#NephJC this Tuesday, Jan 12 and Wednesday, Jan 13: SPLIT trial

We are going deep on this landmark RCT of saline versus balanced solutions.

JAMA has made the article open access for NephJC. Follow this link. JAMA is also going to offer prizes for the best tweet from the Jan 12th and Jan 13th discussions so warm up those twitter clients!

Spironolactone primer

Resistant hypertension is an important clinical problem. It is commonly defined as inadequate blood pressure control despite use of three antihypertensive agents of different classes at optimal dosages; one of the three should be an appropriately dosed diuretic. About 10-15% of hypertensive patients have resistant hypertension.

The magical powers of aldosterone antagonists first started to be publicized in the late 90's and in 2003 Calhoun showed a dramatic effect among patients with resistant hypertension:

“A total number of 76 subjects were included in the analysis, 34 of whom had biochemical primary aldosteronism. Low-dose spironolactone was associated with an additional mean decrease in BP of 21 ± 21 over 10 ± 14 mm Hg at 6 weeks and 25 ± 20 over 12 ± 12 mm Hg at 6-month follow-up. The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors, ARBs, and diuretics.”

This was backed up by additional observational data as part of the ASCOT trial experience. The investigators found dramatic efficacy from modest doses of spironolactone among the 1,411 patients that received spironolactone as a fourth line agent:

“During spironolactone therapy, mean blood pressure fell from 156.9/85.3 mm Hg (SD: ±18.0/11.5 mm Hg) by 21.9/9.5 mm Hg (95% CI: 20.8 to 23.0/9.0 to 10.1 mm Hg; P<0.001); the BP reduction was largely unaffected by age, sex, smoking, and diabetic status. ”

The first randomized, placebo controlled trial in resistant hypertension was published in 2011. The ASPIRANT trial (PDF) showed a more modest, but still clinically significant reduction blood pressure.

An important caution when looking at spironolactone data is that it appears that black patients  are more sensitive to increases in aldosterone, so one could predict more modest blood pressure improvements with spironolactone in a European population. See Tu et al. (Full text).

Another critical aspect of resistant hypertension is addressing non-adherence. 

“A mass spectrometry urine toxicology screening of antihypertensive drugs reported that 53% of patients with resistant hypertension were non-adherent to treatment. Of these, 70% were incompletely adherent and 30% were completely non-adherent. Reduced adherence was not attributed to a particular antihypertensive class. Another urine analysis study found that 23% of patients referred for renal denervation were completely non- adherent to their prescribed antihypertensive treatment.”

— From Rossignol et al. The double challenge of resistant hypertension and chronic kidney disease.

This is why PATHWAY-2's attempt to measure minimize non-adherence is so important.

This week's chat on PATHWAY-2 represents the first randomized controlled trial against an active control group. The fact that aldosterone rises above other fourth line agents to provide meaningful advantages in the treatment of resistant hypertension is important.

We are coming to a new age in hypertension management. On November 9, at 2:00 PM at the AHA meeting in Orlando the SPRINT Trial results will be released. This will almost certainly result in a wave of more aggressive blood pressure control. Almost simultaneously we now have access to the first of the next generation potassium binders, patiromer. This brings the hope of avoiding the most frightening of the side effects from aldosterone antagonists, hyperkalemia. These three seemingly unrelated events are going to be major influences on the treatment of hypertension going forward.

The IV versus PO iron conundrum for Tuesday and Wednesday

Joel said he would write the summary. Suzanne said she would write the summary and in the end wires got crossed and they both wrote the summary. Sigh. We are ardent conservationists and strongly believe that no part of the buffalo should go to waste so here is Dr. Norby's summary of this week's NephJC article:

A randomized trial of intravenous and oral iron in chronic kidney disease

Rajiv Agarwal, John W Kusek, and Maria K Pappas

Kidney International advance online publication 17 June 2015

doi: 10.1038/ki.2015.163

BACKGROUND

Anemia is common in patient with stages 3-5 chronic kidney disease (CKD) due to decreased erythropoietin production as well as iron deficiency, including the functional iron deficiency that can develop while using erythropoiesis-stimulating agents (ESA).

The KDIGO Clinical Practice Guideline for Anemia in CKD recommends (grade 2C) the use of IV iron in adult patients with CKD note yet on dialysis if 1) an increase in hemoglobin level is desired to avoid or minimize blood transfusions and ESA use and/or to alleviate symptoms potentially related to anemia and 2) TSAT is ≤30% and ferritin is ≤500 ng/ml. The Guideline also states that a 1-3 month trial of oral iron may be considered for patients not yet on dialysis.

