Who Wants To Live Forever: Mortality Benefits in the Outpatient Setting

It's been three months since the last post. I've been sitting here for the past 5 minutes trying to come up with some witty excuse of why it's been so long but apparently I'm running low on wit today. So no excuses, let's get wit it. 

There are a couple of questions I've found you can hang your hat on in medicine: "What is the patient's clinical presentation?", "Are they stable or not stable?", and today's topic "Will this affect their mortality?" Because in the end, prolonging quality living is something that most doctors and most patients can agree upon. Also, these are great phrases to say when you have no clue what you're doing. Next time you hear me ask one of these questions it's probably safe to assume I'm mentally regrouping. In lieu of this important question we frequently ask ourselves, I've decided to rehash what exact interventions decrease mortality in the outpatient "Big 3" (Diabetes, Cardiovascular Disease (CVD), and Hypertension). The goal here is to have more of a quick lesson and a point of reference in the future and less of a narrative. So you won't be getting any long drawn out stories today (lucky you).

*Credit goes to Mark Johnson as he has given talks like this previously. 

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Data from Yudkin, JS, BMJ 1993; 306:1313.

DIABETES

MORTALITY BENEFIT:

• Smoking Cessation

  • Males: All cause mortality for smokers increased significantly from 2.3% to 19.8% per 1,000 patient years. [1]

  • Females: All cause mortality for smokers increased significantly from 1.1% to 14.6% per 1,000 patient years. [1]

  • Female relative risk of mortality in IDDM smokers = 1.4. Dose dependent response seen. (Prospective cohort for 20 years in Nurses Health Study, 2001) [2]

• Physical Activity
  • Walking 2 hrs/wk reduced all-cause mortality in diabetics by 39% (HR 0.61 [95% CI 0.48-0.78]). Mortality rates lowest for those who walked 3-4hrs/wk (HR 0.46). [3, cited in this review paper]
  • Physically inactive men with DM2 had 1.7x increased risk of premature death compared to physically active men. [4]
  • Systematic review (12 studies) found a HR of 0.6 (CI 0.49-0.73) for total mortality between the lowest and highest fitness levels in DM1 and DM2 patients. Looking further into the study it looks as though <2 hours/wk and >9 hours/wk were the ends of the ranges. [5]

• Blood Pressure Control
  • ACCORD trial (2008): Found NO difference in mortality (in addition to macrovascular outcomes) when comparing goal SBP <120 and <140 in diabetics. [6]
  • ADVANCE trial (2007): Only major placebo-controlled RCT. Evaluated effects of ACE/Thiazide combo medication in moderate-high (<25% 10 yr risk) to very high (>25% 10 yr risk) CV risk diabetics regardless of history of hypertension. Mean SBP was 139 in mod-high risk and 151 in very high risk. No target BP's but end result was roughly 5 point reduction with combo medication compared to placebo. Final mean BP's were 135.74 and 140/76 when both groups combined. Other medications used at discretion of physicians. Found significantly lower rate of CV and all-cause mortality.
    • However, in my opinion the study is poorly made as the results are only applicable if they are pooled. Both the placebo and treatment arms in the mod-high risk groups were under new JNC 8 goal of < 140 mmHg. Only when you combine mod-high and very high risk do you get the mean averages of 135/74 versus 140/76. It's also probably a given that very high risk patients will already have hypertension. [7]
  • HOT trial (1998): Specifically looked at DBP in individuals. Only in diabetics, the RR of CV events was significantly reduced (RR 0.49) in DBP <80 compared to <90. [8]
  • UKPDS (1999): Means of two groups was 144/82 vs. 154/87. After 8-9 years the lower BP group had 32% reduction in deaths related to diabetes. Ten year follow up study showed for each 10 mmHg reduction in SBP there was 12% reduction in diabetic complications including sudden death. Affect maxed at 120 mmHg.
    • Of course this study didn't strictly look at the now standard SBP < 140 mmHg [9]

NO MORTALITY BENEFIT:

• Glucose controlling medications BUT Metformin decreases myocardial infarctions (MI's)
• Statins BUT they decrease MI's.
• ACE inhibitors BUT they decrease renal disease in those with proteinuria and may decrease CV events compared to calcium channel blockers.

