August 14th, 2013
Advanced Lipoprotein Analysis: Time for Widespread Implementation?
Behnood Bikdeli, M.D.
Traditional LDL- and HDL-cholesterol measurements fall short of perfect prediction of cardiovascular risk. So, several academic and industry investigators have tried to identify supplementary advanced lipoprotein tests that can, at least in part, detect the “residual risk.” These include not only measurements of apolipoprotein B and A-I subcomponents, but also assays that identify LDL particles and their size. Accordingly, advanced lipoprotein analysis has garnered much attention during the past decade, and clinicians continue to wonder where and when they should request such analyses, if at all.
Results from existing studies vary to some degree (see Parish et al.), but several suggest that LDL particle number (LDL-P) might outperform LDL cholesterol (LDL-C) as a predictor of cardiovascular risk (see Greenland et al. and Otvos et al.). For example, in a substudy of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, although both LDL-C and LDL-P were associated with risk for incident cardiovascular disease, only LDL-P predicted incident CVD among people with discordant LDL-C and LDL-P. Given that evidence and assuming that advanced lipoprotein analysis would help to identify a larger group of at-risk patients, several insurance companies have agreed to pay for such tests. But does this additional information actually improve clinical outcomes?
Any recently introduced test has its proponents and critics, but the ultimate clinical value of the test’s results depends on the availability of high-quality evidence to guide practice. Some of the new cardiac biomarkers have recently been used as criteria for including patients in cardiovascular trials or for guiding management. Among those, perhaps use of D-dimer in algorithms to diagnose venous thromboembolism is the most well-known example of a widely available biomarker that has supportive evidence from multiple studies.
Advanced lipoprotein testing may ultimately prove helpful for appropriate risk stratification and guidance of therapy to improve outcomes. As a fan of tailored and “personalized” medicine, I would like to see this happen soon. However, for now, there is a dearth of evidence on clinically proven interventions that specifically target the increased risk identified by such advanced techniques. Therefore, conducting high-quality randomized controlled trials might be a prerequisite to widespread use of these tests.
In this era of a focus on real value to patients, I wonder if advocating for tests that have yet to make a difference to our patients is the best approach. Should insurers be paying for these tests? Please share your thoughts with me and with others here on CardioExchange.
12 Responses to “Advanced Lipoprotein Analysis: Time for Widespread Implementation?”
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I have yet to be convinced that any of the advanced lipid testing has incremental value and /or therapeutic relevance over and above non-HDL or
Apo b levels in vast majority of patients in clinical practice but I am happy if I am proven wrong by robust data that shows otherwise
I think we need a little more research and experience to advocate for advanced lipid testing in the general population. In particular cases is useful and necessary. I believe, in the near future, this testing will be complemented with inflammatory markers and will be very useful. About the insurers I am firm believer that the Medical community must decide the best / appropriate way to prevent, diagnosis ant treat our patients, not the insurance company, so if a good physician think is necessary and medically appropriate for his patient, they have to pay. For the moment, in most cases, this is a utopia.
Thanks for the very helpful discussions.
Dr. Shah, that’s a great point. I completely agree that many clinicians and scientists do not find the existing evidence as satisfactory for superiority of advanced lipid testing for detection of the residual risk. Perhaps my bigger question is –in case we assume such superiority –would that be enough to use these tests in routine practice? Or we need proof that we have tools to appropriately address the residual risk to improve the outcomes?
Dr. Guadiana, I agree that we physicians should act to the best interest of our patients. But for reasons discussed above, I wonder if doing such tests –at least for time being and before we have more data –would translate into better health for people. Further, I think in a collaborative model, policymakers and insurers are key role-players that alongside healthcare providers can help people achieve their desired outcomes.
Maybe In your reply are the answer to your questions. You imply that for the moment we don’t have enough data to be sure this testing will translate into better health for the people, then we have a controversy so it is expected that many insurers wil not support payment. I also believe in a collaborative model working together but many times is mixed up. I also believe in tailored medicine for that in some cases is appropiate to use them. A very important question is Do we have the tools to intervine and change the prognosis after the testing?
I believe LDL-P is the “smoking gun” and treatment to appropriate levels will be proven benificial especially in those patients with TG/HDL-C axis disorders where LDL-C is not nearly as reliable. I only use when non-HDL-C is at goal in the highest risk patients. Proof of benefit will be difficult because after the initial statin “hit” there is probably only small incremental improvement (fibrates, niacin etc).
That being said I also believe because of healthcare cost and safety that tests, procedures and treatments should be proven beneficial before payment begins. There are no easy answers.
