Practice advancement: a multimarker strategy for CVD risk stratification

How many patients are you treating for heart disease or its warning signs, e.g., hypertension or hyperlipidemia? You probably know the number or have a general sense. Now, here’s the harder question: how many of those patients are at higher risk of their disease progressing or of having a heart attack or stroke? In other words, which patients should you be monitoring more closely?

You already have excellent tools in your primary care armamentarium to answer those latter questions: patient history, examination, laboratory testing, and clinical judgment. Still, it remains more art than science to determine which patients warrant closer investigation or earlier or more aggressive intervention.

Evidence shows, however, that testing for multiple markers is a valid approach to risk-stratify patients for cardiovascular disease (CVD). This multimarker approach includes both advanced lipid testing and inflammation testing to better assess risk of CVD, disease progression, and adverse events. Such an approach can help your practice better manage population health to achieve improved patient outcomes and exceed performance benchmarks. Here’s a closer look at the evidence.

The JUPITER and CANTOS Trials

The Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial was the first landmark trial to demonstrate increased identification and stratification of individuals at risk of adverse cardiovascular events using a multimarker approach.1,2 Prior to the results of this 2009 publication, most research focused solely on lowering LDL-C with statin therapy to reduce cardiovascular risk. The JUPITER Trial went beyond this traditional measurement to demonstrate that high-sensitivity C-reactive protein (hsCRP), a marker of general- and cardiovascular-related inflammation within the body, can improve risk stratification of individuals who may benefit from rosuvastatin therapy. The evidence showed that individuals with low LDL-C but high inflammation—as measured by hsCRP—had twice the risk of a cardiovascular event compared to individuals with low LDL-C and low hsCRP.

Incident cardiovascular events in the JUPITER Trial following initiation of rosuvastatin therapy. Adapted from Ridker et al.1

The more recent Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS, 2017) provided further validation of the multimarker approach. CANTOS showed that anti-inflammatory therapy in post-myocardial infarction patients with inflammation, as measured by hsCRP, led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.3

“Our data thus affirm that statin-treated patients with residual inflammatory risk as assessed by means of a high-sensitivity C-reactive protein level … have future event rates that are at least as high as, if not higher than, those among statin-treated patients with a residual risk due to LDL cholesterol level.”—Ridker PM, et al. N Engl J Med. 2017.

Systemic and vascular inflammation

In 2009, Heslop et al. published a study in the Journal of the American College of Cardiology that examined the clinical utility of hsCRP and myeloperoxidase (MPO)—two inflammatory biomarkers with different pathophysiologies. Unlike hsCRP, free MPO within the bloodstream is a vascular-specific marker for vulnerable plaque formation. As shown in the figure below, individuals with elevated levels of both hsCRP (atheroma burden) and free MPO (active atheroma) in the bloodstream had an approximately 4X increased risk of cardiovascular mortality compared to those with only one of these biomarkers elevated.

Cardiovascular mortality according to elevations in hsCRP and MPO. Adapted from Heslop et al.4
*Represents hazard ratio.

 

Vascular inflammation: two sides to the story

The utility of biomarkers, like Lp-PLA2 and MPO may demonstrate different and additive stages of disease. For example, in 2013, Penn and Klemes published a study in Future Cardiology that examined the utility of a multimarker approach—when designed with the physiology of each marker in mind—to identify risk and ultimately acuity of risk.5 In particular, this study highlighted the ability of Lp-PLA2 (lipoprotein-associated phospholipase A2) and free MPO in the bloodstream to identify vulnerable plaque by measuring distinct physiologies. Lp-PLA2 examines macrophage activation underneath the collagen cap within the artery wall, while free MPO examines the white blood cell response in the bloodstream due to vulnerable plaque/erosions/fissures in the artery wall. As shown in the figure below, Lp-PLA2 and MPO are rarely elevated together, and therefore testing for only one biomarker would miss identifying half of the patients with vulnerable plaque. Lp-PLA2 and MPO in conjunction with additional biomarkers provide additional stratification of risk of plaque rupture beyond that of using each biomarker individually.

Risk based on vulnerable plaque risk markers in a stable clinical population of patients. Adapted from Penn and Klemes.5

 

Advanced lipid testing’s contribution

As explained in a previous post, advanced lipid testing can also contribute to more individualized cardiovascular risk assessment, alone or when combined with inflammation testing. Advanced lipid testing can identify and quantify LDL particle number (LDL-P), particle size, and number of other lipoprotein subclasses such as small, dense LDL and large, buoyant HDL. These measures can help assess injury to vessel walls, while inflammation testing can assess the body’s potential response to injury. Together, these sets of markers can help you assess where your patient may be on the atherosclerotic cascade, from initial plaque formation to risk of disease progression, and from vulnerable plaque formation to risk of plaque rupture.

In short, a multimarker approach can help you individualize cardiovascular risk assessment and, by identifying acuity of the risk as well, manage your heart disease population by risk-stratifying which patients warrant closer monitoring or earlier intervention. This ultimately can help your practice run more efficiently by preventing the consequences of undetected heart disease risk: emergency room visits, hospitalizations, and heart attacks that may not have had to happen.

Know which patients are most at risk

Quest Diagnostics offers a complete menu for CVD risk assessment that includes advanced lipid testing, inflammatory marker testing, metabolic markers, and innovative gut microbiome testing. Learn more today. The more you know, the more you can do to help your patients with heart disease stay well for a longer time—and keep your practice healthy, too.


1. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-2207. doi:10.1056/NEJMoa0807646.
2. Ridker PM. The JUPITER trial: results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes.2009 May;2(3):279-285. doi:10.1161/CIRCOUTCOMES.109.868299.
3. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi:10.1056/NEJMoa1707914.
4. Heslop CL1, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol. 2010 Mar 16;55(11):1102-1109. doi:10.1016/j.jacc.2009.11.050.
5. Penn MS, Klemes AB. Multimarker approach for identifying and documenting mitigation of cardiovascular risk. Future Cardiol. 2013 Jul;9(4):497-506. doi:10.2217/fca.13.27.