This never would've happened if the AHA/AAC had put Andrew Levey in charge of their risk calculator

Two items of note struck me this morning. The first was the fumble with the new cholesterol recommendations. The guidelines have been taking heat largely because they dramatically expand usage of statins in populations with that receive little to no benefit front he drug.

TheNNT is one of my favorite websites for patient discussions.

The last thing the new recommendations needed was a headline in the paper of record showing that their calculator over estimated 10 year cardiac risk by a mere 75 to 150 percent:

This week, after they saw the guidelines and the calculator, Dr. Ridker and Dr. Cook evaluated it using three large studies that involved thousands of people and continued for at least a decade. They knew the subjects’ characteristics at the start — their ages, whether they smoked, their cholesterol levels, their blood pressures. Then they asked how many had heart attacks or strokes in the next 10 years and how many would the risk calculator predict. 

Look what that risk calculator did to that Church!

The answer was that the calculator overpredicted risk by 75 to 150 percent, depending on the population. A man whose risk was 4 percent, for example, might show up as having an 8 percent risk. With a 4 percent risk, he would not warrant treatment — the guidelines that say treatment is advised for those with at least a 7.5 percent risk and that treatment can be considered for those whose risk is 5 percent.

That's a big miss and I think it threatens to be a big mess if people lose confidence in our cardiology experts and their guidelines.

 It is interesting that this story is just getting legs today. The alarm was raised on the day the guidelines were released. From Medscape:

To heartwire , Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD), who was not part of the writing committee, said he agreed with 90% of the information in the new guidelines. "To put that in perspective, I probably only agree with my wife 85% of the time," he said. 

Namely, he is a little troubled by the new atherosclerotic risk score. Derived from FHS, ARIC, CARDIA, and CHS, it hasn't performed all that well when applied to other cohorts, such as the Multiethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, he said. The risk score does not take into account family history of premature cardiovascular disease, triglycerides, waist circumference, body-mass index, lifestyle habits, and smoking history. 

"In my mind, we're putting a lot of faith in this risk score," said Blumenthal. "We're probably going to be treating many more people, especially many more ethnic minorities, who get above this 7.5% threshold."

In the end, I think we can agree that the cardiologists should leave the equations and formulas to the nephrologists, namely Andrew Levey. Hence the second item of note. Andrew Levey won the prestigious Belding Scribner Award. Levey is best known for creating the MDRD eGFR estimating formula and its successor the CKD-Epi formula.

I have gotten to know him as he is the editor and chief AJKD and spearheaded the creation of eAJKD. During every one of my encounters with him he has been humble, witty and friendly. During his Scibner acceptance speech he revealed that he considers his greatest moment in nephrology to be donating a kidney to his wife.

Levey donated a kidney to his wife. TLA. #kidneywk13
— Joel Topf (@kidney_boy) November 9, 2013

What a mensch.

There is a great interview with Andre Levey at eAJKD today. Take a moment and read it.

My Best Kidney Week

Every year that I go to Kidney Week it seems to get better. I had a wonderful time at this years Kidney Week in Atlanta primarily because it was full of new experiences and connections.

One of the highlights was getting the honor of introducing the KDIGO Mobile app. This iPad only app contains all of the KDIGO guidelines and support documents. The Chair of the implementation committee, Yusuke Tsukamoto, described me as KDIGO's Steve Jobs. I can't imagine a higher compliment.

Just got my hair cut. Asked for the full Steve Jobs. What do ya think? http://t.co/DT45QxOa
— Joel Topf (@kidney_boy) September 16, 2011

The app is a great way to read the guidelines. We feel these are our first steps and we are excited to push the app forward. You can download it for free from the iPad App Store. Getting a chance to work with the KDIGO folks on this project has literally been one of the highlights of my career.

I aggressively live tweeted every session I attended. This is a huge 180° U-turn for me. See this post from last August where I blast the entire practice. Hobgoblin of little minds and all. Well all that tweeting resulted in me being the largest influencer of Kidney Week 2013.

That will be the only time I will ever be listed ahead of the New England Journal of Medicine.

The middle column is just the number of tweets by different individuals. I would like to call attention to three new tweeters. I maybe wrong, but I believe @rednephron, @ThePeanutKidney and @KatieKwonMD were all tweeting their first KidneyWeek. It is great to see new tweeters, especially ones who are so good at their craft. Welcome to the community.

Impressions is number of tweets times number of followers. Mentions is the number of tweets where an individual is mentioned along with the hashtag #KidneyWk13. To me this is the most important metric, since it indicates tweets that are generating interactions, through retweets and replies.

