic heart failure the best Two drugs

298.44 -> that we have available are RNA and sjlt2

302.22 -> and CKD is a far more smaller predicate

305.4 -> than ejection fraction for prognosis so

308.04 -> halting this deterioration is really

310.8 -> important that's only the only thing I'm

312.78 -> going to say about chronic heart failure

315.18 -> now

316.56 -> if you look back at the kidney the

318.84 -> kidney is a very long chewable and the

321.24 -> reason for the tubal to be very long is

323.82 -> that we need to filter a lot we need to

326.28 -> filter about 100 seeds of water sodium

328.68 -> and toxic substances and of that 100cc

331.44 -> which is filtered only one CC per minute

335.34 -> actually is produced as urine all the

338.58 -> other 99 will be reabsorbed in the

342.06 -> chewables but we need at 100cc to filter

345.479 -> to in order to excrete all the toxic

348.36 -> substances that our body is producing

351.38 -> bear in mind that most of the water and

354.24 -> sodium is reabsorbed in the proximal

356.22 -> parts of the kidney and that is really

358.32 -> exaggerated if you have heart failure I

361.02 -> know Jeff doesn't agree with me on that

362.88 -> but I'm going to show him later that I

365.1 -> am correct and he is wrong

368.699 -> um if you look at normal human beings

371.039 -> they're also and minded to absorb every

373.5 -> bit of sodium that you eat in your gut

375.419 -> we cannot lose sodium in our guts

378.3 -> because we have a very high brass

380.4 -> activity and this resides from the fact

383.4 -> that we used to be uh lizards and then

386.34 -> then we didn't really have access to

388.86 -> sodium and then we were upstanding in an

391.919 -> upright position so we need High

393.66 -> pressures and that's the reason why we

395.699 -> have a very activated rust system

399.9 -> uh no when you eat

402.3 -> um every day one bag of potato chips

404.759 -> with salt you will see that you have an

407.4 -> increased natural recess which is

410.1 -> hampered if you have heart failure but

412.259 -> over time you'll have a positive sodium

414.96 -> balance so that means that the problem

417.36 -> of heart failure doesn't only stop with

419.58 -> the kidney but it starts with the kidney

421.44 -> and we have a problem there because we

423.66 -> have a positive sodium balance also if

426.72 -> you don't have heart failure and most

429 -> people don't really realize that that

431.039 -> that's not like everything that you're

433.02 -> going to eat will be excreted in your

435.36 -> kidneys so it made us think made us look

438.9 -> at at the renal physiologist that you

441.96 -> know really well

444.02 -> I mean also from Yale where he actually

447.44 -> assessed that there are stores where you

450.9 -> can actually hide sodium and we took it

453.36 -> one step further in heart failure

455.039 -> patients and we found out that there's

456.84 -> also a lot of sodium hiding in the skin

459 -> and if you do skin biopsies and heart

461.22 -> failure patients you see more of these

463.08 -> structures in heart failure and you also

465.36 -> see a very activated grass system in

468.3 -> patients with heart failure we're

470.759 -> actually trying to prospectively assess

472.979 -> this by giving heart for your patients

475.139 -> additional sodium and during cereal skin

477.78 -> biopsies to see if the skin actually

480.06 -> reacts in in the face of a different

483.12 -> sodium loading well anyway coming back

486.3 -> to acute heart failure eventually will

488.58 -> have more sodium and water retention our

490.8 -> bodies cannot accommodate it will have

492.96 -> an increase in plasma volume and the

495.479 -> higher the plasma volume the higher the

497.34 -> likelihood that the patients will be

498.96 -> admitted with heart failure if you have

501.479 -> a patient with acute heart failure the

503.52 -> guidelines tell us that we should give

505.259 -> them Loop diuretic therapy in the HFA

508.56 -> guidelines published in 2021 Loop

511.74 -> Diuretics is the only therapy with a

514.68 -> Class 1 recommendation independent of

517.32 -> the ejection fraction to treat

519.3 -> congestion because of course will change

521.339 -> with the sclv2 Inhibitors but in 2021 it

524.94 -> was the only jerk with the class 1

527.519 -> recommendation to treat signs of

530.459 -> congestion now bear in mind that we

533.04 -> don't really have much data to support

536.16 -> this with a Class 1 recommendation and

539.399 -> the only perspective randomized

541.44 -> double-blind trial with Loop theoretics

543.3 -> was the dose strap those as you know was

545.82 -> comparing continuous versus bolus low

548.64 -> versus high doseamide so four different

551.88 -> treatment strategies the primary

554.04 -> endpoint was the neutral and when you

556.68 -> looked at the secondary endpoints of all

558.72 -> cost mortality and we heart flare Rios

560.519 -> realization the risk was up to 60 up to

563.82 -> 50 percent at two months so half of the

567.3 -> patients and those were either dead or

570.42 -> back in the hospital after two months so

572.58 -> another really good results to be really

574.68 -> honest and when you looked at what the

577.08 -> investigators were reporting freedom

579.18 -> from congestion after three days was

581.279 -> only 15 percent so only one out of six

584.82 -> of the patients included in those was

586.92 -> dry at the end of the study periods

590.04 -> there are many reasons for that but also

592.74 -> bear in mind that if you give Loop

594.66 -> Paradox and monotherapy on the left you

597.899 -> see the urinary volume per 40 milligrams

601.019 -> of furosomide and on the right you see

603 -> the urinary sodium and chloride contents

