Tag: hypertension

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More questions from the minds of the M2s at OUWB

The minds of OUWB continue to provide thoughtful questions.
My roommate and I have encountered a question regarding the content on Sodium/Water Balance and also its application to SIADH. We have been using some outside resources to supplement the learning in class, and I feel that they have been somewhat contradictory in these 2 scenarios. The following are the scenarios that I am trying to think through
1) Patient eats a high salt meal, increasing total body Na+, resulting in an increase in ADH release (via increased plasma osmolarity) and eventually reaching baseline Na+ concentration and osmolarity at a higher ECV. Now, the increase in ECV would result in a down regulation of Sympathetic NS and RAAS; however, what I am hearing is that this down regulation would just return the kidney to Na+ in = Na+ out and would not actually return the individual to the original ECV. So, my question is how does this person get back to original ECV? What I am reading is that the person will continue to operate at this higher ECV until sodium restriction takes place. However, I am wondering how decreased RAAS (decrease aldosterone – decrease Na+ reabsorption – increase sodium excretion) wouldn’t do this, and also if pressure natriuresis wouldn’t do this also? Basically, why don’t these mechanisms do the work automatically, and why do you have to sodium restrict?
You have it right. That is the currently accepted understanding of sodium metabolism. It is not quite complete, because, though some subjects increase their blood pressure with increased sodium intake, not all patients increase their blood pressure. As to why the renin-angiotensin aldosterone system does not down regulate itself sufficiently to fully correct the volume overload situation, it is not well understood. The sodium regulating systems in the body strive to match sodium absorption with sodium excretion. With an increase in sodium intake there will be a modest expansion of the extracellular compartment until the sodium excretion is upregulated to match sodium intake. We can see evidence of the increase total body sodium with an increase in body weight associated with increased sodium intake.
2) In SIADH – high levels of ADH cause increased water reabsorption but euvolemic hyponatremia. Fitting in with my previous questions in the earlier scenario, how does the patient maintain euvolemic status? If increased water reabsorption occurs and the ECV is increased, the same down regulation of Sympathetic NS and RAAS would occur. Now, the outside resources in this case state that a decreased RAAS would actually cause increased sodium excretion that would allow for increased water excretion that would maintain euvolemic status. This makes sense because then the hyponatremia that results is not only an effect of the dilution from increased water reabsorption, but also from the increased excretion of Na+. But, this goes directly against the whole logic of needing to sodium restrict in the earlier case (i.e. RAAS can’t do the work to return the individual in scenario 1 back to a normal ECV).
So again you are well versed in what is happening in SIADH. SIADH is largely euvolemic and largely is a situation where patients are in sodium balance, i.e. sodium = sodium out. However if you do meticulous metabolic balance studies you will find that patients do gain weight during SIADH. There is excess water and this does serve to expand the patient’s extracellular volume. This also will suppress the renin-angiotensin-aldosterone-system so that patients will get a modest increase in urine sodium excretion. But I don’t quite understand how you think this is any different than the first scenario. There is a modest increase in sodium excretion but in the presence of continued unremitting ADH activity the patient continues to deal with the modest increase in volume. So like the first scenario, the modulation of the RAAS is unable to fully restore euvolemia.
For more on SIADH and volume status see this post.
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Adding a little Usain Bolt to SPRINT

The SPRINT trial was a home run. The study showed compelling data that lowering blood pressure dramatically below what we were previously targeting was both well tolerated and yielded huge benefits to patients.

Now there are some questions to the method of blood pressure assessment and how this can be compared to previous blood pressure trials, but I believe that the BP assessment used in SPRINT is more reproducible in offices than the standardized BP typically used in trials that no one howls about (you mean your MA does not follow a 12 step checklist when checking patients in?).

