Articles that changed the way I practice: ACCOMPLISH

I was searching PBFluids and could not find any posts about ACCOMPLISH which surprised me. I then went to the Renal Fellow Network and found a similar lack of commentary. Dito for Nephron Power, and Nephrology on Demand. Even The Kidney Doctor with 100+ posts (and in the process putting the rest of the nephrology blogosphere to shame) in the last 2 months comes up empty handed.

Now some of this may be due to faulty blog search and some of this may be due to the fact that the study is approaching 3 years of age, but regardless ACCOMPLISH is important enough that it should get higher profile coverage.

The study was published in the NEJM in 2008

The acronym is an obviously:

• Avoiding 
• Cardiovascular events through 
• COmbination therapy in 
• Patient 
• LIving with 
• Systolic 
• Hypertension

From the title, if not the acronym, the point of the study should be clear: The study pits benazepril and amlodipine (Lotrel) against benazepril and hydrochlorothiazide (Lotensin).

The politics of this fight are interesting as this study tries to right one of the possible mis-steps in the wake of ALLHAT. ACCOMPLISH used the thiazide diuretic that is actually most often used in the U.S. and the only thiazide that is used in combination pills, hydrochlorothiazide (yes I know I'm ignoring Tenoretic, atenolol and chlorthalidone, but every other combination pill uses hydrochlorothiazide). ALLHAT used chlorthalidone as its diuretic and when this largest-ever hypertension study concluded that there was no difference among chlorthalidone, amlodipine and lisinopril on fatal coronary heart disease and non-fatal heart attacks, thiazides became institutionalized as the primary agent to treat hypertension.

Figure depicting the primary outcome from ALLHAT

The money shot from JNC7 (pdf) institutionalizing thiazide-type diuretics

The problem stems from the fact that hydrochlorothiazide and chlorthalidone are unique molecules with significant biologic and pharmacokinetic differences.

This year Dorsch et al re-analyzed data from the MRFIT trial. This was a long-term primary prevention trial from the 70's that changed protocols mid-stream and converted patients from HCTZ to chlorthalidone. This allowed Dorsch's team to look for differential effects of the two diuretics. They found a 21% reduction in cardiovascular events with chlorthalidone:

If you are interested in the reasons behind the differences read John Flack's editorial associated with Dorsch's analysis and look at a 2004 review by Carter et al.

So ACCOMPLISH set out to show that the ACEi CCB combination is superior to the ACEi HCT combination. They randomized 11,506 patients to one of these two arms. The dosing titration seems fair:

1. 20 benazepril and either 5 of amlodipine or 12.5 of dydrochlorothiazide
2. if BP is not < 140/90 (130/80 in CKD and DM) increase to 40 mg of benazepril
3. if BP is not < 140/90 (130/80 in CKD and DM)  increase to 10 of amlodipine or 25 of hydrochlorothiazide
4. if BP is not < 140/90 (130/80 in CKD and DM)  add additional agents as needed

The cohort was rather sick with previously diagnosed hypertension and an additional history of at least one of the following:

• Coronary events
• Impaired renal function
• Peripheral artery disease
• LVH
• Diabetes.

The end point was time to first cardiovascular event, or death from cardiovascular disease.

The study was well run but the blood pressures were not perfectly equal between groups with a small but statistically signifigant difference in the blood pressures between the two groups:

• 131.6/73.3 in the Benazepril-Amlodipine group
• 132.5/74.4 in the Benazepril-Hydrochlorothiazide group
• A difference of 0.9/1.1 in favor of the Benazepril-Amlodipine group

The study was terminated early because the data and safety monitoring committee observed a difference between the two groups that exceeded the pre-specified stopping rule. They found a 20% risk reduction in only 30 months. This represented an absolute risk reduction of 2.2% which translates into a Number Needed to Treat of only 45.