605.459 -> over three consecutive days so what this

608.64 -> slide actually shows is that you have a

610.74 -> decrease in sodium content while you

613.86 -> have a similar urinary output it means

616.68 -> that the quality of the urine is

618.779 -> dramatically changing if you you only

621.24 -> give lucrative therapy over three

623.22 -> consecutive days and there it is in mind

625.44 -> we're going to talk about ad4

627.779 -> so this is a product from Jeff normally

630.18 -> if you give 40 milligrams of furosoma to

632.279 -> a normal human being it should be being

633.839 -> out about three liters of water and

635.58 -> sodium and almost none of our Hardware

638.399 -> patients are doing that especially if

640.92 -> they are already on a loop theoretic

643.56 -> there are many reasons for that but the

645.66 -> main reason is that Luke diuretics were

648.66 -> distal I work at the Loop of handling

651.18 -> which is distal from the site where most

654.3 -> sodium is reabsorbed

656.22 -> and we're trying to overcome that

658.74 -> so we try to write a document a couple

661.2 -> of years ago how we can better guide use

666.42 -> usage of loop theoretic therapy it's one

669.839 -> of the most cited articles in European

671.88 -> Journal of heart failure that has almost

674.1 -> more than 200 000 downloads because it

676.74 -> has a lot of very practical flow charts

679.74 -> I'm gonna just go very quickly over five

682.38 -> of the most important rules first of all

685.14 -> door to theoretic time there's no reason

687.3 -> to wait to give Loop direct to any

690.54 -> patient who comes in with congestion but

693 -> the most important rule is that you have

694.86 -> to evaluate the effect of the loop

696.54 -> theoretic within hours after you get the

699.36 -> direct Loop theoretics work for about

701.579 -> six to eight hours maximum so you should

704.339 -> evaluate the effect within hours after

707.1 -> you gave the diuretic now we propose to

710.16 -> look at natural races so take a urinary

713.76 -> sample send it to the lab and if it's

716.459 -> below 50 Megs per liter it means that

719.519 -> you will never reach your goals and that

721.56 -> you should increase the dose of the loop

723.66 -> theoretic already after eight hours only

727.38 -> stock motivation is dry and continue

729.48 -> guide and directed medical therapy if

731.88 -> possible we actually Incorporated this

735.54 -> flowchart identically the same flowchart

738.3 -> now in our ESC guidelines as a guidance

742.56 -> to use Loop theoretic therapy better so

745.26 -> this is not in Europe just a suggestion

747.36 -> it's really a recommendation now that

749.76 -> you should use another research guided

752.1 -> approach to improve the utilization of

754.86 -> loop theoretic therapy

756.959 -> we're actually testing this algorithm

758.76 -> now prospectively in every continent

761.579 -> outside the United States in more than

764.279 -> 26 centers and I can nobody can tell you

767.579 -> that the results are really Spectacular

769.399 -> Now what is what may be the future for

773.36 -> Loop theoretic it may be subcutaneous

776.339 -> ferosamide there was a small

779 -> observational study presented at HFA

781.98 -> this year for the investigators in

784.56 -> Scotland infused during five hours 30

787.079 -> milligrams of furosamide

789.779 -> the in the first hour and afterwards

792.54 -> 12.5 milligrams and what they actually

794.7 -> showed is that they could evoke more

796.68 -> natural resources and diuresis also with

799.32 -> a Sub-Q ball this has now been this is

802.079 -> now currently being tested in a

804.12 -> prospective trial in patients who are

807.24 -> outpatient to try to prevent the

810.66 -> hospitalization and it's then giving by

813.18 -> heart failure nurses in an outpatient

815.1 -> setting in Scotland

817.26 -> now what is the other option if your if

819.959 -> Loop directs fail to do the job it might

821.76 -> be thiazides and tiazide's work will

823.92 -> also distal the nephron I know you're

826.44 -> all really fond of thiazides and you

829.74 -> know there might Contraband with this

831.3 -> hypertrophy they work in low G of R

833.88 -> States but they have a slow gr

835.44 -> absorption so you have to give them

837.3 -> hours before you give the loop directly

839.639 -> as Jeff also showed that if you give

842.88 -> long-term tires as they are linked with

845.639 -> an increased mortality which is probably

848.16 -> related to a higher likelihood of

850.68 -> high-end disturbances you you know that

853.38 -> if you give this long term all these

855.36 -> patients develop hypernatremia and

857.1 -> hypokalemia so thiazides are a drug that

859.8 -> can be used short term to improve

862.38 -> decongestion but should not be used long

864.66 -> term because they are linked to a worse

866.94 -> outcome

868.139 -> now there has been The Chronic trial

870.18 -> grodic was a Spanish randomized

872.519 -> double-blind trial done over the last

875.279 -> six years where investigators compared

877.92 -> Placebo with Hydrochlorothiazide for

880.079 -> three days in patients with acute heart

881.88 -> failure their primary endpoint was

884.279 -> weight loss and they showed that more

886.98 -> weight loss in the hydrochlorothiazide

889.8 -> the paper has not been published yet but

891.959 -> it has been presented at HFA a couple of

894.3 -> months ago I think everybody's waiting

896.399 -> for the paper to to appear somewhere but

899.699 -> so far it's not been published

903.48 -> the other option that you might think of

905.279 -> is hydrospinal electone so this was

907.86 -> tested in a Tina trial 25 versus 100

