First post and origins

Although an early participant in the world of Usenet newsgroups, I'm a latecomer to the world of blogging. I don't read or participate in blogs often, and as a newbie will undoubtedly make mistakes of etiquette and function much as I did in the very early days of Usenet before I got a feel for the music of the newsgroups. I hope anyone reading this will take this into account and cut me some slack!

I'd been considering for a while now blogging about evidence and medicine, something I spend a fair amount of my time thinking about in any case, but a couple of events pushed me to take the plunge.

The first was when a relative, a woman in her mid-40's, called to tell me that she'd seen her new primary care doctor. The doctor had run tests on her including checking a lipid profile. The lipid profile showed a total cholesterol of 160, an HDL of 44, and an LDL of 105. Based on these results, the doctor informed her that she should be very concerned about her "low" HDL number and told her to start taking fish oil.

This was an interesting interpretation of the results and an unusual suggestion for management, and it gives some sense of my concerns about how evidence is used, ignored, or misused in medicine. This relative had a low normal blood pressure, no smoking history, did not have diabetes, and had no family history of coronary heart disease. As such, there is even  some controversy as to whether she should have had a lipid profile checked at all.

Assuming a lipid profile was worth doing, she should certainly have been told that this was an excellent profile putting her at low risk for a cardiovascular event, and that there was little modern medicine could do to substantially affect her risk. Her 10-year risk of an event (using the 2008 calculator that overestimates vascular risk by including things that probably shouldn't be included -- a blog for another day) works out to about 2.2%. If we pretend that somehow fish oil could increase her HDL to 80 and that she would get all the same benefit as if her HDL were naturally 80, we could drop her calculated risk to about 1.4%. So, if she took medication daily for 10 years, she would reduce her risk of an event (under these outlandishly favorable assumptions) by 0.8%. Not something this relative was interested in doing.

But, do we even know that fish oil raises HDL? The main effect of fish oil on lipids is to lower triglycerides. Most studies suggest that fish oil only raises HDL levels by about 3%, so we might expect an increase from an HDL of 44 to an HDL of 45. It's hard to see how the doctor felt this would fix the woman's "low" HDL.

But, beyond that, we have no solid evidence that raising HDL with  medication improves outcomes. Changing HDL with medication is a surrogate outcome for that medication  -- that is, it is of no direct interest to the patient unless it also predicts better cardiovascular outcomes, and HDL appears to be a poor surrogate.  Some medications that raise HDL appear to cause harm and worse vascular outcomes.

As for whether fish oil supplements are beneficial through some non-HDL mechanism, I think we can safely say that the jury remains out as to whether a woman in her 40s at low cardiac risk could expect any important benefit from fish oil supplementation.

Interestingly, my relative's doctor also checked her vitamin D level and told her that a level of 34 (in the normal range) was concerningly low and that she should start taking 1000 IU of vitamin D per day (she was already taking 400 IU). Vitamin D supplementation is controversial, with lots of people claiming big benefits, but we can safely say for now (again, perhaps a longer blog for another day) that there is no solid evidence that having a woman with a normal vitamin D level start taking additional vitamin D is likely to be of any benefit to her.

My relative asked what I thought these events said about her doctor, but I'm not really sure. I see decisions like this made all the time, where evidence is misunderstood, misapplied, or ignored. I have the sense that this particular doctor may believe she is getting out ahead of the evidence -- suggesting therapies that she believes will be proven down the road to be of benefit. She could, of course, turn out to be right, but we should be very hesitant to give preventive medications without a decent evidentiary basis. Other drugs that raise HDL have increased mortality. Supplementation with other vitamins that were thought beneficial has turned out to cause cancer or increase mortality.

I said there were a couple of events that prompted me to start this blog, but this post seems long enough. I'll talk about other events in future postings.