Entering EBM free zone:

To my eyes, ACCOMPLISH better represents the patients I see than ALLHAT. All of the patients that come to my CKD clinic have high blood pressure and almost all also have the additional co-morbidities needed for enrollment. After fully digesting ACCOMPLISH I have made two changes in my practice pattern:

1. I am starting patients with ACEi + CCB or ARB + CCB. I have been impressed by the effectiveness of Lotrel and Exforge as single pill solutions to a lot of hypertension.
2. I avoiding hydrochlorothiazide where ever possible. This usually requires re-jiggering a number of medications but a common switch will be to move patients from a list that looks like this:
1. Lisinopril HCT
2. Amlodipine

          To a list that looks like this:

1. ACEi CCB combination pill
2. Chlorthalidone

This results in significant improvement in blood pressure control.
I have to thank ACCOMPLISH to opening my eyes to this change.

I love the smell of July 1st in the morning

As has been the tradition since 2008, I had the honor of giving the morning report on July 1st for the St John Hospital and Medical Center Internal Medicine Residency Program. July one, openning day of the academic year. The conference room was crackling with the energy of fresh interns and the equally excited second years ready to run their own teams.

Giving the lecture was a lot of fun. There were a lot of insightful questions, some because the questioner is terrified and others to show how smart she is. Nobody looked sleep deprived, so the ratio of deer-in-the-headlights to asleep-at-their-desk was unnaturally high.

The lecture covered three topics:

1. total body water and how to choose an IV fluid
2. diuretics
3. dysnatremia

There is no way I could get through the deck in the 50 minutes of time we had. It probably would take 90 minutes to cover it all. In delivering the talk I focused on the mood of starting this great adventure.

Here are some tips to using this presentation:

The first slide has Munch's Skrik, which I explain translates as July 1st

Slide 4 has my favorite quote about kidney function. Homer Smith essentially uses 150 words to explain the point that the job of the kidneys is not to make urine anymore than the job of a factory is to make smoke.

The lungs serve to maintain the composition of the extra-cellular fluid with respect to oxygen and carbon dioxide, and with this their duty ends. The responsibility for maintaining the composition of this fluid in respect to other constituents devolves on the kidneys. It is no exaggeration to say that the composition of the body fluids is determined not by what the mouth takes in but what the kidneys keep: they are the master chemists of our internal environment. Which, so to speak, they manufacture in reverse by working it over some fifteen times a day. When among other duties, they excrete the ashes of our body fires, or remove from the blood the infinite variety of foreign substances that are constantly being absorbed from our indiscriminate gastrointestinal tracts, these excretory operations are incidental to the major task of keeping our internal environments in the ideal, balanced state.  

Homer W. Smith from From Fish to Philosopher

Slides 5-9 emphasize that this topic is not a niche topic, the issues of fluids and electrolytes comes up everyday, on every patient.

Slide 11, warn everyone that the unfortunate person who gains 30 kg in this slide is a medicine resident gorging on donuts at morning report.

Slide 18, remind everyone that LR is for surgeons. Deny any knowledge of the reason for this peculiarity. Explain that this is further evidence that they are an alien species unrelated to hard working, honest IM docs.

Slide 27 Explain that the question, "Would you give a drowning man a glass of water?" was taught to me by one of the most foul-mouthed senior residents when I was an intern. I want to show that the lessons learned this year will be the stories you tell interns decades later. Interns will learn more this year than any other year of their life, except their first year of life.

Slide 29 recommend everyone read House of God. 

Here is the lecture in PDF and Powerpoint

Gitelman syndrome and Pregnancy

One of my Gitelman patients (whom I kidding, "one of my Gitelman patients", how about "my only Gitelman patient") finally got pregnant. We had been managing her with amiloride and a truck load of oral potassium and magnesium supplements. I was shocked to find that amiloride is acceptable in pregnancy with a track record of successful births. Prior to starting amiloride the patient was taking twenty-eight 20 mEq pills of KCl a day. She abandoned her prior nephrologists when she was told to further increase her potassium pills.

from UpToDate

We are now using magnesium sulfate infusions 4 grams twice a week to keep her magnesium north of zero. She was able to keep her magnesium around 1.4 with oral supplements and amiloride prior to being pregnant but now, despite 8 grams of weekly IV magnesium her magnesium is sitting around 1.1. This probably represents one of downsides of the up-regulated GFR of pregnancy.

