If you were not convinced nephrologists were total nerds this should close the book on that question.
Old school blogging
In the early days of blogging people would write posts and then other bloggers would comment on the post on their own blog, it was like decentralized comments. So my previous post about the jaded medical student was a post about a blog post, and now Robert Centor, one of the grand wizards of medical blogging has also commented on the same post and mentions my post. Predictably, he has a more productive response than I did. Take a moment to read it.
The written commentary on various blogs brings me back to 2006.
Kevin MD Post tells you what medicine really is from a fourth year medical student who has seen it all
Central Pontine Myelinolysis after Slow Correction of Hyponatremia
This week’s Images in Clinical Medicine is a case that demonstrates how little we know about hyponatremia.
35 year old alcoholic.
Severe hyponatremia with a sodium of 119.
The sodium was corrected over 5 days from 119 to 135. A rate of only 3 mmol/L/day.
Patient developed CPM on the sixth day.
Kenar has a nice post on this case with an alternative approach to try to protect patients.
BS Medicine’s top 20 medications
I’m addicted to podcasts. One of my favorite medical podcasts is BS Medicine. The hosts have deep medical knowledge and an enviable commitment to evidence based medicine. In addition, they approach the podcast from a clinicians perspective and don’t get so lost in the science that they forget we are here to help patients.
For their 300th podcast they did a special episode surrounding the dorm room question: If you could have only 20 medications, what would they be?
They had an interesting list and they spoke extensively justifying their list. The explanation and the list stretched over two episodes. Afterwards they did a third podcast to go over the next 10 medications that barely missed the cut.
I loved the thought exercise but I thought James, Mike, Tina and Mike really missed the boat on a few. Here is their list and mine:
The list is the same through the first three, but then I added normal saline. How can you include epinephrine and not include normal saline? And don’t start with me that salt water is not a drug. Saline will cure everything from a hangover to cholera. Essential medication.
They included oral contraceptives. My feeling is that 99% of the function of OCPs could be replaced by IUDs so women could continue to have control over their bodies and I get an additional medication. I will give up treating dysfunctional urterine bleeding, PCO and other maladies that benefit from OCPs.
I also skipped diphenhydramine. If the allergic reaction is bad enough, then we’ll give epineprine, otherwise tough tootles.
I used pentoprazole rather than omeprazole because I wanted an IV formulation. I skipped the losartan and added apixiban instead. I just couldn’t leave all those people with pulmonary embolism, atrial fibrillation and DVTs to fend for themselves with aspirin alone. The losartan omission is a bit tough to stomache as a nephrologist but truly most of the advantage of ARBs can be duplicated with good blood pressure and glycemic control (at least in diabetics). And the other renal diseases tend to be rare. Additionally I’m not as convinced as the podcasters that ARBs are just ACEi without the cough. I can’t remember seeing ARB heart failure data as impressive as:
Consensus Trial Grade 4 CHF, 1988 |
I don’t know enough ID to vet their antibiotics so I accepted their argument and brought in all three of their antibiotics.
That left me with three more medications after I gave the heave-ho to fluconazole and PEG. To fill this I hadded drugs to treat three of the great infectious diseases that plague this earth: HIV, TB and malaria. Seems morally wrong to ignore them. HAART is one of the greatest medical advances in our lifetime. They have an NNT that approaches one. In 1995, 55,000 Americans died of HIV and they died at young, productive ages causing incalculable losses to the nation. Blood pressure and heart failure medications are hugely important therapeutic target but treatment primarily benefits people in the tail end of their lives. Treating infectious diseases needs to be prioritized because of the age of the people affected.
What’s your list?
My #dotMED16 experience
I was on vacation when I got a DM from Ronan Kavanagh asking me if I would be interested in speaking at dotMED. I said yes without really knowing anything about the conference, but a quick glance at the previous speakers convinced me that speaking there would be a once in a lifetime opportunity. A chance to punch above my weight.
Ronan gave me a blank slate to speak on anything I wanted. I chose social media opportunities in medical education.
My wife and I took a red eye to Dublin and arrived on the Tuesday before the conference. We toured the Guiness Factory Store, Kilmainham Gaol, the Modern Art Museum of Ireland and the Irish Museum. On Wednesday night we were invited to the White coat ceremony at UCD. Pat Murray my old program director at University of Chicago is now the dean of the medical school. Friends in high places and all that.