Safety and risks of IV iron use in the non-dialysis CKD population are not fully understood although an author of the current study, Agarwal, along with other colleagues previously demonstrated that IV iron use can lead to increased oxidative stress, endothelial damage, and even renal injury.

The hypothesis of the current study, REVOKE (randomized trial to evaluate intravenous and oral iron in chronic kidney disease), was that IV iron would result in greater decrease in kidney function compared with oral iron in iron-deficient patients with moderate to severe CKD not yet on dialysis.

METHODS

Design: open-label, parallel-group, active-control, single-center randomized trial

Setting: A safety-net hospital and a VA Hospital, both in Indianapolis, IN; August 2008 – November 2014.

Inclusion criteria:

• ≥18 years old
• eGFR 21-60 ml/min/1.73 m2, not on dialysis
• Hemoglobin <12 g/dl
• Serum ferritin <100 ng/ml or serum transferring saturation <25%

Exclusion criteria:

• Pregnant or breast feeding females
• Known hypersensitivity to any intravenous iron, iothalamate meglumine (Conray 60, Malinckrodt) or iodine
• Severe anemia that required imminent red blood cell (RBC) transfusion (Hgb <8 g/dL) or the potential need for imminent RBC transfusion (e.g., active bleeding) 
• Persons with acute kidney injury
• History of intravenous iron use within the month prior to screening
• Iron overload (serum ferritin >800 ng/nl or transferrin saturation >50%)
• Anemia not caused by iron deficiency (e.g., sickle cell anemia)
• History of surgery or systemic or urinary tract infection within the past month
• Organ transplant recipients
• Persons currently being treated with immunosuppressive agents

Randomization and Blinding: 1:1 ratio, using computer generated permuted blocks, randomized to either oral iron or IV iron using concealed opaque envelopes

Primary outcome: 

• Difference between treatment groups in slope of mGFR decline from baseline to 2 years adjusted for the log of baseline urinary protein/creatinine ratio compared with baseline at 8 weeks, 6 months, 12 months, and 24 months after randomization.  

Secondary outcomes:

• further adjustment of the primary outcome for age, sex, race (Black vs. non-Black), angiotensin-converting enzyme/angiotensin receptor blocker use, and the presence or absence of cardiovascular disease (all determined at baseline)
• between-group % change in proteinuria from baseline to 8 weeks
• difference between hemoglobin response between treatment groups
• change in KDQOL

Statistical analysis:

• Intention-to-treat, if the participant received at least one dose of study medication
• Linear mixed model with GFR as outcome variable
• Assumptions: mean rate of decline in GFR of 4 ml/min per 1.73 m2 per year in the oral iron group and a 50% greater decline in the IV iron group and a cumulative rate of dropout of 25%
• Recruitment target of 100 patients for each treatment group with a minimum duration of follow-up of 2 years to achieve 82% power to detect hypothesized difference in decline in kidney function at the 5% level of significance
• 2-sided t-test considered significant for p<0.05

INTERVENTION

Participants were treated over 8 weeks beginning at the time of randomization. Those randomized to the IV iron group received iron sucrose 200 mg IV over 2 h at weeks 0, 2, 4, 6, and 8. Participants randomized to oral iron were counseled to take ferrous sulfate 325 mg three times daily for 8 weeks.

RESULTS

Trial was terminated early due to higher serious adverse event rate in IV iron group (199 per 100 patient years) compared with oral iron group (168.4 per 100 patient years); adjusted incidence rate ratio 1.60 (1.28–2.00), P<0.0001.  Statistically significant increases in infections and cardiovascular events were observed. In particular, the incidence of lung and skin infections was increased 3-4x and of hospitalization for heart failure was increased 2x in the IV iron group after adjusting for the more favorable baseline characteristics in that group.

Decrease in mGFR between groups was similar between both groups, -3.6 ml/min per 1.73 m2 per year for oral iron group and -4 ml/min per 1.73 m2 per year for IV iron group. 

Hemoglobin increase, change in proteinuria over time, ESA use, and need for blood transfusions were not significantly different in the 2 groups. KDQOL domain scores did not change over time in either group.

