Has the time finally come to measure hsCRP universally in primary and secondary cardiovascular prevention?

Heart attack, stroke, and atherothrombotic cardiovascular deaths are disorders characterized by chronic hyperlipidaemia in the setting of a persistent pro-inflammatory response, often exacerbated by hypertension and behavioural factors such as smoking. Yet, while European internists and cardiologists enthusiastically measure cholesterol and blood pressure in virtually all of their patients, surprisingly few measure high sensitivity C-reactive protein (hsCRP), a validated measure of cardiovascular inflammation. This reluctance is neither evidence based nor in the best interest of patient care. The first North American and European demonstrations in primary prevention that hsCRP predicts risk independently of traditional factors appeared 20 years ago.1–3 In the primary prevention setting, as shown in multiple cohorts and meta-analyses,4 , 5 measurement of hsCRP adds as much to risk prediction as does evaluation of HDL or total cholesterol, both of which are universally recommended in current European prevention guidelines (even in the absence of evidence that raising HDL cholesterol improves outcomes6). Indeed, the risk associated with a 1 SD increase in hsCRP is at least as great, if not greater, than that associated with a comparable 1 SD increase in cholesterol or blood pressure, even after adjustment for a wide range of additional factors. Some European physicians continue to argue that measures of hsCRP are too variable for clinical work, despite studies repeatedly showing that the tracking coefficients over time for hsCRP are fully comparable with those of blood pressure and cholesterol.7 , 8 Other clinicians continue to argue that there is no evidence that treatment options exist in primary prevention for patients with elevated hsCRP. Yet, the JUPITER trial—published more than a decade ago—made it clear that individuals with levels of hsCRP >2 mg/L benefit from statin therapy even in the absence of overt hyperlipidaemia.9 Multiple trials have shown that the benefits of statin therapy relate to both lipid lowering and inhibition of inflammation, with on-treatment hsCRP levels as important a prognostic factor as on-treatment levels of LDL cholesterol.10–15 Very recent data suggest that low levels of hsCRP but not low levels of LDL cholesterol are protective for stroke.16 What then is the situation in secondary prevention? More than 40 studies published since 1995 in prominent journals have demonstrated that elevated levels of hsCRP are a major independent determinant of vascular risk in a wide range of settings, including following acute coronary ischaemia, in stable secondary prevention, post-percutaneous coronary intervention (PCI), post-bypass surgery, and in multiple high-risk patient groups such as those with moderate to severe chronic kidney disease and diabetes (a small sampling of these studies are cited here).17–22 Until the publication of the CANTOS trial, however, there was little evidence that targeting residual inflammatory risk beyond statin therapy could change clinical outcomes.23 Yet CANTOS provided proof of principle that targeting innate immunity, at least with a monoclonal antibody that reduces the critical interleukin-1β to interleukin-6 to CRP pathway, significantly lowers recurrent rates of myocardial infarction and cardiovascular death among patients already treated with high intensity statins. The magnitude of risk reduction observed with canakinumab (an intervention that results in large reductions in interleukin-6 and CRP but no reduction in LDL cholesterol) was of similar magnitude to the risk reduction observed with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition (an intervention that results in large reductions in LDL cholesterol but no reduction in either IL-6 or CRP). Further, the benefits of canakinumab were directly related to the magnitude of hsCRP and IL-6 lowering.24 , 25 The importance of both lipid lowering and inhibition of inflammation is striking; as recently demonstrated in the FOURIER and SPIRE trials, residual inflammatory risk as evaluated by hsCRP remains unabated even among those with LDL cholesterol levels as low as 20 mg/dL.26 , 27 In this issue of the European Heart Journal, Kalkman and colleagues present yet more evidence supporting hsCRP use in secondary prevention.28 Among 7026 PCI patients with serial hsCRP measures treated at the Mount Sinai Hospital in New York between 2009 and 2016, a total of 38% had persistently high residual inflammatory risk (hsCRP >2 mg/L) despite high quality care, and another 10% developed residual inflammatory risk over time. These rates are similar to those found in prior studies of stable