Phenomenal.
The following day I gave a lecture on social media to the staff and students at UCD. Great response.
Big thanks to @kidney_boy who gave an excellent presentn on SoMe & MedEd. You guys attending @DotMedConf are in for a treat.— UCD Medicine (@UCDMedicine) February 11, 2016
And it was great getting a chance to rehearse my dotMED talk in front of a live audience.
The talk went long, about 45 minutes for my 30 minute slot. When I went to the Smockalley Theater later that day for an AV check, I asked Kerry O’Sullivan if a slightly longer presentationwas okay. She turned ashen. I had my answer. So I pulled out the metaphorical scalpel and started my lecture lobotomy.
Looking good at @smockalley for #dotmed16 tomorrow, technical run-through smooth #dotmed16 pic.twitter.com/6YGcE0sssz— Einstein Epigenomics (@EpgntxEinstein) February 11, 2016
Thursday night the speakers met at the Shelbourne Hotel for drinks and then went to The Winding Stair for dinner.
Ronan meets Steve Bergman, A.K.A. Samuel Shem. Ronan looks so happy. |
The Winding Stair is by the Ha’Penny Bridge, the oldest toll bridge in the world. This was before #FOAB (free, open access bridges) |
Muiris Houston, conference organizer at dinner |
Monica Lalanda, conference cartooner showing Dr. Bergman his representation. Dr. Leticia Rivera is behind Monica. |
Monica and Leticia |
The following day we walked from our hotel to the Smock Alley Theater.
Good morning from the theatre! Registration is open and there’s coffee upstairs! #dotmed16 pic.twitter.com/2tatJex1zk— dotMEDconf (@DotMedConf) February 12, 2016
Ronan welcomed everybody and then John Greally, pediatrician and geneticist from Albert Einstein, gave the first talk of the day Learning from Artists in the Digital Age. It was an amazing talk. He started with a history of visual representations of data. From primitive maps, to the first histograms, to maps with epidemiologic data. Fascinating. He reminded us that modern radiology images are just visual representations of what is really quantitive data.
Greatest advance in data visualisation – Napoleon’s march on Moscow #dotmed16 @EpgntxEinstein pic.twitter.com/nUedo5l30L— dotMEDconf (@DotMedConf) February 12, 2016
The history lesson was a set-up for the fact that all advances in data visualization occurred before 1900 and that with the era of big data we need new data visualization techniques. He is spearheading this effort by bringing together artists, data illustrators visualizers and geneticists to comb through big epigenetic data dumps to find unique and useful ways to present it to clinicians and scientists. (Nice NYT article about Greally’s efforts).
I loved John’s definition of big data: any data set too large to fit on a laptop.
OMG. Unbelievably good presentation. How did I get placed after John? This could get ugly. #dotmed16— Joel Topf (@kidney_boy) February 12, 2016
— dotMEDconf (@DotMedConf) February 12, 2016
After John, I was up. I spoke about the evolution of the medical textbook and how social media and mobile will inform future versions.
Clinical nephrologist and medical educator @kidney_boy talks med text books and our own @TheNotoriousMMA #dotmed16 pic.twitter.com/OYyXCRk0Q2— Avril Copeland (@AvrilC) February 12, 2016
— dotMEDconf (@DotMedConf) February 12, 2016
Best part about the talk? I got to use the Madonna/Astronaut microphone.
‘How do you cope with digital sceptics in medicine?’asks @RonanTKavanagh ‘We’ll be pass them by & they will die!’ says @kidney_boy #dotmed16— Dr Ros Taylor (@hospicedoctor) February 12, 2016
One of the best arguments in favor of social media was made by John. He discussed that forensic statisticians do a lot of the post publication peer review of big data research and they typically publicize their work via social media. I did get the final question of the session and my wife says it was the best part of the morning:
@MarieOScully @kidney_boy on ambiguity Q “residual uncertainty means humility which can only be a good thing in medicine” #dotmed16— Dr Damian Fogarty (@DamianFog) February 12, 2016
@mlalanda panel discussion at #dotMED16 @EpgntxEinstein @RonanTKavanagh @kidney_boy pic.twitter.com/iUKaIHZYCb— dotMEDconf (@DotMedConf) February 12, 2016
Next up was Leticia Ruiz Rivera discussing her photo exhibit, Limits, which explores the brutality of medical training. She takes portraits of residents before and after their 24-hour shifts. She gave a 5 minute introduction and then we went upstairs for coffee where we could look at her photo exhibit.
