Differentiating Biological Targets for Cardiovascular Risk Reduction from Risk Assessment Tools

Cardiovascular disease (CVD) remains the leading cause of mortality across the globe. The cornerstones of CVD prevention and treatment are accurate risk assessment — such that the intensity of preventive treatment matches the magnitude of absolute risk — and targeting biological markers that are known to mediate CV risk, respectively.

Biological markers are informed by pathophysiologic disease mechanisms and often are used as a titratable target during treatment, such as low-density lipoprotein cholesterol (LDL-C) levels. On the other hand, risk assessment tools are markers that improve on actuarial CV risk and are at times agnostic to underlying disease pathophysiology. Unfortunately, these two concepts often are conflated — the value of a marker for serving as a biological target can be very different from its utility as a risk assessment tool.

High-sensitivity C-reactive protein (hsCRP) and coronary artery calcium (CAC) score are two such biological markers. In this editorial, we aim to disentangle the utility of hsCRP as a biological target for CV risk reduction and of CAC as an aid to improving CV risk assessment.

C-reactive Protein

CRP is an acute-phase protein produced predominantly by the liver and is a nonspecific marker of systemic inflammation. Plasma CRP levels can be readily measured using standardized highsensitivity assays that are commercially available.

HsCRP as a cardiovascular risk assessment tool:

Systemic inflammation has long been regarded as a CV risk factor, and multiple studies have demonstrated the independent association of elevated hsCRP with CV events. (1,2) Hence, hsCRP has been evaluated as a CV risk assessment tool in several epidemiologic studies. (3-7) However, its widespread utility has been limited by significant gender and Discuss this article at www.lipid.org/lipidspin ethnic variations in levels, as well as its association with smoking, diabetes, and visceral obesity — established risk factors that portend accelerated atherosclerosis. (8,9) The incremental value of hsCRP for CV risk prediction was evaluated by the Emerging Risk Factor Collaboration in more than 160,000 asymptomatic people from 38 cohorts.(10) HsCRP yielded a net reclassification improvement (1.52%), and the addition of hsCRP to a model containing traditional risk factors led to a minimal but significant improvement in risk discrimination (change in C-statistic 0.0039), an effect that was limited to men. (10) Lastly, using an hsCRP level of >2 mg/L as the cut point for defining elevated CV risk has performed poorly in some studies and may be inadequate to inform risk assessment.(11,12)

HsCRP as a biological target for reducing cardiovascular risk:

Despite a number of presumed mechanistic links, genetic studies have confirmed that CRP largely is not causally related to CVD.(13-15) Rather, it is a barometer of vascular inflammation and atherosclerotic risk factors — including obesity — that result in CRP release from the liver in response to cytokines, principally interleukin-6.(16,17) Thus, CRP is not a direct biological target, per se, but it could be used as an indicator to determine who would most benefit from anti-inflammatory therapies.(17) This hypothesis was assessed in the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which randomized asymptomatic patients with LDL-C <130 mg/dL and hsCRP >/= 2 mg/L to rosuvastatin or placebo and demonstrated a robust reduction in adverse CV events with rosuvastatin along with a concomitant reduction in LDL-C and hsCRP levels.(18) However, a post-hoc analysis demonstrated that elevated hsCRP did not independently predict an enhanced effect of statin therapy, thereby refuting the paradigm of statins preferentially benefiting those with elevated hsCRP.(19) Similarly, recent analyses from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) trials did not demonstrate enhanced relative risk reduction with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors among patients with higher hsCRP.(20,21) However, in the SPIRE trial, on-treatment hsCRP levels were independently predictive of CV events while on-treatment LDL-C no longer was associated with outcomes, spotlighting the concept of residual inflammatory risk. (21)

The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial recently provided evidence to support the hypothesis of targeting inflammation without lowering LDL-C for CV risk reduction.(22) Here, canakinumab (monoclonal antibody targeting interleukin-1 beta) was shown to reduce recurrent CV events independent of LDL-C in patients with previous myocardial infarction (MI) and hsCRP >2 mg/L. (22) Interestingly, a post-hoc analysis of CANTOS examined 3-month on-treatment hsCRP levels to determine response to canakinumab.(23) The subgroup of patients who achieved an hsCRP level <2mg/L had a significant reduction in the primary composite endpoint as well as CV death and all-cause mortality, with no significant reduction in any of these endpoints in those whose on-treatment hsCRP remained ≥2mg/L.(23) The direct clinical relevance of this analysis is the potential to measure hsCRP after one dose of canakinumab to determine who most would benefit from ongoing treatment with this expensive agent. Coronary Artery Calcium Score CAC is a marker of subclinical coronary atherosclerosis burden, and CAC scores are measured using non-contrast computed tomography of the chest.(24)