Pushing the twitter at #kidneywk13 pic.twitter.com/BWNoNKeMdR
— Joel Topf (@kidney_boy) November 6, 2013

The summary statistics show increasing twitter use at the meeting. Here are 2013's numbers compared to 2011 and 2012:

Tweets and participants are rising.

I also did a fair amount of blogging:

• KDIGO App — Past, Present and Future
• Coronary, getting to the heart of AKI
• ZS-9, A Potassium Binder That is Tested and Works
• HDPAL
• Plenary Sessions
• Lori Hartwell and the President’s Award
• Need an organ? Print an organ
• Looking at our data through genetic tinted glasses

I showed my poster on the nephrology blogosphere:

And I was invited to present my NephMadness abstract during an oral presentation. What an honor. I don't have any photos but I did a screen cast of the presentation:



Nephmadness Unplugged is available here.

So now that we know that ZS-9 lower potassium, how much do you think it will cost?

One of the only positive trials at Kidney Week's Late Breaking Trials Session was ZS-9, a novel potassium binding crystal that hopes to take the place of Kayexalate (Sodium Polysterene) in the hyperkalemic cocktail.

I wrote about the trial for eAJKD and was quoted in an article for MedPage Today.

Here is the skinny:

• ZS-9 uses potassium specific pores to bind potassium rather than a cation exchange resin. It is highly specific for potassium, especially when compared to SPS.
• In the phase 2 trial 10 grams lowered the potassium by 0.04 mEq/L per hour
• In the phase 3 (753 patients!) trial the 10 gram dose lowered the potassium 0.78 mEq/L in 14 hours
• No diarrhea
• GI side effects were equal in the placebo and drug arms

I suspect this drug is on a smooth glide path for approval. My question is how expensive will it be? My guess is $200 per 10 grams. Please add your guess or over-under bet to the comments or @kidney_boy on Twitter.

Tolvaptan, ADPKD, and lack of vision at the FDA

About a year ago the ASN Kidney Week hosted the most exciting Late Breaking Trial Session I have attended. The session included the first public disclosure of the EVOLVE trial and the incredibly exciting results from the TEMPO 3:4 trial. I blogged about this for eAJKD and felt then, and still feel now, that this was an incredible breakthrough for nephrology. Unfortunately that announcement may ultimately be the high point for tolvaptan. In April the company acknowledged previously unsuspected liver toxicity. Then in August the FDA denied the application for an indication for ADPKD. Tolvaptan is still approved for hyponatremia and doctors can always prescribe the drug off label but the drug is so expensive I think few patients will be able to get it approved by their insurance companies leaving them to face the $273,000/year bill alone. I always suspected that Otsuka would change the price of the drug when they got a second indication for the drug that changed it from a short-term, in-house drug to a chronic out-patient indication. We may never know.

This is the second significant set back for tolvaptan. Otsuka had investigated it for heart failure with the flawed (in my mind) Everest Trial. Tolvaptan never sought an indication for heart failure because their trial was negative. This is what makes the FDA’s decision so upsetting, the TEMPO trial was positive, the drug met its primary end point (P=0.001), it slowed cyst growth. The secondary end-point, and more clinically relevant end-point, of decreased change in GFR was also positive (P=0.001).

Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P=0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P=0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P=0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).

Side-note about the choice of change in kidney volume rather than change in GFR for the primary end-point: This was used because ADPKD is such a slowly progressive disease that investigators feared if a treatment was required to slow the change in GFR, it would be prohibitively expensive and slow to evaluate therapies. The change in kidney volume was adopted by the ADPKD research community as an acceptable intermediate end-point after observational imaging studies found a tight relationship between change in kidney volume and renal prognosis.

When I heard about the denial  I figured the liver toxicity must have much more severe than I suspected. That turns out not to be the case. Bill Brazell (Bill is a former board member of the PKD Foundation and reader of PBFluids, who was at the FDA hearing) described the liver toxicity founding the TEMPO trial:

A small number of patients experienced potentially important elevations of liver enzymes (4.9 percent, compared to 1.2 percent of those who took a placebo), but the panel focused for hours on the simultaneous elevations in both liver-enzyme levels and bilirubin that occurred in just three patients out of the 860 who took the drug. In all three, the elevations occurred within 18 months. After those patients stopped taking tolvaptan, their levels returned to normal. No one suffered permanent damage

Certainly tolerable to my eyes, especially considering the health implications of dialysis and kidney transplant.

The thing that frustrates me the most is that there are no other proven treatments. We have nothing to offer our patients that works, the only effective therapy was denied approval. Silly FDA what do they expect these patients to do?

I hope Otsuka stays the course, provides additional outcomes data so we can get this approved and I hope the FDA opens it's eyes and begins to see that in the absence of perfect we should accept good.

The article I linked to by Bill Brazell is an excellent discussion of the same issue from a patient perspective. Read it.