#dotmed16 Leticia Ruiz Rivera about her photos pf doctors before and after 24h at work pic.twitter.com/YGOGwBuBD1— monica lalanda (@mlalanda) February 12, 2016
After the combination coffee break and photo exhibit the conference resumed downstairs with a Pitch off. Four start-ups in the health space competed to win the conference.
Time for dragons den style pitching competition for medical innovators @DotMedConf #dotmed16 pic.twitter.com/BcwMkXJj9l— June Shannon (@juneshannon) February 12, 2016
The first company was Humane Engineering with their app Cove. Cove is digital diary that allows you to create music to fit your mood and acts as a non-judgmental, always available, grief counselor. It was an amazing presentation and my personal favorite. As we spend more and more time staring at our phones, reimagining them as tools for psychotherapy seems innovative, important and the type of idea that could change the world. One day psychotherapy will delivered via computer and I don’t know what it will look like but if it is done well and is effective it will be a great thing.
Short video similar to what was just shown on screen here @cove_app #dotmed16 https://t.co/1qtn0E5411— dotMEDconf (@DotMedConf) February 12, 2016
The next company was N-Silico that had an EMR-like product that focused on a specific type of meeting that seemed to me to be like a tumor-board meeting. They developed software that would help the team mates collaborate. It maybe a great idea, but seemed like JAFEMR (just another fracken EMR). Though he did have the best line of the conference, “Paperwork wouldn’t be so bad without the paper…or the work.”
— dotMEDconf (@DotMedConf) February 12, 2016
— dotMEDconf (@DotMedConf) February 12, 2016
The third presenter was the Beats Medical. They have a smart phone app that treats Parkinson’s disease. Apparently the shuffling gait and freezing can be ameliorated by a metronome like beat. This company has created an app than takes a 2 minutes walk test (done by shuffling around with the phone in your pocket) and then creates a custom metronome beat for your disease. It is customized for the individual in pitch and tempo. This was my wife’s favorite and she was not alone:
We should probably stop the pitches and give @BeatsMedical the prize. Sorry everyone else. #dotMED16— Jason Carty (@Doctor_J_) February 12, 2016
Every breath you take PMD follows great presentation from @BeatsMedical at #dotmed16 pic.twitter.com/Yy1Bo5n9bM— martin kelly (@martykelly) February 12, 2016
— dotMEDconf (@DotMedConf) February 12, 2016
#dotmed16 TY @R1chardatron, judges @HIHCork for recognising and supporting @PMD_Respiratory #everybreathcounts pic.twitter.com/EaVUvJgdSA— PMD Solutions (@PMD_Respiratory) February 12, 2016
The wonderful @PantiBliss in conversation with @muirishouston @DotMedConf #dotmed16 pic.twitter.com/u2tPMYw7nU— June Shannon (@juneshannon) February 12, 2016
If u click on troll’s profile they have about 4 followers 😂😂😂 @PantiBliss on social media trolls hateful people have few friends #dotmed16— June Shannon (@juneshannon) February 12, 2016
Pantibliss talking about being diagnosed with HIV in 1995. Managing death. Mixing the hemophiliacs, the gays, and the drug addicts #dotMED16— Joel Topf (@kidney_boy) February 12, 2016
On taking 38 tablets per day “You could always tell the AZT queens because they rattled” Rory O’Neill @pantibliss #dotMED16— Einstein Epigenomics (@EpgntxEinstein) February 12, 2016
Pantibliss: I’m single and that’s partly because I’m annoying but HIV is part of it too. #dotmed16— Joel Topf (@kidney_boy) February 12, 2016
Truvada whores: The thought that people who take pre-exposure truvada will go whoring around–Pantibliss #dotmed16— Joel Topf (@kidney_boy) February 12, 2016
“Air, food, water, shagging. That’s what we are.” @PantiBliss #dotmed16— Pat Rich (@pat_health) February 12, 2016
@mlalanda live drawing @muirishouston interviewing @PantiBliss at #dotMED16 pic.twitter.com/W3L25yQIdJ— dotMEDconf (@DotMedConf) February 12, 2016
There was a lunch break and that we were back to the conference. We started with the dulcet sounds of Colm Mac Con Iomaire. It was amazing and let’s face it not many medical conferences can boast a session highlighted by a 300 year old Irish love song.