UNCLEAR

• Aspirin 
  • 2003 - No difference in mortality or CV outcomes found in subgroup analysis of RCT (1,031 patients). Patients were > 50 years old. [10]
  • 2008 - Japanese RCT (~2,500 patients) found significantly decreased fatal CV and cerebrovascular events in low-dose (0.08%) versus non-aspirin (0.8%) groups. (NNT 139) However, no difference in all-cause death or other CV outcomes. [11]
  • Low dose aspirin not associated with any increased bleeding risks compared to non-diabetic patients. [12]

Summing up the above data. You would be an evidenced based doctor making clinically significant recommendations by telling your patient to walk at least 2 hours a week and ideally up to 9 hours+, quit smoking, and to keep BP somewhere in the <140/90 range. The BP data presented above is somewhat of a moot point when considering that the JNC 8 recommendations simply make the goal <140/90 across the board. No more of the nuanced guidelines for diabetics.

Aspirin is of course less clear when considering raw data versus major guidelines. Preceptors will frequently remind me "are they on a baby aspirin?" and of course I always feel bad for not remembering. But I am less convinced now that it would make a difference. As of 2013, the ADA recommends (p. 59) aspirin in patients with 10-year risk of events >10%. This recommendation pretty much includes all males/females > 50/60 years old with diabetes. Comparing that to USPSTF's recommendation of low-dose aspirin for all males/females > 45/55 years tells me that anywhere in the 45-50 and 55-60 age range is probably fine. I'll probably continue the low-dose aspirin for now while of course weighing risks and benefits but now I'll allow myself some leeway when I forget.

Now that was simply regarding mortality. Of course, there are other clinically significant outcomes that we care about that don't address mortality such as non-fatal macrovascular events and microvascular disease that can affect quality of life (blindness, dialysis). But if it is a matter of life or death for our diabetic patients then there are only 3 tools we can use as physicians. 

Part 2: Hypertension to be continued

Get In Mah Belly 2: Fun Size Food Facts

CALCIUM & VITAMIN D

What originally started as a "fun size food facts" blog has quickly turned into "all you can eat buffet world eating champ facts" blog. I've combined calcium and vitamin D as you really can't talk about one without talking about the other and quickly found out that I bit off more than I could chew. A lot like real life eating for me actually. Much of this might be review for you (especially SFH residents) but it's always good to have a refresher. And since calcium-vitamin D is a pretty dry topic, I have decided to post random pictures of cheese for your viewing pleasure.

If there was a single vitamin or mineral that my mom used to back her opinions on food, it'd be calcium. Every healthy thing in our fridge or pantry was a "good source of calcium", especially foods I hated (looking at you, beans). I kind of think she stole it from the boxes of cereal that would advertise that same statement. In actuality, it's not that hard to get a decent amount of calcium on a traditional American diet. Cheeseburger here. Milkshake there. Metformin for dessert and you're done. But what about more calcium or vitamin D for either the general public or those at higher risk for osteoporosis? 

The now well known landmark study that helped propel the calcium-vitamin D discussion was the Women's Health Initiative (WHI) [1]. In short, the massive study looking at women aged 50-79 years old found a small benefit in terms of bone mineralization but no significant benefit in fracture rate in those taking 1,000mg calcium and 400IU vitamin D supplementation when compared to placebo. [2] The study did have some limitations as it was looking at a general population and not specifically at higher risk patients (decrease calcium-vitamin D in diet, known low bone mineralization) in addition to being a relatively low dose of both. But overall it gave some evidence to the thought that maybe the ol' calcium-vitamin D combo wasn't as potent as once thought.