Comments

[Dan Hackam MD PhD]

David,
This relative should have had a non-invasive test to determine whether subclinical atherosclerosis was present, such as a carotid total plaque area determination. If considerable plaque was already present at her tender young age (not to mention gender), I would have started her on a statin for her low HDL. Some of the landmark statin trials suggest there is greater benefit at lower levels of HDL than at higher levels of HDL (makes sense). I would not have treated her with fish oil or niacin. The problem with your risk calculator is that the very best risk calculators will still miss 20-25% of events over 10 year follow-up (and think how many they would miss over 10-30 year follow-up). If plaque is already present and advanced, which it commonly is in patients who end up having atherosclerotic events, we should then intervene. I therefore screen all my patients with TPA - total plaque area.

[Jonathan Vafai]

Glad to see you started a blog. I always enjoyed presenting cases to you at HCA, I am glad I can keep hearing your perspective on things!

[riv]

It's all so useless anyway. If she did have carotid thickening, what is the good doctor to do? Put her on Vytorin? (Sic) See NEJM recent.

The idea there is some *thing* that can be done is what must fall.

Happy to see you've finally moved over to blogging Dr. Rind. What's kept you?

Female
TC 12-14 mmol
HDl 2.6
No cardiovascular disease.
No fish oil. No statins.
No less chocolate cake.
Yes. It's who you think it is.

[Reka Morvay]

Welcome to the world of blogging, Dr. Rind. If I may offer one suggestion, it would be to use either tags or categories for your posts, so when they become more numerous than they are now, it will be easier for your readers to find posts on topics of interest to them.

Looking forward to more of your writing.

[Kevan Gelling]

"my relative's doctor also checked her vitamin D level and told her that a level of 34 (in the normal range) was concerningly low and that she should start taking 1000 IU of vitamin D per day (she was already taking 400 IU)."

Assuming the units are ng/ml, your relative lives in Boston and the vitamin D test was in the last couple of months then the "low" diagnosis is probably correct.

Vitamin D levels are seasonal at Boston latitudes. Levels peak in early Autumn and then drop (due to a lack of UVB) to a minimum at the end of winter.

In the UK the average drop is about 16 ng/ml (1). Boston is at a lower latitude and has a shorter 'UVB winter' (November to February - 4 months to the UK's 6 (2)). It's not unreasonable then to suggest that a Bostonian's drop may 2/3rds the UK's drop, so about 10 ng/ml.

If your relative's doctor is using 30 ng/ml as the level of sufficiency, then your relative would be below sufficient levels come February (~24 ng/ml).

A very rough guide for dosage is 100 IU/d = +1 ng/ml (better estimates are available (3)) so a supplementation of 1000 IU/d is valid (for the selected sufficiency level).

1. Hypponen, E. & Power, C. "Hypovitaminosis d in british adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 85, 860-868 (2007). (www.ncbi.nlm.nih.gov/pubmed/17344510)
2. Webb, A. R., Kline, L. & Holick, M. F. Influence of season and latitude on the cutaneous synthesis of vitamin d3: exposure to winter sunlight in boston and edmonton will not promote vitamin d3 synthesis in human skin. The Journal of clinical endocrinology and metabolism 67, 373-378 (1988). (www.ncbi.nlm.nih.gov/pubmed/2839537)
3. Heaney, R. P. The vitamin d requirement in health and disease. The Journal of steroid biochemistry and molecular biology 97, 13-19 (2005). (www.ncbi.nlm.nih.gov/pubmed/16026981)

[David Rind]

Kevin Gelling suggests that my relative was reasonably told to take additional vitamin D. Even if I accepted all the assumptions of where vitamin D levels would go in winter months (I don't buy that these actually apply to someone getting most of their vitamin D from supplements, but perhaps there are studies demonstrating this?), there would still be the questions of:
What is the evidence that having a vitamin D level between 20 and 30 is harmful?
What is the evidence that higher dose supplements of vitamin D provide some important clinical benefit beyond altering a lab value?

[Kevan Gelling]

> "I don't buy that these actually apply to someone getting most of their vitamin D from supplements"

Your relative is not getting most of their vitamin D from supplements - 400 IU/d contributes about 4 ng/ml. The average US diet contributes about 100 IU/d. Your relative, like the rest of us, will get most of their D from the sun.

> "What is the evidence that having a vitamin D level between 20 and 30 is harmful?"