DISCUSSION

Since this study was limited to patients with stage 3-4 CKD not yet on dialysis, results cannot be generalized to patients already on dialysis. 

The primary outcome of comparing decline in mGFR between groups could not be evaluated due to early termination of the study due to safety concerns related to increased risk of infection and cardiovascular events.  While additional studies evaluating the long-term safety of IV iron use in this population are necessary, should the oral route be preferred when initiating iron supplementation in patients with stage 3-4 CKD?  Moreover, based on the time course of hemoglobin increase in patients in the oral iron group of this study, it would seem reasonable that a trial of oral iron be given to patients with CKD not yet on dialysis for a full 3 months, rather than at least 1 month and up to 3 months as suggested in the KDOQI guidelines.

Being Mortal: Chapter Seven

I did not like the Immortal Life of Henrietta Lacks. I thought the story of the HeLa cells and the story of Ms Lacks and her family was interesting and introduced me to a history of medicine that had previously been invisible. The story was fascinating but the book fell flat because of the way that the author, Rebecca Skloot, inserted herself into the story. Every chapter that was told from Ms. Skloot's point of view came across as having low stakes and was generally uninteresting. I finished the book with the belief that this point-of-view writing was a poor technique for non-fiction.

I was wrong. While it didn't work for the Immortal Life, Dr. Gawande uses it to dramatic effect in Being Mortal. Gawande is a recuring character in the book and the previous chapters we are taken on his journey from a doctor with conventional western medicine understanding about dying o a much deeper and richer understanding. In chapter seven, however, Gawande changes from a researcher to an active participant as his dad suffers a devastating illness and he needs to put his new found knowledge of hospice, assisted living, palliative care and end-of-life decisions to use.

“The scan revealed a tumor growing inside his spinal cord.
That was the moment when we stepped through the looking glass. Nothing about my father’s life and expectations for it would remain the same. Our family was embarking on its own confrontation with the reality of mortality. The test for us as parents and children would be whether we could make the path go any differently for my dad than I, as a doctor, had made it go for my patients. The No. 2 pencils had been handed out. The timer had been started. But we had not even registered that the test had begun.”

In 2006, Gawande's father, Dr. Atmaram Gawande, went for an MRI to diagnose a slowly progressive pain in his neck associated with numbness in his left hand. The scan revealed a spinal cord tumor.

The Gawande's then consulted a pair of neurosurgeons, one in Boston and one at the Cleveland Clinic. Gawande explains the bedside manner of both doctors by describing a paper by the medical ethicists Linda and Ezekiel Emmanuel that described the three type of relationships doctors could have with patients:

1. Paternalistic
2. Informative
3. Interpretive

Gawande describes all three types. The first is the doctor we read about from the 50's. The all knowing God-like figure that tells the patients what they should do and does not discuss options that the doctor does not think are optimal. We would like to think that we are past this but in reality it is more common than we care to admit. 

The second type, informative, is the opposite of the paternalistic relationship. The doctor informs the patient of the facts and figures needed to figure out the best option and then lets the patient make the decision. Gawked explains that this works best for for simple issues with clear choices and straightforward trade-offs. The more complex and emotional the issue the more this method breaks down.

The Emmanuels third option, interpretive, is a hybrid of the two earlier models. “Here the doctor’s role is to help patients determine what they want. Interpretive doctors ask, “What is most important to you? What are your worries?” Then, when they know your answers, they tell you about the red pill and the blue pill and which one would most help you achieve your priorities.”

The chapter winds its way through his father's illness and we see Gawande struggle to use the lessons he has learned to help his father. They make some excellent decisions, they make some mistakes, they meet some excellent physicians and some clunkers. The face decisions on hospice, medical decision making and hospice. Despite some missteps, by the end of the chapter his father is in hospice and living a surprisingly full life.

“But walking slowly, his feet shuffling, he went the length of a basketball floor and then up a flight of twenty concrete steps to join the families in the stands. I was almost overcome just witnessing it. Here is what a different kind of care—a different kind of medicine—makes possible, I thought to myself. Here is what having a hard conversation can do.”

Being Mortal: Chapter Five

Francesco Iannuzzella wrote the summary for chapter 5.

Chapter Five: A Better Life

In order to maintain the integrity of their social network, and enjoy a higher quality of life, most elderly people would prefer to remain in their homes as long as possible. Nevertheless, at some time during their life, many of them will be admitted to a nursing home.