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There was also another study that also came out in 2006 but this one pointed to some benefit. It was a double-blind five-year RCT that looked specifically at elderly females (>70yo). They were randomized to take calcium carbonate (600mg BID) versus placebo and found that there was indeed a significant decrease in fracture incidence (10.2% vs 15.4%; HR, 0.66; CI 0.45-0.97). But the kicker? It was only seen in those were took their supplements greater than 80% of the time. [3] Surprise - you have to take your medications for them to actually work.

That was 2006. But what did 2007 bring? More evidence for the calcium-vitamin D tag team.

A meta-analysis of 29 RCTs looking at all adults greater than age 50 found a significant decrease in both all fractures (RR 0.88, CI 0.83-0.95; p=0.0004) as well as bone-mineral density. They also note again that compliance was a big component as there was a greater fracture incidence reduction (24%) in those with high compliance (>80% of the time taken). Dose was also a big variable as those taking less than 1200mg had less of a benefit than those taking more than that dose (0.80 vs. 0.94; p=0.006). So what do we take away from this? Again, dose and compliance seem to be major players in preventing fractures in older adults. [4]

So it looks like there's some growing evidence for calcium supplementation in older, compliant adults.

Now what about vitamin D?

Again, looking back at the WHI study. We saw that the combination of calcium and vitamin D yielded no benefit in terms of fracture incidence. One thing to remember is that they studied a relatively low dose of 400IU daily. Looking back at the 2007 meta-analysis above, they found a small but significant incidence reduction in fractures when patients supplemented with 800IU or more versus those with less than that amount (RR reduction 3%, p=0.03). So it might just be a dose dependent thing?

Unfortunately, the years 2007-2010 say no.

From 2007-2010, several studies came out that showed no evidence for fracture incidence reduction in those taking only vitamin D. [5,6,7] These studies mainly looked at all adults greater than age 50 and most studies included in these pooled analysis looked at vitamin D dosages greater than or equal to 800IU. The largest and most recent of these [7], had a mean age of 69.9 years and looked at over 68,000 patients. It found no evidence for either 10 or 20 microg doses of vitamin D (aka 400 or 800IU). Bummer.

But wait! The years 2011-2012 say.... maybe?

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A meta-analysis was done for the USPSTF in 2011 that looked at the potential benefits and harms of vitamin D with and without calcium supplementation [8]. This study ended up showing a significant reduction in fracture incidence for institutionalized patients (RR=0.71, CI 0.57-0.89]) but not in community-dwelling patients when supplementing with calcium-vitamin D. They also found no significant reduction in incidence for any dose of vitamin D. This was the start to the 2013 recommendation by USPSTF, which we'll see in a little bit. On the flip side, an equally large meta-analysis in 2012 showed there was actually a benefit to fracture incidence reduction in higher vitamin D dose supplementation (>800IU) in those 65 years or older. [9]

Ok, let's regroup.

All this back and forth is great and stuff but there isn't a really reliable trend in all of this data, especially for vitamin D - leads us to February 2013, when the USPSTF came out and gave no recommendation for vitamin D and calcium supplementation (Meta-analysis). Specifically, they gave an "I" recommendation for insufficient evidence to adequately weigh the harms and benefits of calcium and vitamin D supplementation. So why the sudden change from previous recommendations?

A very long story short(er) is that there just wasn't enough robust data to trump the sporadic data showing potential harms. Specifically, those harms involve kidney stones and cardiovascular disease (CVD). Initially in the WHI, they proposed that they would actually see a benefit in terms of CVD outcomes. However, they ended up finding no benefits at all and some subsequent studies in 2010 and 2011 actually showed a potential increase in CVD outcomes in those with calcium and vitamin D supplementation. [10,11] One of these two studies actually reanalyzed the WHI data set to specifically look for those women who began supplementation after the start of the trial. They found a RR of 1.24 (p=0.004) for risk of MI's. Their rationale for why the WHI showed no change in CVD outcomes was that a vast number of participants were actually taking supplements prior to the trial, thus negating and difference seen in the control and study groups.