One of the important corollaries that I emphasize when I teach SPRINT is that the study enrolled a very specific patient and we don’t know just how generalizable these findings are:

  • 50 years of age
  • Systolic blood pressure of 130 to 180 mm Hg
  • Increased risk of cardiovascular events defined by one or more of the following: 
    • Clinical or subclinical cardiovascular disease other than stroke
    • Chronic kidney disease, excluding polycystic kidney disease, with eGFR of 20 to 60
    • 10-year risk of cardiovascular disease of 15% or greater on the basis of the Framing- ham risk score
    • Age of 75 years or older
  • Patients with diabetes mellitus or prior stroke were excluded
After you accept the all of these concerns and limitations you are left with a study that reduced the risk of death by 27%. NNT for the primary outcome was 62. This is pretty darn good in medicine.
But when counseling a single patient, it is not very compelling. You have to expose 62 people to multiple drugs and the risks of over treatment in order to save one life. Those other 61 people, are all exposed with no benefit. This is just the nature of internal medicine. All we can do is give out a handful of pills in order to load the dice in patient’s favor. No guarantees. Just better odds.
But what if I told you I had a way 
to reduce that NNT from 62 to 26?

Is that something you might be interested in?
Francis Wilson, is pushing the data. He has dissected the SPRINT database further and can select patients that benefit from the aggressive blood pressure reduction while excluding those that won’t. He calls it an Uplift Model to Personalize Intensive Blood Pressure Control. This system allows him to reduce the NNT from 62 to 26. 
This is Wilson’s entry in the NEJM SPRINT Data Analysis. The voting is open until February 28th, go check out the site and vote for the best one, or just vote for the nephrologist.
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Down goes SYMPLICITY.

SYMPLICITY-3 was Medtronic’s play to get into the hypertension business. They have a device that allows physicians to apply burn the sympathetic nerves of the renal arteries and lower the blood pressure. In a previous randomized trial it worked and SYMPLICITY-3 was what they were going to take to the FDA to get approval.

I started the day with our local hypertension guru explaining the inclusion criteria for Symplicity-4. An hour later this hit the wire:

Full press release

I was a huge fan of renal denervation and a bit of me died when the tweets started flying. Our local Symplicity PI says that the follow-up study with looser enrollment criteria, SYMPLICITY-4, has been cancelled. MedTronic supposedly is still going to carryout a trial of renal artery sympathetic nerve ablation in heart failure. If that is positive then it is possible the field will carry on, but if they abandon that, it may be lights out for the entire concept.

First CORAL, now SYMPLICITY 3. It’s been a bad couple of months for the renal arteries. They should get a better PR person.
— Joel Topf (@kidney_boy) January 9, 2014

Some thoughts on simplicity 3. The trial was on patients with severe resistant hypertension: office blood pressure over 160 on three blood pressure medications. These are hardcore hypertensives. This may not be an appropriate crucible to test the hypothesis of weather this works.

Thought two is that sympathetic discharge is thought to drive a lot of the hypertension in CKD and ESRD. (See this, this, and most importantly this editorial review)  So maybe when SYMPLICITY-3 excluded patients with GFR’s less than 45 they were excluding the very patients where the treatment would be most effective.
Thought three is that maybe in an effort to increase enrollment there were more inexperienced doctors doing the ablation. Unlike renal artery and coronary artery stenting there is no convenient sympathetic nerve ablation analog to TIMI-3 flow. At the end of the procedure the team has no idea if they successfully and adequately ablated the nerves. This could be a confounder. 
It will be interesting in subgroup analysis pif they find a signal pointing to efficacy being related to operator experience or a signal to better efficacy with worse GFR.
I blogged about SYMPLICITY here. Here is what Renal Fellow Network wrote about renal denervation when it was one of the top stories on 2010 and in an insightful post by Matt Sparks. 
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AASK: a cautionary tale for bardoxolone?

Robert Leversee had some questions regarding my presentation on diabetic nephropathy. You can see his concerns in the comments after the post. he was specifically concerned about this slide.