910.56 -> milligrams that did not show a reduction

912.899 -> in anti-pro BMP that also did not show

915.48 -> an increase in diuresis so spinal lectin

918.42 -> is extremely important as in this

920.94 -> modifying agent that is not an agent

923.399 -> that will help you to decongest patients

925.32 -> easier

926.579 -> the reason for all of that is in my mind

929.82 -> that all these agents work distal really

933.72 -> distal from the side where most sodium

936.24 -> is reabsorbed that is the proximal part

938.639 -> and the oldest drug that we had to

941.699 -> improve the natural resis that works on

946.38 -> the proximal parts of the kidneys and

948.18 -> cetazolamides cetazolamide is a carbon

950.94 -> any Trace inhibitor it blocks there for

953.88 -> the uptake of sodium it interferes with

957.18 -> the Sodium proton exchanger and which is

960.42 -> responsible for more than 60 percent of

963.18 -> the sodium reabsorption in the proximal

965.04 -> bars of the kidney we've done a small

968.06 -> perspective randomized double-blind

971.22 -> trial almost a decade ago very compared

974.959 -> acetozolomite plus Loop Diuretics with

977.88 -> Loop Diuretics only in acute heart

979.68 -> failure in a dead small trailer we

981.899 -> showed in in almost a doubling of the

985.019 -> natural reasons in and I think it was

988.199 -> like 80 patients this was the

990.779 -> rationality to develop the ad4 trial and

994.26 -> that first stands for acetozolamide in

996.6 -> the compensated heart failure patients

998.459 -> with volume or movement

1000.62 -> this is uh just to show it if there are

1002.899 -> fellows around it took us almost six

1005.779 -> years to conduct the trial we needed

1008.66 -> about 2 million euros it's a little bit

1010.579 -> more than you can get from any yeah

1012.98 -> sponsor so we had to back to the

1016.16 -> healthcare authorities to get the money

1017.72 -> there was absolutely zero company

1019.399 -> interested to give us the money but it's

1021.8 -> a lot of work if you want to do a trial

1023.72 -> like this and we were Aiming High

1025.819 -> because we thought the only way to to

1028.52 -> prove to Jeff the stani that this drug

1031.28 -> would work is to do a double-blind

1033.079 -> randomized prospective multi-center

1035.839 -> trial but that's not so easy to

1037.88 -> accomplish with a trial steering

1040.16 -> committee

1041.299 -> with a lot of international and famous

1044.6 -> people from Europe we had 29

1047.24 -> participants fighting sites only in

1049.46 -> Belgium we only recruited in Belgium

1051.74 -> because it was the Belgium Healthcare

1053.419 -> authorities you were going to pay for

1054.799 -> the child and that they did not allow us

1057.38 -> to go abroad

1059.179 -> patient recruitment so we estimated that

1061.88 -> we would finish finalize the trial

1063.44 -> within two years we needed 519 patients

1066.62 -> it took us three years because of course

1069.74 -> of coffee during the first covet wave

1072.559 -> everything stopped and what we did

1074.24 -> almost the same in the second covet wave

1077.419 -> they also have done a biomarker sub

1079.88 -> study if any of you is interested we

1081.98 -> collected blood samples urine samples

1084.62 -> and about 130 patients this was also a

1087.799 -> lot of work because we didn't have

1089.12 -> funding for that so when I was on call

1091.22 -> at 1am in the morning I was actually

1093.38 -> taking blood samples to to put in the

1096.32 -> biobank

1097.4 -> the budget was 2.2 million

1100.52 -> um

1101.24 -> it's not so much for a trial which is

1103.34 -> publishing a New England Journal of

1104.539 -> Medicine but it's still a lot of money

1106.64 -> it's actually the money that you need if

1108.86 -> you want to do a trial like this so what

1111.02 -> was the trial design again prospective

1113.059 -> maltes and randomized academic trial no

1116.12 -> industry funding I can actually tell you

1118.94 -> we reached out to one of the companies

1120.679 -> that made acetozolomite but there are

1123.62 -> absolutely zero interest and then I

1126.5 -> asked them you know can we get 10 000

1128.6 -> vials of a set of dolomite which is a

1130.64 -> powder and they said sure you can get it

1132.86 -> so I asked them can we get them for free

1134.9 -> and they said no

1136.88 -> anyway so we paid for everything what

1139.58 -> was the inclusion criteria it was a

1141.32 -> pragmatic trial so we wanted the

1143.66 -> patients to be admitted with acute heart

1145.46 -> failure with at least one sign of volume

1148.039 -> Overload at them on the legs and or

1150.799 -> pleural effusion and or ascitis

1154.22 -> since we were Aiming High We

1157.66 -> demanded to the investigators that if

1160.34 -> they would say there was plural of

1161.72 -> fusion or ascitis that that needed to be

1163.58 -> confirmed by technical exam so they had

1166.22 -> to do an ultrasound or radiography of

1169.28 -> the of the chest or an ultrasound of the

1171.62 -> abdomen to actually confirm that there

1174.2 -> was fluid present patients needed to be

1177.02 -> at least one month on maintenance

1178.64 -> therapy of Overlook theoretics and their

1180.799 -> antipropmbs needed to be above 1000. we

1183.919 -> needed the samples as a 519 to detect an

1186.98 -> absolute risk reduction of 10

1189.28 -> absolutely we're not talking about

1191.179 -> relative risk here we're talking about

1192.799 -> absolute risk reduction so this is a

1195.559 -> really clinical benefit at 10 absolute

1199.22 -> risk reduction it came down to 66

1202.16 -> percent of relative risk reduction now

1205.52 -> we base ourselves upon dose and in the

1207.98 -> dose since the control group in ad4 was