— monica lalanda (@mlalanda) February 12, 2016
Much of early practice in medicine is rehearsal to deal with realities without becoming an automaton: @deborahbowman #dotmed16— Pat Rich (@pat_health) February 12, 2016
#dotMED16 a play about young doctors in love and the hospital spilling into the rest of your life pic.twitter.com/FE7iYDRwSR— Joel Topf (@kidney_boy) February 12, 2016
“The patients who come home with you, the people who haunt you, the interactions you can’t shake off.” We all have these. #dotmed16— Ellie (@ellieornot) February 12, 2016
#dotMED16 more from the play James and Emily. After a failed resuscitation. pic.twitter.com/QdzZzeoeI9— Joel Topf (@kidney_boy) February 12, 2016
— monica lalanda (@mlalanda) February 12, 2016
#dotMED16 monsters. Authors view of waking with a lover he fears he may have infected with genital herpes. pic.twitter.com/kfj8XLishF— Joel Topf (@kidney_boy) February 12, 2016
#dotMED16 his image of his own OCD pic.twitter.com/ZiymNCnF9B— Joel Topf (@kidney_boy) February 12, 2016
— Einstein Epigenomics (@EpgntxEinstein) February 12, 2016
@TheBadDr presentation was great. Entranced by his cartoons….I just managed this at #dotmed16 pic.twitter.com/eoC4BxhljQ— monica lalanda (@mlalanda) February 12, 2016
After Ian, Ronan convened a panel of the two illustrators, Ian and Monica, and Laticcia, the photographer to discuss visual imagery in medicine.
@TheBadDr @RonanTKavanagh @subcitygalway Great panel discussion on medicine in comics #dotmed16 pic.twitter.com/nf0V2fjEZa— Karl Sweeney (@karljsweeney) February 12, 2016
— Joel Topf (@kidney_boy) February 12, 2016
Then to close out the meeting, the headliner, Stephen Bergman, AKA Samuel Shem. The name of the talk, “Staying Human in Medicine in a World on Fire.”
Ladies and gentlemen, Dr. Samuel Shem (Stephen Bergman) at #dotmed16, erudite and funny pic.twitter.com/20TMywQJVe— Einstein Epigenomics (@EpgntxEinstein) February 12, 2016
Early in his talk he recounted how he was given advice to begin his novel with lots of humor to engage his audience and leave a lot of the punch to the end. Which is exactly how he structured his talk at dotMED.
#dotMED16 when he started to write House of God he was told it needed to ride on humor. But the last third gets really dark.— Joel Topf (@kidney_boy) February 12, 2016
He started with a charming story about how during medical school he did his OB rotation in Dublin at Hollis Street. He said it was the drunkest period of his life. He says he and his buds would get hammered at a pub then stumble back into OB ward and deliver a couple of kids. The nurses would only give him the easy ones, the moms that were delivering kid number 20. The audience was laughing uncontrollably but looking back it is kind of a horrifying story. Just like the House of God, I guess.
He told the story of how he got House of God published. He wrote the first 50 pages and he sent it off to an agent. He didn’t know what he was doing and the drat was single spaced and filled with typos and notes in the margin. A few weeks later he had forgotten all about it and received a call from the agent saying he was either insane or a genius. Later on the publisher asked if anyone in the book was identifiable. Stephen thought, “everybody” but answered just one, the chief of medicine, a renologist, who tucked his stethoscope into his pants. Son the lawyers gave him a large birthmark on his face to vaccinate them from a lawsuit.
He talked about the most important thing in medicine is connecting with a patient.
#dotMED16 how do you teach students how to deliver bad news. Do what the Fat Man does.— Joel Topf (@kidney_boy) February 12, 2016
#dotmed16 Samuel Shem talks of the healing power of connection with the pt. The kindness & simplicity of connection is key no matter what!!!— Valerie Keating (@fvkeating) February 12, 2016
Inserting ‘we’ into discussions with patients builds a relationship: House of God author Sam Shem at #dotmed16 #hcsmca— Pat Rich (@pat_health) February 12, 2016
He elaborated on the healing power of connection by talking about his own alcoholism. He in recovery and a believer in alcoholics anonymous. He wrote a play about the origin of AA called Bill W. and Dr. Bob and explained that the core truth about AA is about connection:
#dotMED16 The only thing that can keep a drunk sober is telling his story to another drunk. The treatment is connection.— Joel Topf (@kidney_boy) February 12, 2016
The problem is that meaningful use and modern medicine are separating us from our patients. It is preventing connection.