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Even more recently, there have been studies in the past 2 years looking at calcium supplementation that showed potential excess CVD risk in adults aged 35-64 as well as men aged 50-71 but not women. [12,13] Combine this with the WHI also finding a small but significant increased risk of kidney stones (HR, 1.17; CI 1.02-1.34) and you have yourself a nice smear campaign going. But of course in the midst of all these negative studies there was also a meta-analysis that found no increase CVD risk with calcium supplements and even a small benefit (RR=0.90) for fracture incidence for vitamin D. [14] It's important to remember though that there has not been a single study yet (as far as I know) that has shown an increase in all-cause mortality. The only adverse studies have been with regards to CVD events.

You can now start to see that the once clear waters of calcium appear to be quite milky murky.

With regards to adverse effects of vitamin D, there aren't many unless you're taking outrageous doses (500,000IU single dose increasing fracture risk) or for some other reason have elevated levels in your body. One study looking at several different nutrients and vitamin levels (B12, folate, iron, vitamin D) in adults aged greater than 75 found that both low (<20ng/mL) and high (>30-50 ng/mL) vitamin D levels were correlated to mortality.  [15] That really doesn't mean much to me except don't take exorbitant amount of vitamin D.

So what did I take from all of this? To me, calcium is much like fish oil in that you'll never find a negative study on it as long as it's dietary. All of the main positive fish oil studies were dietary and all of the negative calcium studies have been supplements. So overall, I'd probably take a cup of milk or a slice of Gruyere over a calcium pill. If I had a patient with increased fracture risk and no cardiovascular history, I'd probably advise them to take 1200mg calcium and 800IU of vitamin D. If the opposite were true, I'd probably advise them not to take any calcium-vitamin D supplements. I'm less convinced either way with Vitamin D alone as there isn't really a concerning side effect profile but there's also not a ton of great evidence for it with regards to fracture risk. I'd probably tell my patients I'm fine with 800IU vitamin D either way, especially if they have a history or risk of falls.

In the end, the best medicine is probably not a supplement but to tell your patient to smile and say "cheese".

Lights, Cameras, Action: The Curious Case of Marshawn Lynch

The following is in no way evidence based. I have never met Marshawn and this is probably completely off base. That being said…

I’m on vacation this week. Most of it has largely been spent being sick in the luxurious confines of my office chair.  Also if you haven’t heard yet, the Seahawks are in the Super Bowl. Those elements have created an oversaturation of Super Bowl coverage for myself. It’s not a bad thing but I’ve seen and heard everything to the point of near boredom.

Near boredom.

The one thing that has stood out to me this week is the curious case of Marshawn Lynch. For the past two media days, Marshawn has had press conferences of 6 and 7 minutes. The expected time for these press conferences?

Forty-five minutes.

This isn’t the first time Marshawn has given a curtailed interview but it’s the Super Bowl. America’s magnifying glass is out in full force and ESPN is in full-fledged TMZ mode for 2 weeks. I was showering on Tuesday (where I do my best work) and overheard 710 ESPN talk to John Clayton about the shortened interview. It’s probably the most angry I’ve ever heard him. He was livid not only at the fact that Lynch cut the interview short but also because he broke a deal he made with the NFL to talk to the media. A deal that had to be remade after he broke it the first time and was fined $50,000.  

Of course with all my spare time this week I have also been able to go on Twitter quite a bit. I am currently following 420 people on twitter and probably 385 of them are Seahawk fans. The outpouring of support for Lynch has been unanimous. Nobody cares if he gives interviews. In the end, we are all a bunch of Al Davis’s. Just win baby and we’re all happy. But what was interesting was all of these people saying how Lynch had a social phobia or fear of public speaking. So that is my question for the day.

“Does Marshawn Lynch’s behavior meet criteria for a DSM diagnosis?”

With this exercise I’m going to look at some of the theories I’ve seen strewn about Twitter and see if their long distance diagnoses hold up. The first is social phobia, which is now known as social anxiety disorder (SAD) in DSM-V. In the DSM-V, the criteria for a SAD is that the “person must suffer significant distress or impairment that interferes with his or her ordinary routine in social settings, at work or school, or during other everyday activities.” The anxiety must be out of proportion to the actual situation and the symptoms must be persistent for six months or longer.