Robert felt it minimized the GFR gains found with bardoxolone. What is not clear from the deck is that 56 weeks, represents the GFR one month after stopping the drug. In the lecture, I pointed out that patients that were on bardoxolone all had a higher GFR than at baseline, while patients randomized to placebo had a lower GFR.

As a reminder, the primary end-point of the study was the change in GFR at 24 weeks and that was dramatic.

The reason I included the slide showing the 56 week data was my concern that bardoxolone may be pulling a creatinine slight of hand. My personal concern is that the changes in GFR are due to simple hemodynamic changes like were seen with amlodipine in AASK.

AASK was a trial of hypertension therapy in African Americans with a renal end-point rather than a cardiovascular end-point that are more common in hypertension trials. The trial is a two by three design with two blood pressure targets (MAP 102-107 vs <92) and three blood pressure medications (amlodipine, ramipril, metoprolol).

The data is difficult to interpret because the amlodipine caused an acute hemodynamic-related bump in the GFR, but after 12 months the loss of GFR in the amlodipine group was faster than with ramipril. The study designers designated co-primary end points, a total change in GFR and a chronic change in GFR that ignored the initial 3 months.

Ramipril was superior to amlodipine in the chronic phase but not in the total change in GFR. Though this ambiguity was not represented in the conclusions of the trial:

The fact that amlodipine improved renal function for one year makes me nervous about the one year duration of the bardoxolone study. Thankfully BEACON is in full swing enrolling patients so a definitive answer is just ahead.
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We’ve got one! Finding a functional adrenal adenoma

A year ago, a slender, 40 year old, white female presented to my clinic with new onset elevated blood pressure. The hypertension was discovered during a routine visit for a minor injury. The family practitioner refused to believe the vitals and kept having the patient return for follow-up visits before resigning himself to the diagnosis. Surprisingly, this otherwise healthy woman, was resistant to multiple medications. He began to suspect a more sinister diagnosis and initiated a work-up for secondary hypertension and referred her to me.

The initial work-up showed a aldosterone of 16 but the renin was not done. She also had modestly elevated metanephrines, but not high enough to suggest a pheochromacytoma. Her blood pressure typically ran 140-160/100 with labetalol 100 mg bid, but she admitted to being forgetful regarding her medications.

One of the findings that stood out for me was the hypokalemia on the initial labs

We repeated the renin-aldo ratio and did a EKG. Unfortunately she had LVH. For me, this ruled out white coat syndrome. The demonstration of end-organ damage also helped the patient see that this condition was “real” and after that she was compliant with the medical therapy.

The repeat Aldo was only 3 with a fully suppressed renin at 0.15. This is an aldosterone-renin ratio (ARR) of 20, however, I was taught a low total aldosterone ruled this diagnosis out. In other words, one needs an elevated aldosterone, not just a suppressed renin to make the diagnosis of primary hyperaldosteonism. This always made sense to me but the Endocrine Society states that this is not always true and questions the requirement for a high aldosterone:

Against a formal cutoff level for aldosterone are the findings of several studies. In one study, seated plasma aldosterone levels were less than 15 ng/dl in 36% of 74 patients diagnosed with PA after screening positive by ARR defined as more than 30 and showing failure of aldosterone to suppress during fludrocortisone suppression testing (FST), and in four of 21 patients found by AVS to have unilateral, surgically correctable PA.

Her potassium remained low at 3.1 despite potassium supplementation. She was breast feeding at the time so we did not use an ACEi or ARB and were successfully treating her blood pressure with a combination of nifedipine XL and labetalol.