1211.1 -> really comparable with those we

1212.84 -> estimated that the likelihood of

1215.539 -> decongestion was 15 in the control group

1218.059 -> and we hope that the acetosol might

1220.1 -> would push that up to 25 percent

1223.46 -> so we trained investigators to fill in

1225.74 -> this congestion score comprised of Edema

1228.74 -> plural effusion and ascites patients

1231.86 -> were deemed to be dry if they had a

1233.66 -> congestion score of less or equal to one

1237.679 -> the trial was really pragmatic so what

1239.96 -> were we comparing three days Loop

1242.96 -> theoretic therapy twice the home dose

1245.419 -> intravenously plus Placebo versus three

1249.32 -> days same amount of loop direct therapy

1251.66 -> twice the home dose every day plus 500

1254.6 -> milligrams of acetazolamide

1256.88 -> the primary endpoint was successful

1259.82 -> decongestion after three days so meaning

1263.299 -> is your patient dry if it uses theoretic

1267.08 -> strategy after three days so the control

1269.78 -> group was almost like those and the

1272.059 -> intervention group was those plus 500

1274.52 -> milligrams of acetazolamide bear in mind

1277.28 -> again that this primary endpoint is

1279.38 -> going to be very relevant because it's a

1281.6 -> class of one recommendation in our HF

1283.7 -> guidelines

1284.74 -> if you look at the basic characteristics

1287.179 -> of patients included in in at 4 they

1290 -> were really similar there were 78 years

1293 -> of age ejection faction mean was 43

1295.58 -> percent two tourists that have Beth one

1298.039 -> third and half ref median antipropine p

1301.64 -> over six thousand so these were elderly

1304.58 -> patients with a lot of comorbidities and

1307.7 -> this is what we're seeing in Europe I

1309.919 -> don't know about the us but this is

1311.6 -> exactly what we're seeing in Europe 78

1314.78 -> years of age antipropine piece 6000 poor

1318.679 -> renal function that's just what we're

1320.72 -> seeing this is where our emergency rooms

1323.12 -> are flooding with we have the same in

1325.76 -> the Swedish HF registry which is a

1328.34 -> registry in Sweden we have the same in

1330.62 -> the European Registries and heart

1332.12 -> failure elderly people with a lot of

1334.28 -> comorbidities

1336.08 -> if you look at their congestion score

1338 -> they all had severe edema on their legs

1340.88 -> but 60 of the pleural effusion and 10

1343.88 -> have ascites

1346.039 -> when we compared ourselves with the

1348.02 -> order of fermenting trials those Athena

1350.72 -> and caress like caress was an

1352.34 -> ultrafiltration versus step

1354.02 -> chromological and diuretic therapy you

1356.78 -> could see that patients were old were

1358.7 -> Elder and ad for remoron MREs and at

1362.419 -> higher anti-pro bmps just reflective of

1365.659 -> a pragmatic trial this is really

1367.7 -> pragmatic trial including patients that

1370.039 -> we're seeing in Daily clinical life

1372.62 -> this was the primary endpoint and the

1375.559 -> placebo group it was 30 percent and this

1379.1 -> was a worry for us because the only

1381.26 -> thing that we knew a little bit during

1383.059 -> the trial it was double blind of course

1384.919 -> was that there seemed to be more

1386.659 -> patients dry than what we had

1388.34 -> anticipated because we had anticipated

1390.62 -> 15 so if it was 30 percent we knew that

1395.659 -> the absolute risk reductions should even

1398.96 -> be higher otherwise we could never reach

1401.78 -> statistical significance but we were

1404.36 -> lucky in a way that we reached it so

1407.78 -> there were 42 percent of the patients

1410.299 -> dry after three days with acetazolamide

1412.82 -> B value your highly specifically

1414.98 -> significant relative risk production of

1417.5 -> 46 percent

1419.9 -> there was absolutely no interaction with

1423.2 -> any of the predefined subgroups as you

1426.5 -> could see elderly ejection fraction

1428.36 -> antipropylene P sex they all favored the

1431.6 -> acetazolamide group

1433.64 -> now very importantly what was the

1436.28 -> decongestion rate at this charge because

1438.799 -> you might think you know I don't use a

1441.14 -> cetazolamine I give it thiazide or I do

1443.6 -> something else and I don't listen to ad4

1445.7 -> and I'll make it up you know I don't

1448.159 -> need it so that's why we also analyzed a

1451.64 -> discharge so the investigators did a

1453.86 -> pretty good job they had 62 percent of

1456.14 -> the patients dry at the moment of

1458.72 -> discharge but and he said the zolomite

1461.78 -> arm they had almost 80 percent dry

1464.84 -> number needed to treat of six so only

1468.2 -> six patients needed to be treated for

1470.299 -> three days with acetazolamide to have

1472.76 -> the spectacular Improvement in

1474.98 -> decongestant rates at discharge again

1477.14 -> these were double blinded this was a

1480.26 -> double-blinded trial so this means that

1483.32 -> you cannot make it up and why is that

1486.5 -> there is an incremental benefit of

1489.32 -> acetazolamide over consecutive days

1492.38 -> the incremental benefit I know but now

1494.659 -> from several sip analysis is not so much

1497.12 -> the benefit of acetazolamide per se but

1500.059 -> it's the prevention the prevention of

1503.12 -> loop theoretic resistance it's the

1505.76 -> prevention depth of more and more sodium

1508.76 -> reabsorption in the proximal parts of

1511.22 -> the kidney and that drives the problem

1513.74 -> and acetazolamide is now the only drug

1516.38 -> which has proven that it can prevent

1519.22 -> diuretic resistance far better than

1522.74 -> giving just Loop theoretic in