Well, this has definitely been going on for six months but really that’s where the diagnosis ends. This is not something that affects Marshawn’s ordinary activity. I suspect that when Beast Mode steps outside his front door in Oakland he doesn’t have throngs of reporters with their cameras in his mug. Even so, few would consider that ordinary activity. In addition, the anxiety must be out of proportion to the actual situation. I have a sneaky suspicion that the average joe would behave more like Michael Bay than Russell Wilson when placed in that environment.

Ok, so social anxiety disorder is out of the question.

Next up? Specific phobia. Even more specifically it would be the phobia of public speaking.

DSM-V criteria are the same as DSM-IV criteria in that there must be a “marked and persistent fear that is excessive or unreasonable, cued by the presence or anticipation of a specific object or situation.” The situation in Lynch’s case would be speaking in front of the media. Yes, he does seem to have an excessive objection to speaking with certain media. It’s unclear if this is a fear though. I would argue it’s more of a disdain. On top of that, he actually does quite well with certain media members.

Exhibit A: 

Exhibit B: 

and everyone’s favorite…

Exhibit C: 

Pretty convincing I have to say, especially the latter two.  I do recognize that the media interaction is on a smaller scale but it’s clear that he is not only comfortable but is engaging. He’s not simply answering questions more easily but being quirky, playful, and loving in front of media members.

Conclusion? I don’t think he has a specific phobia of public speaking or of the media either.

So what is it then? In my opinion, the issue can be glaringly obvious when placed into the context of his life history.

It’s an issue of trust.

The first five minutes of the E60 feature on Lynch gives great insight into Beast Mode’s psyche. With his father in and out of jail growing up, his mother and a small, close-knit community in Oakland essentially raised him. Lynch’s high school football coach, Delton Edwards, nailed it when he said “he don’t want people to let him down. It’s hard to get in that zone with him. If you can get in that little zone and that little shell? You’re good. He’ll love you for the rest of your life. But if you let him down? He holds grudges.

This quote was brought up to Lynch in the documentary by Jeffri Chadiha (who’s own scumbaggery will be ignored for the sake of the article).

Chadiha: “Coach said that one thing that he saw in you early on was that if you trusted somebody you’d do anything for then. But if you didn’t….”

Lynch: “F*** em”

After multiple arrests in Buffalo, Lynch undoubtedly read many scathing things about himself in the paper and on TV. Being called a “thug” and other synonymous terms in the media only further solidified the distrust Lynch had of the media as a whole.  But again, it comes down to one’s own life history. Richard Sherman has recently gone through the same crossfire if not worse as Lynch did previously but it is something he has embraced because of his make-up.

Different make-up, different response. Both normal.

It makes sense that Lynch would trust the innocence of foreign reporters asking about candy, working with a charitable organization, or a former NFL player in Deion Sanders. While at the same time spurning the requests of those that likely wrote about his on and off the field failures. Lynch said it himself during the interview with Sanders. When asked, “you just don’t want to talk really?” Lynch replied with the now infamous:

“I’m just bout that action, boss”.

But the more poignant response was what he said just prior to that statement.

“I ain’t never seen no talkin’ win me nothing”

That last statement opens up a clear window into Lynch’s history. A history where his actions, not his words, largely determined his success and failures.

In the end, there is nothing psychologically wrong with Marshawn Lynch’s behavior with the media. He does not have a social anxiety disorder, social phobia, or a specific phobia. His attitude towards the media as a whole is an understandable response that many others would have, especially those who have shared similar experiences as he has. He is a man that emphasizes not lights. Not cameras.

But action.

Go Hawks!

After hearing Marshawn Lynch's interview with Deion Sanders, I couldn't resist the urge to throw it into my sampler. Not the biggest sports fan, but I don't see why I can't enjoy the Town comradery in my own way, right? Go Hawks and stuff. Oh, and our next show is February 8th at Columbia City Theater.