The low aldosterone appeared to rule-out primary hyperaldo but with the unexplained hypokalemia I ordered a third ARR and hit pay-dirt

An ARR of close to 300 with a sky-high aldosterone of 29. Remember, when you calculate the aldosterone-renin ratio make sure the units are correct:
  • aldosterone in nanograms per deciliter
  • renin measured as plasma renin activity (PRA) in nanograms per milliliter per hour
With a positive ARR, the endocrine society recommends a confirmatory test. There are four recommended tests, all of which are variations on attempts to suppress endogenous aldosterone via sodium loading or fludrocortisone suppression. I did not do this. I feel that the critical diagnosis to make is the functional adenoma that is surgically curative. Whether the patient has bilateral hyperplasia or simply aldosterone driven hypertension that doesn’t meet the criteria for primary aldosterone is not important to me because I’m going to treat both of those conditions identically, with spironolactone or eplerenone.

So we proceeded with the work-up for a functional adenoma and sent her for a CT scan. We found a 1 x 2 cm left adrenal mass.

Here is where it gets tricky. This sounds like a functional adenoma, however functional adrenal adenomas are rare diagnosis, and even in the presence of documented hyperaldosteronism, non-functional incidentalomas are too common (0.35-5%) to assure that a CT finding of an adrenal mass represents a functional adenoma. Following a CT scan, you can neither rule-out nor rule-in the diagnosis of a surgically correctible functional adenoma. Patients still need to get adrenal vein sampling. Here is the experience from University of Texas Southwestern:

Twenty patients had unilateral CT abnormalities, and 14 (70%) of them lateralized to the same side (concordant). Of the remaining 6 patients with unilateral CT abnormalities (3 left and 3 right), 1 patient each lateralized to the opposite side and 2 patients each had bilateral hypersecretion. Only 5 of 15 patients (33%) with bilateral CT abnormalities showed concordant bilateral aldosterone hypersecretion. The other 10 patients (67%) demonstrated unilateral hypersecretion. Of the 5 patients with normal-appearing adrenal glands on CT, 1 patient each lateralized to 1 side, and the other 3 patients had bilateral hypersecretion.

The authors did not provide a 2×2 table to determine sensitivity or specificity (insert rant regarding surgical literature here) so I put one together. This is how I interpreted the data above:

  • Positive test: 20 with unilateral findings, 14 true positives and 6 false positives (I considered the CT scan identifying the wrong affected adrenal as being a fail)
  • Negative test: 15 patients with bilateral findings, 5 were true negatives and 10 were false negatives
  • Negative test: 5 patients with normal adrenals, 2 lateralized, false negatives and 3 true negatives
The two-way table looks like this:
What? You’re still using Epocrates’ medical
calculator? Don’t be a tool, get a tool, MedCalc
It should be apparent that a CT scan looks truly terrible at diagnosing a functional adenoma. A negative predictive value of only 40%. Ughh! Note: these numbers assume the adrenal vein sampling is a valid gold-standard.

We sent her for adrenal vein sampling to see if the aldosterone secretion lateralizes. It did with a 20-fold increase in aldosterone on the left side. Because aldosterone levels can be unreliable due to dilution and technique, it is recommended that an adjusted aldosterone (aldo/cotisol) exceed the contralateral adrenal by three fold. In our case, it was 10-fold.

She went for an laparoscopic left adrenalectomy and is now normotensive off all medications.

The endocrine society had published consensus recommendations on screening, diagnosis and treatment of primary hyperaldosteronism. I love it when important articles are available in PDF for free.

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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.

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Doctors are like the pyromaniac fireman

A patient, on Friday, explained that doctors are like the pyromaniac fireman who when he’s not putting out fires is secretly setting them so he can fight them.

Ridiculous?

Well, on that same day I saw a patient who previously had uncontrolled blood pressure. I had gotten her blood pressure under control with a combination of torsemide, spironolactone, carvedilol and amlodipine. Her office blood pressure  was 123/72 with a heart rate 86. During the visit she told me that she had fallen three times in the last few weeks. Her standing blood pressure was 96/53 with a heart rate of 96. On her previous visit I had extinguished and set a new fire at the same time. Her previous blood pressure had been in the 150s. Controlling her blood pressure was the right thing to do medically but undoubtably it was the cause of her recent falls and my attempt to trim long term morbidity resulted in her being exposed to increased short term morbidity.