Interestingly, she saw her labs and saw that her sodium was 132. Modest hyponatremia is a normal finding in pregnancy, so she decided to increase her dietary sodium intake. Bad move, increased renal sodium loads increases renal magnesium losses. Her serum mag fell 30% to 0.8.

Happy July 1st.

For the third year in a row a I had the honor to present the first morning report of the academic year. Fluids, diuretics and dysnatremia:

Fluids And Electrolytes July1

View more presentations from Joel Topf.

Renal Week 2008: CKD and CVD: Antihypertensive therapy

Case report of a patient with HTN
Ray Townsend is the MC (sweet). He presnts a patient with HTN and modest CKD. Cr 1.4 up from 0.9 in 2001.

Ray passes off to Domenic Sica.

Antihypertensive Drug Therapy in patients with HTN and CKD.

Volume expansion

• Patient was on 25 mg of HCTZ. No need to change to loop if the patient is euvolemic. Chlorathalidone vs hctz
• Ernst HTN 2006. chlorathalidone reduced 24hr mean bp more (7 vs 12) non-ckd patients. night time bp drop was even more pronounced 6 vs 13 mmHg.
• Recommends switch within class from hctz to chlorthalidone
• the increase in calcium may help with PTH. interesting.
• elison JCI 83: 113; 1989 images of hypertrophy of DCT with loop diuretics
• He's pushing torsemide
• Using FeNa to determine if patient is responding to loops (look for fena>3%)
• Why is there variability in bioavailability of furosemide: floculation of pills stops some absorption. Use of liquid furosemide doesn't help because of only a limited area of absorbtion: early duodenum only.
• He likes the torsemide

Drug accumulation

At gfr 30-50 need to think about dose adjustment.
Renally cleared: atenolol, nadolol, betaxolol

Hepatically cleared
propanolol, metoprolol, carvedilol

Dose response to beta-blockers is flat in CKD.

Don't titrate atenolol. It is renally cleared and patients are already retaining the drug before you increase the dose. Though the BP effect is not dose dependent, the adverse effects are.

Aldosteronism

• 20% of patients with CKD.
• Likely this patient will have aldo level of 14-20 and renin less than 1
• Aldosterone antagonists (AA) reduce proteinuria
• Need diuretic on board to get much BP effect
• Half-life of spironolactone is 24 hours, in liver disease 120 hours, and in CKD multiple days. These figures include active metabolites. He feels eplerenone is safer because you won't get accumulation.
• Consider qod dosing of spironolactone. Consider 12.5 mg qd
• beware of heparin causing hyperkalemia with AA
• Similar warning for ACEi, ARB, TMP/SMX

Clonidine

• in CKD clonidine is renally cleared. This decreases rebound htn by extending the half life
• initially clonidine has a steep dose responce at low doses but then flattens
• causes dose dependent volume retension. this is worse with TTS
• at higher doses the peripheral alpha stimulation will overcome the central reduction in alpha activity so patients get increase in BP. This is seen in clonidine OD or with autonomic dysfunction.
  

CCB

• Amlodipine has half-life of 40 hours
• nifedipine's half-life goes from 2 to 4 hours in renal failure
• Edema with CCB is worse in patients with CKD because they already have increased volume

ACEi

• 10 in the US
• fosinopril and trandolopril have significant hepatic clearance
• ARB are not renally excreted
• dialyzable: captopril, enalepril, lisinopril. Use in overdose.

Statin

• AUC of simva increases 4 fold with diltiazem
• Cool case report of a patient on 80 of simva who was admitted for A-fib with RVR and gets started on a diltiazem gtt. He developed rhabdo a few days later.
  

That's it. Question time.

Bumex, same short pharmacokinetics of lasix with better bioavailability

I'm working more at Providence Hospital and I find that the intensivists and cardiologists love the Bumex. This opinion is shared by some prominant nephrologists. Unfortunately bumetanide suffers from the same short pharmacokinetics as furosemide: half life of about 90 minutes after oral or IV dosing. The big advantage bumetanide has over furosemide is more predictable bioavailability after oral dosing. Torsemide trumps both of them with excellent bioavailablity and a half-life of 210 minutes.