#dotMED16 he surveyed Boston and New York interns about how much time they spent in front of screens: 80%— Joel Topf (@kidney_boy) February 12, 2016
Closing point of Bergman’s talk. So true.
“We are paid to be with people at the most significant moments of their lives” Sam Shem at #dotMED16— Pat Rich (@pat_health) February 12, 2016
After his talk, Muiris interviewed him. Muiris started by mentioning that peope are always warned against meeting their heroes but meeting his hero, Stephen Bergman, has been wonderful.
The Laws of the House of God ; Dr.Stephen Bergman in conversation with @muirishouston at #dotMED16 pic.twitter.com/A4aQBBVkiq— dotMEDconf (@DotMedConf) February 12, 2016
The rules of #TheHouseOfGod may not be compatible with current #sepsis guidelines. #dotMED16 pic.twitter.com/rfQFyFVb7E— Ian Williams (@TheBadDr) February 13, 2016
You can forget knowledge, but you cannot forget what you understand – Samuel Shem #dotMED16— dotMEDconf (@DotMedConf) February 12, 2016
What a priviledge to listen to the author of The House of God at #dotmed16 pic.twitter.com/aaW5874OJl— monica lalanda (@mlalanda) February 12, 2016
Following the interview there was a wine and appetizers mixer. It was great to get a chance to chat with everybody at the conference. One of the remarkable things about dotMED was just how interesting everyone in attendance was. It was great chatting with them.
Then we went off for one last dinner and finally wrapped up up dotMED at Dex.
See that big smile on @RonanTKavanagh‘s face!? Well done to everybody involved in planning #dotmed16! pic.twitter.com/APjRAtpV2j— John Brownlee (@clearJB) February 12, 2016
Just an awesome meeting and a great week in Dublin.
–UPDATE–
Smoother coverage of the meeting:
Marie Ennis-O’Connor put together a storify
NephJC needs your help!
If you take a look at the side bar you will see I’m a totally pathetic assistant professor. Help me get promoted by filling out the NephJC survey so we can publish!
We actually went through the trouble of getting IRB approval and everything. Get more details (if you care) here, but really just fill out the survey.
Patiromer and a possible role in preventing aldosterone escape
Aldosterone is a bad actor. It is cardiotoxic. It drives a lot of hypertension. It is likely a progression factor in chronic kidney disease. (presentation with a lot of references to the primary data by Adrian Covic can be found here).
This is why aldosterone antagonists are such effective drugs in heart failure, such good antihypertensive agents and have potential in CKD. ACEi and ARB lower aldosterone because one of the two primary stimulants for aldosterone release is angiotensin 2. But about half of patients started on RAAS inhibition experience something called aldosterone escape, where within a few weeks of starting drug therapy, aldosterone levels returns to pre-treatment levels. I suspect a lot of this escape is mediated via increases in potassium.
Aldosterone Escape from joel topf on Vimeo.
The addition of patiromer in a situation like this could lower aldosterone levels and result in improved outcomes. So my call for outcome studies beyond changes in serum potassium is not a plot to derail the drug but to give the drug an opportunity to prove how it can actually improve renal and CV outcomes independent of just allowing patients to stay on RAAS inhibition.
The key is that if the studies are not done we will not know.
Patiromer and patient oriented outcomes
Recently I have been tweeting back and forth with some biotech investors that have some strong feelings about patiromer. The recuring pro-patiromer theme is the drug will allow people to stay on their ACE inhibitor or angiotensin receptor blocker without fear of hyperkalemia. This is not a stretch belief by team patiromer, it was one of the figures in the supplementary material of the NEJM study:
So if what we say about ACEi and ARBs is true, staying on them is a good thing. But do we need to do a clinical trial to determine if the benefits of RAAS inhibition are also seen in patients who can only tolerate RAAS inhibition with the addition of a potassium binder? I think we do. Here is my logic.