1524.419 -> monotherapy

1525.799 -> when we looked at Diaries and natural

1528.2 -> reasons there was a tremendous increase

1530.48 -> in Natures over the first two days we

1533.6 -> didn't we did not measure that during

1535.22 -> three days we did during collections

1537.14 -> during the first two days a lot more

1539.419 -> natural reasons than diuresis when we

1542.9 -> looked at secondary endpoints predefined

1545.059 -> length of stay was significantly reduced

1547.76 -> with one day

1549.2 -> which is important for healthcare

1550.88 -> related costs but also for quality of

1553.279 -> life but we did not reduce all cost

1555.799 -> mortality and heart failure

1557.059 -> rehospitalization bear in mind that our

1559.76 -> travel is of course underpowered to do

1562.039 -> so and this is a diuretic trial this is

1564.98 -> not a trial which has which which needed

1567.86 -> to show long-term outcomes this was just

1570.14 -> a trial to show that you can reach more

1572.48 -> effective decongestion

1575.48 -> and we do the source the coveted

1578.24 -> sensitivity analysis which showed that

1580.46 -> there was no inference of covet on the

1582.559 -> primary endpoint

1584.419 -> there was also no difference in

1586.159 -> utilization of Loop Diuretics between

1587.84 -> the two groups and there was a little

1590.48 -> bit of increase in MRA used in

1593.62 -> asphalamide treated patients what about

1596.179 -> safety there was Zero signal of harm

1599.72 -> when we looked at the trial there was no

1602.36 -> increase in renal endpoints there was no

1604.88 -> increase in hypotension there was no

1607.039 -> increase in severe metabolic acidosis or

1609.76 -> hypokalemia and also bear in mind that

1612.2 -> the drug has been used for more than 70

1614 -> years so I think it has shown a safety

1616.64 -> profile over the last decades

1619.34 -> now I know there's a lot of comments

1622.52 -> about our exclusion Criterium to exclude

1625.4 -> stl2 Inhibitors and we specifically

1628.36 -> excluded this in the trial why was that

1631.88 -> well the trial started in 2016 and at

1635.12 -> that moment there was absolutely zero

1638.32 -> data that sle2 and embarrassed should be

1641.419 -> used in heart failure or however at that

1645.26 -> moment we already published a review

1646.9 -> stating that these are these were very

1650.059 -> promising agents for heart failure

1651.86 -> because they also work in the proximal

1653.48 -> part of the kidney but we there was no

1656.059 -> indication and we wanted to prevent this

1659 -> balance in the two treatment groups for

1661.7 -> these drugs now if you look at the

1664.159 -> mechanism of effect of facility there is

1667.1 -> an approximal tubal they block glucose

1669.799 -> uptake and that glucose sodium channel

1672.98 -> is only responsible for five percent of

1675.74 -> the sodium uptake which is completely

1678.38 -> different from cetazolamide so if

1681.26 -> anything then these drugs will work

1683.02 -> synergistically but not mutually

1685.52 -> exclusive when you look at all the

1687.919 -> transit Scala twin bearers they are they

1690.98 -> show that you have an increase in

1692.84 -> diuresis but not so much an increase in

1696.08 -> natural resistance so should they use be

1698.779 -> used in combination absolutely should

1701.419 -> ac32 inverse be used as a diuretic agent

1704.179 -> I don't think so but they should be used

1706.58 -> in all art for their patients

1708.679 -> chronically and acetozolomite is a

1711.32 -> diuretic agent which is completely

1713.12 -> different

1714.559 -> and so these are our conclusions I think

1716.84 -> edfer was the largest era electoral and

1718.76 -> acute hydler ever performed with a very

1721.279 -> important clinical endpoint adver was

1723.98 -> the first trial and acute heart failure

1725.84 -> where the positive endpoint it showed

1728.299 -> that the addition of 500 milligrams of

1729.919 -> acetozolamide to standardize

1731.919 -> ivulptoretic therapy was associated with

1734.779 -> a 46 percent higher incidence of

1737.12 -> decongestion the benefit was consistent

1740 -> across all pre-specified subgroups and

1742.94 -> the three patients treated with this

1744.32 -> that was a little more it had more

1745.58 -> natural resist at a shorter Hospital

1748.34 -> stay and were more likely to be

1750.799 -> discharged without volume orbitals again

1753.44 -> number needed to treat of six and not 20

1756.559 -> not 100 only six

1759.08 -> there was no reduction or cost mortality

1761.48 -> or hardly hospitalization but the

1763.7 -> trailer was under power to do so and the

1766.279 -> rates of these endpoints were

1768.38 -> considerably lower than was was reported

1771.799 -> in those Although our patients were

1774.26 -> sicker the rates were considerably lower

1778.22 -> there was no higher incidence of Adverse

1780.62 -> Events and the results highlight the

1783.559 -> importance to Target congestion early

1786.2 -> and they also further support the use of

1788.659 -> natural releases as an indicator of

1790.52 -> diuretic response and we feel that

1792.98 -> adverse supports utilization of this

1794.899 -> drug as it is a cheap drug it costs 8

1797.84 -> Euros a day eight not eight hundred it's

1800.6 -> of patent it's very easy to use once

1803.6 -> daily safe and it turned out to be very

1806.24 -> effective to improve decongestion if you

1809.36 -> look at our HF or our ESC guidelines

1811.76 -> these are the guidelines with diuretic

1813.559 -> therapy so lupter laser class one tire

1816.86 -> that's a plus two a indication again I

1820.159 -> refer to the class one with Loop the

1821.899 -> analytics although we don't really have