Traditionally, nursing homes have been organized to provide an efficient medical care to frail and impaired individuals with little or no attention given to quality of life. Fortunately, the deepest changes usually start on a very small scale and one single successful experience can radically change the way of doing something. 

In the beginning of chapter five, Gawande describes the biography of one of these heroes, Bill Thomas, a man who rewrote the manual on how nursing homes operate.

Bill Thomas’s experience began in the early 1990s when he got a new job as medical director of Chase Memorial Nursing home in the town of New Berlin, NY. He was only thirty-one with little or no experience in eldercare. With his newcomer’s eyes, Bill began to question the basic assumptions all had taken for granted since then.

He identified “The Three Plagues” of nursing home existence:

1. boredom
2. loneliness, and
3. helplessness.

Then, he tried to fix them experimenting a new approach to eldercare. His aims were clear: he wanted to replace boredom with spontaneity, loneliness with companionship, and helplessness with a chance to become involved in caring for another being. At the beginning, he didn’t make a great change in everyday Chase Memorial healthcare practice, but he adopted an easy and effective approach to bring life to its inhabitants: he introduced a lot of pets, gardens and children to the nursing home.

“He said, “Now, what about cats?”
I said, “What about cats?” I said, “We’ve got two dogs down on the paper.”
He said, “Some people aren’t dog lovers. They like cats.”
I said, “You want dogs AND cats?”
He said, “Let’s put it down for discussion purposes.”
I said, “Okay. I’ll put a cat down.”
“No, no, no. We’re two floors. How about two cats on both floors?”
I said, “We want to propose to the health department two dogs and four cats?”
He said, “Yes, just put it down.”
I said, “All right, I’ll put it down. I think we’re getting off base here. This is not going to fly with them.”
He said, “One more thing. What about birds?”
I said that the code says clearly, “No birds allowed in nursing homes.”
He said, “But what about birds?”
I said, “What about birds?”
He said, “Just picture—look out your window right here. Picture that we’re in January or February. We have three feet of snow outside. What sounds do you hear in the nursing home?”
I said, “Well, you hear some residents moaning. You possibly hear some laughter. You hear televisions on in different areas, maybe a little more than we’d like them to be.” I said, “You’ll hear an announcement over the PA system.”
“What other sounds are you hearing?”
I said, “Well, you’re hearing staff interacting with each other and with residents.”
He said, “Yeah, but what are those sounds that are sounds of life—of positive life?”
“You’re talking birdsong.”
“Yes!”
I said, “How many birds are you talking to create this birdsong?”
He said, “Let’s put one hundred.”
“ONE HUNDRED BIRDS? IN THIS PLACE?” I said, “You’ve got to be out of your mind!”

Wilma and Libby

The results were extraordinary:

• The number of prescriptions halved
• With a particular reduction in the use of psychotropic drugs
• Mortality fell about 15%.

This was the starting point for a larger program, named Eden Alternative, which over the last 20-years de-institutionalized nursing homes and ultimately lead to the so-called Green House project. Since the first Green House was built in Tupelo, Mississipi, in the year 2000, more than 150 Green Houses have been built in twenty-five states. With no more than twelve residents each, all Green Houses are small and communal with a physical environment made to preserve quality of life, self-sufficiency, privacy, and dignity.

How to explain the Eden Alternative success?

To answer this question, Gawande cites an American philosopher, Josiah Royce (1855-1916), who believed that in order to live a worth living we need loyalty, i.e. a dedication to a cause beyond ourselves. It doesn’t matter if this cause is small (as small as the care for a pet) or large, what matters is that is such a cause provide meaning to one's life. We all need loyalty, and elderly people need it even more.

“The elderly need loyalty to give meaning to both their life and their death.”

They need loyalty to give meaning to both their life and their death. With aging, simple pleasures,  we all take for granted during our adulthood, may become a source of loyalty, a comfort to our pain. To testify to this truth, Gawande reports the interviews tof nursing home residents he met, whose quality of life strictly depends upon simple pleasures: living in a private room, going to the cinema, reading Fifty Shades of Grey, using a computer, preserving social interactions.

Gawande describes his experience visiting two different projects in the Boston area. The first one, it is a new human size retiring community called NewBridges on the Charles with great financial resources due to substantial philanthropic support.  The second project is a subsidized apartment building (Peter Sanbord Place) for low-income elderly people, whose director Jacquie Carson deeply changed to allow her residents to continue to live their own lives.