Why bother on an essential molcule like cholesterol?
It’s been known for a long time that low cholesterol gives a premature death.
All old aged people have a higer total cholesterol than those that didn’t make it to an elder age.
High LDL and low HDL is due to excess of toxic carbohydrates in the diet.
Have less than 100 g (<4 oz) of carbohydrates per day and get rid of the obesity and iabetes epidemy.
It's that easy to decrease the cost of health care by at least 50 %.
Times are tough here in the US. I don’t believe we should ask insurers (or the Federal Government) to pay for new tests without proving that performing these tests will improve patient outcomes.
It’s clear that so far opinions re implementation are mixed. However, data from a number of studies suggest that about half of all first MIs occur in people with normal cholesterols. Even with other known factors, such as inflammation, I think it is important that we do, in fact, implement more widespread use of LDL particle size and other subcomponents.
I’m certainly in favor of more research, but with CHD still the number one killer, it’s time to move to widespread testing of subcomponents, while continuing research. History tells us that new, more refined diagnostic techniques in many areas of medicine lead to better outcomes, including earlier, improved treatments, and less mortality. One could even argue that it is doing patients a disservice to withhold the newer diagnostic indicators.
Björn Hammarskjöld has nicely described cholesterol myth. I cannot but quote: A good theory makes a number of predictions that may be falsified by observation; if the observations disagree with the theory, it should be modified or abandoned. (Uffe Ravnskov: J Clin Epidemiol Vol. 51, No. 6, pp. 443–460, 1998)
Wonderful discussions, I appreciate all –and I think many points are shared within them.
I wonder what we do with the results of advanced tests, especially if patients are already on statins. I really liked Dr. Guadiana’s phrase “Do we have the tools to intervene and change the prognosis after the testing?” I believe that should be the way forward and we need to find tools…but do we have any tools now? This is also reflected in Dr. Wolkowicz’s note.
Dr. Maiese, I agree that further risk reduction in patients already on statins is not easy. But if so, how would the results of advanced lipid tests help us? Are we going to advise more exercise, or other lipid meds for which there is limited evidence for additive benefit? Alternatively, trying to detect people with normal LDL-C but impaired advanced lipids in order to target them with statins seems plausible (somewhat similar to JUPITER), but I doubt if we have clinical trial data to support this. I pose the same question also to Dr. Smith. Let’s assume we detect some of the residual risk. What do we do?
Dr. Hammarskjöld, some people, including Dr. Ravnskov, question the cholesterol hypothesis. We all know that evidence is conflicting (many consider cholesterol as causal). Yet, this might not be a key point. Irrespective of being causal or not, cholesterol, and other advanced lipid tests may very well be risk markers. And for example, we know from numerous trials that statins –which also impact the lipids –have undeniable effects on CV risk in many settings. So, perhaps we can some day find the risk by other advanced tests, too, and try to lower the risk by an intervention. My only concern is that at the moment I am unaware of one such intervention.
And I know that the carbohydrate hypothesis is ahot topic , but I wonder if we have enough hard evidence to recommend such a radical shift. Is there a big comparative effectiveness study to support that carbohydrate free diet is as beneficial?
Yet another proposed test to add to the already overcrowded field of overdiagnosis. We need to approach with caution any test that proposes to increase the number of people who have no hint of disease, but in whom additional screening tests will find many more who would never be affected by an abnormal lab number than would be helped by earlier intervention.
Use should be highly personalized by the physician who weighs the potential value of the additional information on all levels. In an 84 year old woman with a 44 year old habit of spending the entire day searching for more food, adheres poorly to her prescriptions, with much room for improvement in reaching targets through current medication adherence, LDL-P may not be a primary concern. In a 44 year vigorous businessman with T2DM and 4 children who participates in marathons but who is still sloppy about calorie intake and may be motivated by, or who would greatly appreciate knowing, whether or not a high LDL-P is present, perhaps yes. Especially if he needs a nudge toward improving statin adherence.
To guide as to whether the cholesterol “hypothesis” is true-or any variant thereof–totally non-applicable. As a guide to prescribing a low CHO or total fat diet–also non-applicable. A moderately low CHO Mediterranean Diet with a customized total calorie intake has universal appeal and effectiveness.
“Routine screening”–hardly, because at present physicians can barely keep up with patients who would obviously benefit from treatment indicated by conventional lipid profiles and glucose/A1c’s, and reward is offset by a large expense burden. For a screen that improves LDL-C performance without the expense, use non-HDL-C.
LDL-P of academic interest?–definitely. One will be shocked at the amount of unrecognized residual risk that exists.
Richard Kones, MD