1823.159 -> data for that so it makes us Wonder of

1826.46 -> course how is ESC going to position the

1829.279 -> use of a catholamide this is what we

1832.58 -> think of this is of course not this is

1834.5 -> not a guideline and this is just what I

1836.12 -> made up is that the Solomon on top of

1838.159 -> theoretics might be recommended for

1840.679 -> patients with acute heart failure we're

1842.659 -> admitted to fluid overload who were

1845.12 -> previously treated with oral Loop

1846.799 -> Diuretics to improve the incidence of

1849.02 -> decongestion plus b because we have one

1851.72 -> randomized control trial then it should

1854 -> be one or two a depending on the voting

1857 -> Committee of the calculates

1859.34 -> the data has been published now in the

1861.02 -> New England Journal of Medicine and I

1862.52 -> also would like to emphasize that out of

1864.62 -> the six first orders five of them are

1867.08 -> PhD students so this is really supports

1870.52 -> should support the young people there or

1873.74 -> even younger than I am that even if

1876.5 -> you're young and really motivated that

1878.48 -> you can get to the New England Journal

1879.98 -> of Medicine so this I think was a little

1882.14 -> bit the slogan that we're trying to

1883.82 -> emphasize during the ESC meeting door to

1887.24 -> combo diuretic time and I think we have

1889.88 -> proven now that acetazolamide is the

1891.919 -> only agent which has shown a positive

1894.799 -> endpoint with regards to decongestion

1896.899 -> thank you for your attention and I'm

1898.88 -> open for any questions you might still

1901.1 -> have

1902.72 -> thanks so much Dr Mullins that was great

1905.6 -> um we have a number of people on the

1907.76 -> call today so

1909.32 -> um if you'd like to ask any questions

1910.58 -> please just feel free to unmute yourself

1912.679 -> or you could uh place your question in

1915.799 -> the chat if you'd like and I could read

1917.899 -> it to Dr Mullins or I'll raise your hand

1920.24 -> and I will call on you so I see Jeff is

1923.419 -> ready to go first

1925.64 -> well for fantastic stuff uh really a big

1929.419 -> Advance as you said biggest diuretic

1931.82 -> trial it's really great to see it

1933.559 -> published and uh and embraced by the

1936.26 -> community as it has been so the one

1938.6 -> thing that's been puzzling me is the

1942.86 -> the the trends though obviously not

1946.58 -> powered at all for death and

1947.84 -> re-hospitalization but

1949.52 -> why did they turn in the wrong direction

1950.899 -> and and it would this was really easy

1953.299 -> for me to blow off when I first see it

1954.98 -> but then of course I'm sure you've seen

1956.179 -> the chlorotic results

1957.919 -> where they had you know totally

1959.419 -> different mechanism Etc but they had

1961.039 -> more decongestion there as well and

1963.679 -> again Trend towards more death and

1965.24 -> re-hospitalization and you know I've

1966.679 -> been on the podium for the last 10 years

1968.059 -> saying if you decongest people more

1969.679 -> they're gonna do better

1972.5 -> um and we have two trials the first two

1974.12 -> trials now that actually have caused

1976.22 -> more reduction in fluid during the

1977.779 -> in-hospital setting yet neither trended

1981.2 -> I mean alternated the wrong direction

1983.059 -> not the right direction so so any any

1985.1 -> thoughts on that

1987.88 -> yes I know I I don't think Jeff that the

1991.159 -> short-term acting agent like I said the

1993.559 -> zolomite will translate in longer term

1996.82 -> prognostic effects

1998.899 -> I think we have to look at this as a

2001.24 -> diuretic trial which which we used to in

2004.72 -> a daily life to try to decongest

2006.399 -> patients better patients come in with

2008.559 -> fluid overload they call that's their

2010.299 -> main complaint they don't complain that

2012.7 -> they will die within that five years

2014.5 -> they complain about fluid overload and

2017.44 -> we don't really have a good therapy to

2019.12 -> to treat to to do that and I think this

2023.919 -> this should be seen as diuretic agents

2026.019 -> and I think we should add AC altitude as

2028.179 -> soon as possible because that will

2029.559 -> translate in a better outcome but I

2032.019 -> think we're we're expecting too much

2033.76 -> from acute Hardware trials where we give

2036.34 -> short-term acting agents and to improve

2039.159 -> long-term outcomes and it of course it

2042.34 -> puzzles me and of course we would have

2043.899 -> hoped that it also would have trended

2046.299 -> towards the right direction but for now

2049.179 -> I think it's it's also play of chance I

2052.48 -> know for example I know now which

2055 -> patients were allocated to acetazolamide

2056.98 -> in my Center I didn't know it then and

2059.5 -> when I looked at the ones who died they

2061.96 -> just came in in like a pre-shock

2063.639 -> condition with really gfrs of 22 just

2067.359 -> above the base just above the so if they

2070.359 -> if we wouldn't have included those three

2072.159 -> the trend would would have been the

2074.2 -> other way around

2075.639 -> so it's also a player if you look if you

2077.8 -> only the numbers are really low here

2080.08 -> we're talking about them the second

2082.419 -> thing is and I never tell that but I can

2084.46 -> share it with you if you look at

2086.08 -> in-hospital mortality this was

2088.839 -> statistically significantly better for

2091.419 -> the acetazolamic group so the

2093.639 -> in-hospital mortality was I'm not saying

2095.74 -> reduce because that's wrong but if if

2098.2 -> you ask me it's reduced that's even