The chapter ends by returning to the story of Lou Sanders who has deteriorated to the point where he no longer can live in assisted living and is admitted to a nursing home. However, he enters a Green House with private rooms and a thoroughly de-institutionalized philosophy. He rapidly adapts and explains that he knew it was the place for him when he saw that all the rooms were single. Little things can make all the difference.

Being Mortal: Chapter Four

Swapnil Hiremath summarized chapter four, bringing us to the the halfway point. Remember the chat is next Tuesday and Wednesday, July 14 and 15.

Chapter 4: Assistance

“Life is pleasant. Death is peaceful. It’s the transition that’s troublesome.”

— Isaac Asimov

Atul Gawande continues in Chapter 4 with vignettes of frail elderly individuals facing loss of independence, and the difficult choices they face. This time it is the story of Lou Sanders, a gregarious ex-veteran living in a working class Boston neighbourhood. Lou's comfortable life starts unravelling soon after his wife’s passing. As an aside, it is notable how a ‘tipping point’ often is the death of a partner (and though there have been no stories so far of single/unattached individuals, I suspect they would be doing much worse at this stage). [note to self: buy flowers on the way home tonight]. Being a very social person, Lou is adamant in refusing to move to a nursing home ‘full of old people.’ He even forces his daughter to swear to never ship him off to a nursing home. After a heart attack, followed by Parkinson’s and additional falls, he agrees to move in with his daughter Shelley, an extraordinarily supportive and willing caregiver. The realities of the modern nuclear family however intrude, and this transition is not as smooth – unlike the story of the author’s grandfather Sitaram living in a large joint family. The toll of being a full time working professional, homemaker, and also caregiver for her father’s increasing needs proves to be too much for Shelley. Medical problems include hearing difficulty, prostatism, incontinence and continuing falls. The last is exacerbated with postural hypotension (likely due to the autonomic dysfunction common with Parkinson’s – and/or the drugs used to treat it). Lou continues to refuse moving to a nursing home, and is ultimately and unhappily transitioned into an assisted living facility.

The story of assisted living facilities, and how they came into being is one of the amazing stories that make Being Mortal such a compelling story. It is the story of Keren Brown Wilson, and her stroke-struck mother’s plaintive request to her, ‘Why don’t you do something to help people like me?’ Keren mother's request was a plea for autonomy and respect.

“She wanted a small place with a little kitchen and a bathroom. It would have her favorite things in it, including her cat, her unfinished projects, her Vicks VapoRub, a coffeepot, and cigarettes. There would be people to help her with the things she couldn’t do without help. In the imaginary place, she would be able to lock her door, control her heat, and have her own furniture. No one would make her get up, turn off her favorite soaps, or ruin her clothes. Nor could anyone throw out her “collection” of back issues and magazines and Goodwill treasures because they were a safety hazard. She could have privacy whenever she wanted, and no one could make her get dressed, take her medicine, or go to activities she did not like. She would be Jessie again, a person living in an apartment instead of a patient in a bed.”

So Keren and her husband, both academics, sketched out a plan for a new kind of place, and cleared endless bureaucratic and and financial  hurdles to open ‘Park Place’ in Portland, Oregon. It had many innovative, almost radical, components – one of the most important being that the residents were called ‘tenants’, not patients, and had many more rights – such as a locked front door to their apartments.  Despite this increased freedom, there was no trade-off with worsening safety as feared. The state of Oregon made Wilson track data – and it revealed improved outcomes (including satisfaction) with lower costs. In hindsight, much of this is now unsurprising, if we consider Maslow’s hierarchy of needs.

ource: https://en.wikipedia.org/wiki/Maslow's_hierarchy_of_needs#/media/File:MaslowsHierarchyOfNeeds.svg ; used under Creative Commons license.

Much of the research in this area is done by Laura Carstensen, now a Stanford Professor in Longevity, but once a high school educated almost single mother (read chapter 4 for the truly amazing story of how everything changed for her). Perspectives change as the end of life appears closer on the horizon, and comfort and companionship become valued over other ambitions. Unfortunately, the kind of assisted living started by Keren Brown Wilson has now morphed into something else entirely, with very few facilities including the core concepts from her original vision. The fate of Lou Sanders was in one such place. After initially coping and adjusting, the falls and more critical events force Shelley to ‘place’ him in a nursing home...

“a medically designed answer to unfixable problems, a life designed to be safe but empty of anything they care about.”