Pyro fireman.

Another patient I saw has advanced diabetic nephropathy, CKD stage 4. He needs an ACE inhibitor or an angiotensin receptor blocker to stave off dialysis, unfortunately he cannot tolerate them because of recurrent of hyperkalemia. A few months ago I added a loop diuretic to control edema and hypertension and a couple of weeks ago he returned for a follow-up. His potassium was 4.6 mmol/L. The loop diuretic had increased kaluresis enough that I felt that I had some room to give another trial of renin-angiotensin blockade. Yesterday I received a call informing me of a critically high potassium in this patient.

Pyro fireman

These cases are not limited to clinical medicine, the ACCORD trial tried to determine if normalizing the Hgb a1c in diabetics reduced cardiovascular mortality. Better diabetic control caused increased total mortality.

In OnTarget the combination of an ACE inhibitor and an angiotensin receptor blocker was tested to see if it could reduce cardiovascular events. The  combination was a favorite among nephrologists as a way to stave off dialysis in patients with persistant proteinruia despite single drug renin-angiotensin blockade. Dual blockade was the fashion mostly in response to the subsequently retracted COOPERATE trial. In OnTarget there was significant increase in renal dysfunction with dual ACEi/ARB and a trend toward increased dialysis:

“…whereas the rate was increased in the combination-therapy group, with 65 patients (0.8%) undergoing dialysis”

Pyro fireman, academic style. 
It’s what makes medicine so difficult, the more you try to help your patients the more you expose them to unintended, adverse reactions. I feel that so little of medical education prepares us to balance these competing end-points, how do you judge what is an acceptable risk of hyperkalemia, how do you balance the risk of hypertension versus the risk of orthostatic hypotension?
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Patient called me with a blood pressure of 170

He has resistant hypertension that has been well controlled since we added spironolactone. He reported that his systolic blood pressures were between 170 and 205 over the last three hours. In the morning his blood pressure was 120 and for the last week he had been getting blood pressures of 115 to 135, trending toward the lower end of that range.

I told him that I wasn’t worried about the isolated spike in blood pressure. The goal of therapy is to get the average blood pressure down and that chasing individual isolated episodes of hypertension becomes a hopeless game of whack-a-mole.

The treatment of hypertension is like trying to change the climate, not control the weather.

What do you do when they get this phone call? Do you chase after elevated blood pressures with prn clonidine? Is there an evidence based approach to this?

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iPhone: the ultimate tool for patient empowerment.

I walk into a patient’s encounter today and he is reading Twitter on his iPhone 4. We exchanged Twitter handles and began discussing his diabetic nephropathy.

I ask how his blood sugars have been and he fires up Glucose Buddy and proceeds to show me all of his blood sugar reading since March of 2010. Then he e-mails me the data.

When we discuss blood pressure, he fires up the iPhone again and shows me iBP. When he sends me his home blood pressure readings I get the choice of receiving them as text, html or CSV. Awesome.

Glucose Buddy for the iPhone
iBP for the iPhone

Here’s is what the e-mail output looks like:

This was the first patient I have met who is using his phone to document his health. I hope this is a trend because I am sick of patients telling me that they wrote down all of their blood pressures but left the notebook at home. It’s nice to see a cell phone do something other than interrupt a clinical encounter.
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Great site with lots of resources on hypertension

The Michigan Department of Community Health has put together a great resource, High Blood Pressure University, which links to resources all about hypertension. The links are divided into three campuses:

  1. Professionals for medical providers
  2. Community for church’s and community organizations
  3. Patient for people with high blood pressure
Take a look at the Vital Signs fact sheet from the professional campus. This is from the CDC and summarizes some of the broad epidemiology of lipids and hypertension.