2100.66 -> significantly with the set of zolomite

2102.94 -> but I'm not going to say that I'm going

2105.22 -> to say it now but I'm never gonna write

2106.9 -> it somewhere because I don't think

2108.52 -> that's fair but the same comment comes

2110.92 -> from Greg phonora you know it goes in

2112.54 -> the right wrong directions there you

2114.04 -> know it's at 500 trial there are not a

2117.46 -> lot of mortalities here look at what

2120.339 -> you're I mean not you what we all are

2122.56 -> doing acute heart failure we have 50

2124.78 -> mortality or civilization after two

2126.94 -> months we we barely have 28 percent then

2129.94 -> we're doing a great job think with this

2132.339 -> trial so if you look at it from in

2134.5 -> perspective

2136 -> I don't really see a signal of arm

2140.38 -> but I understand the comment then but if

2142.9 -> you type deep dive into the trial you

2145.78 -> see you know there's nothing wrong here

2148 -> yeah I don't I don't think any of us see

2150.88 -> harm it's just like

2152.8 -> you know if you would have asked me

2154.24 -> beforehand if we have a you know this

2157.18 -> big reduction in residual congestion

2159.04 -> we'll kind of at least see a

2160 -> re-hospitalization trend maybe not

2161.74 -> significant but but Jeff these we're

2164.92 -> still we're still analyzing this of

2166.42 -> course that but these patients are 78

2168.28 -> years of age so about 18 is Rios plus

2172.24 -> after three months if you're 78 with a

2175.359 -> GFR of 40 and you have a less than 20

2179.099 -> rehospitalizations after three months I

2181.359 -> mean that's a tremendous good result huh

2183.579 -> yeah I mean there these are not 50 year

2186.82 -> old people these are really elderly

2188.98 -> frail people who just come into the

2191.56 -> hospital for a hardly related event

2193.839 -> that's where that's what we're showing

2195.88 -> we didn't we didn't say that they came

2198.28 -> in with a lot with 10 liters of volume

2200.079 -> again they just came in with a

2201.82 -> heartfully related event which might

2203.68 -> have been atrial fibrillation which

2205.66 -> might have been a non-stemi which may

2207.28 -> have been a pneumonia which caused a

2209.26 -> little bit of pulmonary edema that's

2211.06 -> what we're saying we did we don't so we

2213.579 -> have to delve a little bit more into

2214.9 -> this to solve this problem but it's not

2217.9 -> that they're coming back with 10

2219.16 -> kilograms of volume again

2221.8 -> right but I get the point

2224.2 -> so I think we just need to redo this in

2225.94 -> the U.S where everybody leaves super

2227.44 -> congested and comes back you know half

2229.54 -> the time in six months and yeah I mean

2231.64 -> you also have to look at the reconjust

2233.92 -> you can just discharge I mean people are

2236.2 -> staying in hospital for nine days and

2237.94 -> and I know a lot of people in the US say

2239.859 -> yeah if we would have kept them nine

2241.48 -> days it would also been in drug yeah I

2243.22 -> mean that's our job huh and I know the

2245.079 -> system is against you to keep them

2246.76 -> longer in the hospital those nine days

2249.339 -> on average they were dry after five to

2251.74 -> six days the three additional days is

2254.2 -> also social reasons many of these people

2256.48 -> are elderly you take them to the

2258.04 -> hospital again the confused people the

2259.839 -> family say I cannot take them home and

2261.82 -> then they sell a couple of days more in

2263.44 -> the hospital which is of course not

2264.64 -> correct but that's the way Healthcare

2266.92 -> systems are still set up in in our

2269.56 -> countries

2271.96 -> we have a question in the chat and then

2273.88 -> I I saw Lobby on mute herself as well

2275.92 -> I'll ask the question real quickly here

2277.78 -> then Lobby if you have a question maybe

2279.099 -> you can go after this one

2281.079 -> um uh and the chat says asks if there's

2282.94 -> any differences in electrolyte

2284.56 -> disturbances or a higher need for

2286.9 -> electrolyte correction in the

2288.76 -> acetazolamide group

2291.339 -> um the the second thing I cannot answer

2293.8 -> because we didn't collect it but I know

2295.9 -> there was a little bit more if you

2297.46 -> because we what we collected was the the

2300.099 -> ions so we know there's a little bit

2301.9 -> more hypokalemia in the cetozolamide

2304.06 -> group but I'm not saying that that's a

2306.64 -> bad thing that might just mean that

2308.14 -> they're just being a more because of the

2310.72 -> the combination of the diuretic agents

2312.76 -> that Loop arrays are more effective but

2315.04 -> we don't we we didn't collect the number

2317.26 -> of let's say low right infusions that

2320.38 -> was not captured but we just looked at

2322.54 -> the lab absolute values were a little

2324.88 -> bit lower and institutional micro group

2326.619 -> for a bicarbonate there was

2329.079 -> there was no statically significant

2331.119 -> difference no and well for you guys it's

2334 -> a it's 500 of of Diamox with a grandma

2336.88 -> mag correct yeah so the Magnesium I know

2340.54 -> the question also comes up so we gave

2342.28 -> the Magnesium

2343.599 -> um not because we thought it needed to

2345.82 -> be but that's just common practice in

2348.16 -> Belgium centers most of us have been

2350.38 -> trained in one Center which is living

2352.24 -> and there they used to give it so

2354.04 -> everybody took this for granted so

2356.2 -> initially we asked to the investment do

2358.359 -> you give something and Muslims said yeah

2360.28 -> we give a little bit of glucose and some

2361.9 -> magnesium and that's why we put it in