"Optimal vitamin D concentrations for reducing [insulin resistance] were shown to be 80-119 nmol/l [32-47.6 ng/ml]"

von Hurst, P. R., Stonehouse, W. & Coad, J. Vitamin d supplementation reduces insulin resistance in south asian women living in new zealand who are insulin resistant and vitamin d deficient - a randomised, placebo-controlled trial. The British journal of nutrition 1-7 (2009). (www.ncbi.nlm.nih.gov/pubmed/19781131)

> "What is the evidence that higher dose supplements of vitamin D provide some important clinical benefit beyond altering a lab value?"

Heaney, R. P. The vitamin d requirement in health and disease. The Journal of steroid biochemistry and molecular biology 97, 13-19 (2005). (www.ncbi.nlm.nih.gov/pubmed/16026981)

[Dan Hackam MD PhD]

David, I was disappointed that you did not comment on my post suggesting that the patient undergo subclinical atherosclerosis imaging. As you know, with an AUC-ROC of about 0.78, Framingham will misclassify nearly a quarter of events, and that at a follow-up of only 10 years. With atheroma imaging (such as through a carotid total plaque area [TPA] measurement), we can see whether disease is already present, how established it is, and whether we should intervene. In RCTs, this modality strongly motivates adherence as well. Without it, I feel blind in my assessment of my patients' vascular risk.

[David Rind]

Dan, my sense is that if you would check an imaging study in a woman in her 40s with no CVD risk factors that you would recommend this in almost everyone. I can't say I agree with such a strategy. There is a review in last week's JAMA by Tzoulaki discussing the lack of high quality evidence that any of the novel risk factors have been proven to improve prediction beyond those achieved with Framingham Risk Scores.

[Dan Hackam MD PhD]

Hi David,

I thought this individual had a low HDL - perhaps the single most important lipid predictor of vascular risk after high LDL levels are excluded. Therefore, to say she had "no CVD risk factors"...

I would definitely not recommend ultrasound scanning to low risk patients with no risk factors. Even though cardiovascular disease is the #1 cause of death and disability in adults in industrialized and developing countries (certainly more so, than say breast or cervical cancer, and mammography and pap smears are routinely indicated). If she was still concerned about her risk after reassurance based on the absence of all risk factors, I would then suggest carotid ultrasound.

I would say that the predominance of Framingham Risk Scores simply reflects the fact that "Framingham got there first". There were simply no other good cohort studies in the 1950's and 1960s (other than perhaps the 7 Countries Study, which focused largely on diet and cholesterol), and so all new technology is being compared to it as the "gold standard". But is it the gold standard? The AUC-ROC for Framingham is 0.78, which hardly makes it an ideal test. Furthermore, many of the risk factors in Framingham are subject to great variability, such as lipid levels and blood pressure.

I do agree fully however with the review by Tzoulaki ... but it takes a leap of faith to accept that Framingham should be the gold standard just because it has always been there (and got there first).

[Romanens Michel]

Dear David and Dan,
there is so much time we can spend discussing Framingham and TPA. The question is: which statistical method allows us to appropriately define, if TPA gives significant additional information on top of FRS. For this purpose, we have discussed the matter on the Eur J Prev&Rehab (kardiolab.ch/stats09.pdf). There is one piece missing in the puzzle: is TPA based upon a net reclassification analysis (NRI) really better than FRS alone? We are working on that. In the mean time: I see so many subjects with little higher than normal lipid levels in Switzerland not treated. Once they reach the TPA assessment, ahterosclerosis is frequently advanced and the time gap between risk accumulation and risk lowering intervention sadly enough too high.

[Dan Hackam MD PhD]

I completely agree with Michel and think he is ahead of the curve on this. Simply put, atherosclerosis imaging is here to stay. I do not see any RCTs validating echo, ECG, CXR, electrolyte testing on hard outcomes but all have become part of the arsenal (even though, in many cases, there are pitfalls). I have noticed in my own patient population a great improvement in the ability to stratify risk and we have published this. I have also noticed enhanced adherence with the visualization of plaque for the patient and then plaque regression following intensive therapy.