Words of caution about “simple tests could save lives and money” story

A reader in California asked that we review and comment on a story by Healthline seen on Yahoo Health news: “Simple Tests for Heart Attack Risk Could Save Lives and Money.”

Whenever you hear or see the phrase “simple tests,” you should head for the hills because there’s nothing simple or uncomplicated about most health care tests.

I’m working on a grant proposal and didn’t have time to respond to our reader’s request, but I asked expert reviewer and guest blogger Harold DeMonaco to take a look.  Here’s what he wrote:

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Cardiovascular disease is a leading cause of death and disability in the United States and in the “developed” world.  Identifying those at risk for future or imminent events is an admirable and long sought after goal.  A laboratory test or a series of tests in combination would be preferable to a more invasive and perhaps more definitive test such as coronary artery catheterization.  Indeed over the past twenty years a host of markers have been proposed alone and in combination.  Here is a partial listing of the markers and tests identified to date as potentially important in defining a person’s risk of heart disease:

• Activated factor VII,
• Adiponectin,
• Angiotensin gene (CardiaRisk AGT),
• Anti-thrombin III,
• Apelin,
• Apolipoprotein A-I (apo AI),
• Apolipoprotein E (apo E),
• Apolipopritein E genotyping,
• B-type natriuretic peptides,
• Chromosome 9 polymorphism 9p21,
• Circulating microRNAs,
• Coronary artery reactivity test,
• Factor V Leiden,
• Fibrinogen,
• HDL subspecies (LpAI, LpAI/AII and/or HDL3 and HDL2),
• Homocysteine,
• Interleukin 6 (IL-6),
• Interleukin 6 -174 g/c promoter polymorphism,
• Kinesin-like protein 6 (KLP6),
• LDL gradient gel electrophoresis,
• LDL subspecies (small and large LDL particles),
• Leptin,
• Lipoprotein remnants: intermediate density lipoproteins (IDL) and small density lipoproteins,
• Lipoprotein(a) enzyme immunoassay,
• Lipoprotein-associated phospholipase A2 (Lp-PLA2) (PLAC),
• Long chain omega-3 fatty acids composition in red blood cell,
• Mid-regional pro-atrial natriuretic peptide,
• Myeloperoxidase (MPO),
• NMR Lipoprofil,
• steoprotegerin,
• Peroxisome proliferator-activated receptor,
• Plasminogen activator inhibitor (PAI–1),
• Protein C,
• Prothrombin gene mutation testing,
• Resistin,
• Retinol binding protein 4 (RBP4),
• Tissue plasminogen activator (tPA),
• Tumor necrosis factor alpha (TNF-a),
• Total cholesterol content in red blood cell membranes,
• VAP cholesterol test,
• Visfatin and von Willebrand factor antigen level.

This list demonstrates that we do not lack biomarkers of interest.  We do however not know how best to use them, alone or in combination.

The recent poster presentation from the International Society For Pharmacoeconomics and Outcomes Research meeting in Montreal supported the concept of multiple coincident testing of biologic markers as a method of identifying persons at risk,  Indeed all three markers identified in the economic evaluation have been previously implicated.  It would seem reasonable then to improve the reliability of the tests if they were combined.

Myeloperoxidase is an enzyme secreted from activated neutrophils and monocytes.  It is also found in atherosclerotic plaques and may be involved in the development of coronary artery disease. Similarly, Lp-PLA2 has been proposed as a potential marker of inflammation and there is a FDA approved test kit for its determination.  However, data on Lp-PLA2 have been somewhat contradictory.  HS-C-Reactive Protein has also been proposed as a marker of inflammation in patients with coronary artery disease.  HS-CRP has been shown in studies to reduce risk of a cardiac event in patients with presumably low risk of having cardiovascular disease other than an elevation of the biomarker, (the so-called  JUPITER Study: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin published in the New England Journal of Medicine in 2008).

Based on previous work then, it would seem quite reasonable to combine tests that have demonstrated a reasonable level of predictive value.  By combining tests, you can theoretically reduce the risks associated with “false” positives tests and increase the combined sensitivity for identifying persons at risk.  However, definitively demonstrating the value of the combined tests requires a bit more study and validation.  Suggesting at this point that the combined testing should be mainstreamed may be ultimately found to be correct, but I would argue, not at the moment.

The poster presentation is unfortunately not available online so a more detailed critique is not possible.  We have previously cautioned reporters against doing stories on studies presented in abstract and in posters at national meetings. By definition, posters, abstracts and proceedings presentations provide a limited amount of information.  The information has not been subjected to peer review.  As a result, caveat emptor would seem to be a product admonition.

Let’s take a closer look at the story by Healthline that appeared on Yahoo News.  The Cleveland Heart Lab is a commercial entity developed as a spin-off from the Cleveland Clinic.  The first person interviewed in the story is the Chief Medical Officer of the company.  The second person interviewed in the story is the co-founder of the “Bale/Doneen Method and the Heart Attack & Stroke Prevention Center. He is a principal instructor in the Bale/Doneen Method, training other medical providers across the country.” Both are ardent devotees of the use of inflammatory markers in cardiovascular disease. No independent sources are provided in the story.

The story notes, “Researchers from Cleveland HeartLab (CHL) and economists from Analysis Group calculated that if a commercially insured U.S. health plan with one million members adopted this approach, 2,018 heart attacks and 1,848 strokes could potentially be avoided, resulting in $180.6 million in cost savings over five years, compared to outcomes if standard screening methods were used.”  We are provided with no information on how these numbers were calculated or the frequency of testing necessary to achieve these reductions.  We are however provided with a hint, “Multimarker testing detects 37 to 43 percent more at-risk patients than would have been identified through checking levels of LDL (bad) cholesterol alone.” These results are noted as being published in Future Cardiology in 2013.  This journal is not available online without paying a $60 fee and I am not that curious.   Presumably then, these numbers were used to extrapolate the potential savings described.

To truly know the value of the testing as proposed a reader would need quite a bit more information.  No test or group of tests is going to be 100% accurate in identifying only those with the disease.  We are only provided with relative value (37 to 43% more at risk patients).  What were the absolute numbers and how were these relative values calculated?  How often would the testing be required? How many people would need to be screened to identify one at risk?  What are the costs associated with each person identified? At what age should the testing be performed?  Without a more detailed description, we only have the reporter’s story and that of two ardent supporters of the approach.

The American College of Cardiology guidelines for coronary artery calcium scoring calls for its use in asymptomatic people with intermediate risks scores (using the Framingham CV Risk Calculator ) and in people over the age of 40 years with diabetes. Based on the evidence to date, this recommendation balances the benefits of the test against the risks and costs.  Before proclaiming that, “ thousands of heart attacks and strokes could be prevented” we need a good more information.  Basing a treatment regimen on an untested series of laboratory tests potentially subjects a large number of people to adverse drug events and added costs.  The NNT.com website notes the risks and benefits of statin therapy (a natural next step if the tests are to be believed) in people without know heart disease taking the drug for five years:

• None would be helped (life saved)
• 1 in 60 would be helped in the prevention of a heart attack
• 1 in 268 would be helped in the prevention of a stroke
• I in 50 would develop diabetes
• 1 in 10 would suffer muscle damage

These numbers are extrapolated from existing randomized clinical trials noted on the site. While they may not be exact, they do point to the potential downside of screening.  Treatments do have downsides.

Indeed, the use of multiple tests to identify people at risk could “save lives and money.”  But it remains to be seen if this is the case.  A bit more skepticism would have been desirable in reporting on this story.

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