The reason that bumex is preferred is the beleif that it is a more potent diuretic than furosemide. According to Brater, all of the loop diuretics have similar potency and decisions among the loops should be based on pharmaokinetics (as opposed to pharmacodynamics). Here is the statement in his NEJM review of diuretic therapy.


Phamacokinetics of torsemide, bumetanide and furosemide from the package inserts. And here is the table from Brater's reveiw:

Sodium and Potassium for ER residents

Yesterday I lectured the St John ER residency program. The ER residency has an impressive commitment to education. They set aside a half day every wednesday for their resident to get dedicated didactic time. They have great attendance with a good number of attendings showing up.

I have been asked to give three lectures and yesterday was the first. I gave a double lecture (running time about 90 minutes) on sodium and potassium. The fact that I could run over the standard 50 minute alotment normally given for medicial education is due to the fact that they have blocked an entire afternoon rather than try to shoehorn a lecture into lunch or before rounds.

The sodium lecture was the first time I used the Sodium handout I created for the St John IM residents. I gave the lectuer Seder-Style with the residents reading different sections, answering questions and me adding commentary. The ER residents are smart and empowered to ask questions. I felt that there was great two-way interactivity.

Dont Panic Sodium

Publish at Scribd or explore others: Health & Medicine attack panic attacks

Sodium iPhone format
Sodium booklet format

The potassium lectuer is an abrdged potassium lecture which is stripped to the bare bones of differential and treatment. It is a traditional powerpoint lecture. Immediately when I started this lectuer I saw about half a dozen exhausted interns fall asleep. My next project is to create a potassium haggadah.

Potassium powerpoint

The Acid-Base lecture for the residents of St John Hospital

Today I gave my second lecture of the year for the St John Residency.

I used my Acid-Base workshop handout and added a slide show to facilitate the large group.

I still called on individual residents to answer questions to keep them involved.

I started the lecture with some audience participation. My previous lecture on IV Fluids, diuretics and dysnatremias began with me stating how ubiquitous these subjects were.

I had everyone stand then I asked people to sit down if, in the last three weeks they had not:

• Used any diuretics: no one sat down
  
• Used any IV diuretics: about half a dozen people sat down
• Used a thiazide diuretic to counter the effect of loop diuretic resistance: lost a lot of people there but still had about a dozen left
• Used a lasix drip to counter loop diuretic resistance from heart failure: everybody sat down but about 3 residents and the amazing Dr. Dhungel, my first year fellow on the consult service.
• Used torsemide instead of furosemide for better pharmacokinetics: only Dr Dhungel remained standing.

I then tried to repeat the excercise for IV fluids and dysnatremias but it didn't work very well. Should have quit after the first one.

When I gave that IV Fluids, diuretics and dysnatremias lecture I didn't have a hand out. In the last three weeks I have worked up a handout:

iPhone version
Booklet form

July first lecture on IVF, Diuretics and dysnatremia

Today I gave the first lecture of the '08-'09 Academic Year. This was morning report for internal medicine. I did a lecture on IVF, diuretics, total body water and dysnatremia. It was a good lecture but Powerpoint only. I am about half-way done with the killer handout I am working on and am disapointed that I didn't finish it. Hopefully will have it done for the next lecture in two weeks.

Fluids And Electrolytes July1

View SlideShare presentation or Upload your own. (tags: diuretics sodium)

Getting ready for a Fluids and Electrolytes lecture

Only a nephrologist ever capitalizes Fluids and Electrolytes.

I am so excites. I get to give the first lecture on July 1. I love the nervous energy that comes with fresh second years and new interns still getting used to the length of their newly lengthened coats.

I am working over my standard F&E Emergencies. I am putting together a new handout designed to be kept in the pocket. While working on the talk I re-found this classic review of diuretic therapy by Craig Brater. Dr. Brater was elevated to Dean of Indiana University Medical School right before I got married at the end of my residency. We had our rehearsal dinner at this Columbia Club on the Circle. I bumped into Dr. Brater right before dinner and congratulated him on becoming the dean.