atherosclerosis29 and in a very recent analysis of post-myocardial infarction patients in the US National Health and Nutrition Examination Survey.30 Equally important, Kalkman and colleagues followed these patients over 12 months and found that rates of recurrent myocardial infarction were 7.5% for those with hsCRP persistently above 2 mg/L as compared with 4.3% for those with persistently lower hsCRP. Rates for all-cause mortality were 2.6% and 0.7%, respectively, for those with and without residual inflammatory risk. In subgroups analyses, adverse outcomes associated with elevated hsCRP were present among women as well as men, and among those with LDL cholesterol levels above and below 70 mg/dL. These results demonstrate that persistent high residual inflammatory risk is observed frequently in patients undergoing PCI with significantly higher all-cause mortality and myocardial infarction rates at 1-year follow-up. Therefore, residual inflammatory risk in these patients should be identified in order to explore further treatment options. Following lifestyle advice related to diet, exercise, smoking cessation, and blood pressure control, the next step in atherosclerosis prevention is statin therapy, a powerful lipid-lowering and anti-inflammatory intervention.31 For secondary prevention patients, after the further addition of aspirin, it is crucial to recognize that persistent hyperlipidaemia and/or a persistent pro-inflammatory response represent a continuum of biological risk (Figure 1). For some statin-treated patients (such as those with predominantly residual cholesterol risk and LDL levels that remain >100 mg/dL or 2.65 mmol/L), the underlying biology driving recurrent events is persistent hyperlipidaemia, and consideration of further LDL reduction is an evidence-based strategy supported by the IMPROVE-IT, FOURIER, SPIRE, and ODYSSEY trials. For other statin-treated patients (such as those with predominantly residual inflammatory risk and an hsCRP that remains >2 mg/L), the underlying biology driving recurrent events is a persistent vascular inflammation, and consideration of further inflammation reduction is an evidence-based position supported by the effectivness of the interleukin-1β antibody canakinumab as demonstrated in CANTOS. The spectrum of residual inflammatory risk and residual cholesterol risk. Following exercise, diet, and smoking cessation, statins should be initiated in primary and secondary cardiovascular prevention to lower both LDL-C and hsCRP. Subsequent therapeutic choices should be based on absolute risk and on a consideration of the underlying biological process driving that risk, whether it be persistent hyperlipidaemia, a persistent pro-inflammatory response, or a combination of these two processes. Physicians can only address the biological processes they measure. Without assessment of LDL cholesterol, it is impossible to identify and manage hyperlipidaemia effectively. Without knowledge of systolic and diastolic blood pressure, it is impossible to identify and manage hypertension effectively. Without measuring hsCRP, it is unclear how we will effectively identify and manage residual inflammatory risk. Today while the management of the residual inflammatory risk involves more aggressive and guideline-based treatment of the currently known risk factors, the introduction of effective anti-inflammatory drugs in the near future will provide even better control of this residual risk. As prominently noted by Professor Eugene Braunwald in the pages of this journal 7 years ago, objections to hsCRP screening do little more than create controversy where none exists.32 That controversy, however, has resulted in less than optimal preventive care for millions of high-risk European patients. Conflict of interest: P.M.R. served as the Principle Investigator of the JUPITER and CANTOS trials, funded by AstraZeneca and Novartis, respectively; has served as a consultant to Novartis, Corvidia, Inflazome, CiVi Biopharma, and Pfizer; and is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that pertain to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens. W.K. served on the Executive Steering Committee of JUPITER and CANTOS, as a consultant for Amgen, DalCor, Kowa, Novartis, Pfizer, and Sanofi, and has received modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer, and Sanofi. J.J.K. served on the Executive Committees of the JUPITER and CANTOS trials and as a consultant for Affiris, Amgen, Civi Biopharma, Esperion, MedImmune, Madrigal, Pfizer, North Sea Therapeutics, and Staten Biotech. F.M. served as the Switzerland Principle Investigator for the IMPROVE-IT and FOURIER trials. T.F.L. has received research or educational grants and honoraria from Amgen, Novartis, and Roche Diagnostics.