CAC as a cardiovascular risk assessment tool:

CAC score is a well-established independent predictor of CVD events. (11) The significant advantage of using CAC for CV risk assessment is a consistent improvement in risk discrimination and risk reclassification in asymptomatic individuals. These findings stem from numerous prospective, population-based cohorts of adults without overt CVD. (25-30) The degree of improvement in risk discrimination and reclassification afforded by CAC is much higher than with other non-traditional risk factors (TRF), including hsCRP.(31,32) For example, in the Rotterdam Study, the hazard ratio for incident coronary heart disease (CHD) was greater than sixfold in those with the highest versus lowest CAC quartile, while it was only 1.6 for the same quartile comparison for hsCRP.(31) The powerful CV risk information conferred by CAC testing has the potential to guide appropriate preventive therapy.(33-35) In an analysis of a JUPITER trial-eligible 12 LipidSpin • Volume 17, Issue 1 • January 2019 “CAC is a powerful risk marker and an effective adjunct to TRF in identifying those at highest CV risk who would most benefit from preventive therapies.” Official Publication of the National Lipid Association 13 population of the Multi-Ethnic Study of Atherosclerosis (MESA) study, applying CAC scores markedly splayed CVD risk and utility of rosuvastatin, such that the 5-year number needed to treat for preventing CVD events was 124 with a CAC of 0 versus only 19 with a CAC >100.(36) MESA investigators also demonstrated that, among those with statin indication per the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, approximately one-half have a CAC score of 0, placing them in a risk group where statins generally would not be warranted.(33) Additional studies have extended this paradigm to aspirin use and blood pressure management whereby CAC testing can enhance the efficiency of these treatments.(37,38) In all of these scenarios, CAC testing is agnostic to the underlying biology contributing to CVD risk, but it identifies those with the highest absolute risk and provides an opportunity to accrue the greatest absolute risk reduction with primary preventive therapies.

CAC as a biological target for reducing cardiovascular risk:

Given the strong independent association of CAC with CV risk, it is tempting to track the effectiveness of preventive interventions with serial CAC scanning. However, several lines of evidence point to the fallacy of this approach. In the placebo-controlled, randomized Saint Francis Heart Study, patients with elevated CAC (≥ 80th percentile for sex and race) randomized to atorvastatin had significant reductions in LDL-C and trended toward a 30% reduction in CV events compared to those randomized to placebo, but there was no difference in the progression of CAC over time in these two groups.(39) Similarly, a sub-analysis from the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) trial demonstrated that, despite greater than 50% lowering of LDL-C in the arm randomized to atorvastatin with baseline CAC of ~ 200, the increase in CAC over two years was similar to that in the placebo arm.(40) If one serially reassessed CAC in patients similar to these trial populations, one erroneously would assume they “failed” statin therapy.

One potential explanation for these observations is that statins can promote coronary atheroma calcification independent of their beneficial plaqueregressive effects.(41,42) Also, the baseline CAC score dominates the risk estimate, and progression or change over time adds little to risk estimation for most patients.(43) Lastly, CAC progression has been shown to be an inevitable process that happens in a predictable manner.(44) These observations cast serious doubts on the benefit of serial CAC scanning to monitor response to preventive therapies and discredit its value as a titratable target for CV risk reduction.(45,46)

Conclusion

CAC is a powerful risk marker and an effective adjunct to TRF in identifying those at highest CV risk who would most benefit from preventive therapies. The 2018 AHA/ACC Guideline on the Management of Blood Cholesterol recommends that CAC scanning may be considered in guiding primary prevention decisions among individuals at intermediate 10-year risk (7.5% to 20%) of developing an atherosclerotic cardiovascular disease (ASCVD) event (class of recommendation IIa). (47) However, it reflects CV risk by approximating the total burden of atherosclerosis and not by elucidating specific biologic pathways that can be targeted. In contrast, hsCRP is a modest predictor of CV risk and its elevated levels are considered an ASCVD risk-enhancer in the current cholesterol guidelines. (47) The landmark CANTOS trial, which offers the potential to specifically target inflammation, has led to the re-emergence of hsCRP assessment. HsCRP may serve as a trackable biologic indicator of those who are deriving the greatest benefit from emerging anti-inflammatory therapy.

Disclosure statement: Dr. Mehta has no financial disclosures to report. Dr. Khera has no financial disclosures to report.

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