2363.7 -> the protocol so both groups I'm not even

2366.46 -> saying they received it we told the

2368.26 -> investigators it's okay that you give

2369.82 -> this but don't give them sore

2372.28 -> if you give anything give that as a

2374.38 -> flute 500 cities of glucose with some

2376.72 -> magnesium and for the rest we didn't

2378.64 -> recommend any do you have a subset that

2381.28 -> didn't get mad I'm just curious if you

2383.2 -> know because in the US no one does that

2384.82 -> I'm wondering is there some sort of

2386.56 -> magic Synergy with diamoxin we don't

2389.619 -> even know how many people got it this

2391.42 -> was just a recommendation that that

2393.22 -> another recommendation was just if you

2395.2 -> give something you can do this you don't

2396.82 -> have to tell us but you're not allowed

2398.26 -> to give sodium chloride

2400.18 -> bracelets

2402 -> salavi had to jump off to do some

2404.14 -> clinical care but her question was

2407.68 -> um why do you think the decongestion was

2410.079 -> so good in the placebo group with higher

2412.839 -> risk patients with higher BNP

2415.42 -> and older age

2417.82 -> yeah but I think it's a I understand the

2421.06 -> question so it was almost double of

2422.8 -> those it's those I think first of all we

2425.2 -> looked at other signs of congestion than

2427.06 -> those we looked at volume overloads yeah

2429.52 -> well those results in jvp which is very

2432.94 -> difficult clinically to be very honest

2434.859 -> so we were looking at volume overload

2437.32 -> second answer to that is I I don't think

2440.44 -> patients come in as volume overloaded

2443.079 -> anymore as they used to be doing 10

2444.94 -> years ago especially out in Europe

2446.8 -> because access to care is pretty easy

2449.2 -> especially in Belgium so most patients

2451.599 -> come in in Belgium with five six

2453.52 -> kilograms of excess volume but not more

2455.92 -> than that so I think they have high

2458.56 -> anti-propine piece yes but there are

2461.32 -> less volume overloaded than 10 years ago

2463.2 -> and the assessment of congestion in our

2466.24 -> trial is different than it was in those

2468.64 -> foreign

2471.119 -> with the uh the bio samples

2475.18 -> uh you

2476.32 -> you submit a proposal we can look at it

2478.66 -> Jeff

2480.4 -> we don't have a plan yet no we don't

2482.98 -> have a plan but the the sub analysis

2484.96 -> with them with bicarbonate is extremely

2487.839 -> intriguing

2489.28 -> and the higher the bicarbonate you have

2491.26 -> when you when you admit it it's it's a

2493.24 -> basically an indication of neuromonal

2495.339 -> stimulation because especially those

2497.44 -> patients that react really well to

2498.88 -> accept this overnight because now you

2501.4 -> can absorb more sodium in a proximal

2503.14 -> price I mean it's it's really intriguing

2505.06 -> yeah

2506.22 -> I missed I missed the slide how many

2508.54 -> patients did you say ended up in the in

2510.4 -> the Bible Repository

2511.78 -> exchange how many how many patients were

2513.94 -> in the Bible Repository

2516.16 -> in in the trial uh no in the uh it was

2519.4 -> only a subset that got the power

2520.599 -> repository right the biomarkers about

2522.4 -> 130 yeah that's a nice nice end but in

2527.079 -> those we have urines we have blood three

2529.359 -> of everything in those yeah

2531.22 -> great another question in the chat

2533.98 -> um in the in the event that a patient

2536.38 -> would not respond to IV Loop diuretic

2538.599 -> plus IV acetazolamide and you needed to

2541.66 -> move to a third agent to try to uh block

2545.32 -> the nephron what would be your choice of

2547.42 -> agent sglt2 inhibitor or thiazide or you

2550.119 -> know something I think sclt2 is clear I

2552.579 -> would give it to everybody so I don't

2554.5 -> see it that as a diuretic although it

2556.54 -> also will help to decongest of course by

2558.94 -> a neuromonal inhibition and so I would

2561.7 -> give that to everybody so that's not for

2563.38 -> me diuretic agent anymore but if you

2565.72 -> don't get there with titrated Loop

2568.18 -> Terminix based on the algorithm that we

2570.46 -> have to increase the dosages three times

2572.26 -> a day with the setos alarm at one time I

2575.14 -> probably will also advertise that I'm

2576.94 -> not again tire size huh I'm just in

2579.819 -> favor of a drug which is now shown

2582.22 -> unique privately that it helps and with

2584.44 -> Dietz we just have the observation that

2586.54 -> we think it helps

2588.22 -> we know there is harm if you give it too

2590.319 -> long and this is not the case for

2591.88 -> certain someone right

2593.38 -> but I get why a lot of people give

2595.3 -> thyroids but I think you should change

2597.579 -> your practice based on the evidence now

2599.319 -> or at least try with with the drug which

2601.839 -> is showing to be more effective

2604.359 -> for what it's worth anecdotally I've

2606.16 -> made use of of acetazolamide much more

2608.98 -> frequently since your paper came out and

2610.48 -> I've had great success with my patients

2613.66 -> um

2614.68 -> any other uh questions or comments out

2617.319 -> there from the group

2623.98 -> okay well uh Dr Mullins again thank you

2626.92 -> so much for taking the time I know we

2628.599 -> know it's approaching 10 o'clock P.M

2630.16 -> there in Belgium and uh uh happy that

2633.099 -> you made the time to share this with us

2635.02 -> and um we wish you all the best and I

2637.24 -> hope that we get to meet in person

2638.38 -> sometime down the road it's a pleasure

2641.7 -> yeah bye-bye

Source: https://www.youtube.com/watch?v=BRXdqKFCY5w