The benefits of RAAS inhibition in CKD are not dramatic:
In patients with microalbuminuria, it is difficult to find any clean win. The PREVEND trial and the CASE-J trial (PDF) both showed a benefit in sub group analysis (stage 4 patients, but not in any other stages):
Renal outcomes by CKD stage (doubling of sCr, Cr>4, dialysis) |
No benefit in the whole cohort |
The TRANSCEND trial did not show a renal benefit from the ARB, telmasartan, but in post hoc analysis, patients with albuminuria did have fewer renal outcomes. But subgroup analysis of negative studies is generally considered poor form. Do you really believe that telmasartan increases renal outcomes in the absence of proteinuria, another post-hoc finding.
Anyway you cut it renal function deteriorated faster with ARB |
In the end the recommendation for ACEi and ARB with microalbuminuria in KDIGO gets only a 2D recommendation:
“The Work Group suggests ACE-Is or ARBs as the preferred class of BP-modifying agent in CKD patients with microalbuminuria. This recommendation is based on observational data and subgroup and post hoc analyses, hence the grade of 2D.”
On the other hand the data on macroproteinuria, even in non diabetics is not subtle:
These trials include RCTs in patients with CKD of various causes, primarily glomerulonephritis,191 African-Americans with hypertension, and patients with advanced CKD (a GFR of 20–70ml/min/1.73m2). A meta-analysis of in- dividual patient data from 11 RCTs compared antihypertensive regimens including ACE-Is to regimens without ACE-Is in 1860 patients with predominantly non-diabetic CKD. In adjusted analyses, ACE-Is were associated with a HR of 0.69 for kidney failure (95% CI 0.51–0.94) and 0.70 for the combined outcome of doubling of the baseline SCr concentration or kidney failure (95% CI 0.55–0.88). Patients with greater urinary protein excretion at baseline benefited more from ACE-I therapy (P 1⁄4 0.03 for kidney failure and P 1⁄4 0.001 for the combined outcome).
Here are some of the key figures from the above mentioned meta-analysis (11 studies, 1,860 non-diabetic patients, RCT ACE-i vs non-ACEi) from Annals of Internal medicine:
Those lines are diverging over time. Right? |
Looks like a solid RR of 0.6 to 0.7 with ACEi |
The higher the proteinuria the greater the benefit. |
The NNT to prevent the composite end-point of ESRD or doubling of serum creatinine is a robust 14!
Of note from this study 4% of patients were withdrawn due to ACEi side effects, which included the dreaded hyperkalemia.
But the question that I have; the question that nags at me, is, “Are the patients that live at the left end of the bell curve, the ones that were unable to tolerate the ACEi due to hyperkalemia, do they have the same physiology and neurohormonal milieu as the rest of the cohort? Could those patients have naturally low angiotensin 2 levels or low aldosterone levels?” It seems likely.
And if that is the case, it also seems more likely that these patients would be among the 13 patients in our NNT of 14 that do not benefit by not doubling their creatinine or going on dialysis. It’s like their bodies have endogenous RAAS inhibition.
If that is the case, that these patients do not benefit from RAAS inhibition then they are not harmed by stopping the drug and hence they would not get a benefit from patiromer.
The essential issue is that though we have shown a benefit of RAAS inhibition for renal outcomes in CKD, we have never shown that benefit in patients who could not tolerate the drug and I think the sliver of patients who cannot tolerate RAAS inhibition may represent a population different enough from the whole cohort to deserve study.
I plan on using patiromer in my patients but it is hard to be a cheer leader for the drug or feel that it is an essential part of the treatment regiment until we see the benefit in this targeted population.
@kidney_boy what about possibility that hyperK on RAASi means that RAAS is MORE activated? that rise in K is assay for effective drug?
— David S Goldfarb (@weddellite) February 1, 2016
@weddellite has anybody done TTKG before and after ACEi and correlated it with clinical outcomes? Does ↓ TTKG ☞ improved outcomes?
— Joel Topf (@kidney_boy) February 1, 2016
And got this hit:
My search criteria was almost a perfect match for the title of the article. The article shows worse outcomes for patients with increased serum potassium but it did not separate out people by the change in serum potassium or look at renal potassium handling, both of which would be ideal. But that said, there is no signal that increased potassium is a harbinger of increased benefit from ARBs.
Take a look at the response too.