Reducing Inflammation to Reduce Atherothrombotic Risk
- Authors:
- Ridker PM
- Citation:
- Clinician’s Guide to Reducing Inflammation to Reduce Atherothrombotic Risk: JACC Review Topic of the Week. J Am Coll Cardiol 2018;72:3320-31.
The following are key points to remember about reducing inflammation to reduce atherothrombotic risk:
- Many patients sustain life-threatening cardiovascular (CV) events despite control of conventional risk factors.
- Inflammation, measured by high-sensitivity C-reactive protein (CRP) or interleukin (IL)-6, is strongly associated with future vascular events.
- The inflammatory biomarker high-sensitivity CRP predicts CV risk with magnitude of effect comparable to low-density lipoprotein (LDL) or high-density lipoprotein; IL-6 measurement is not clinically available.
- The recent multicountry CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed for the first time that reducing inflammation by targeting IL-1 beta reduces vascular events in proportion to high-sensitivity CRP reduction without lowering LDL cholesterol.
- CANTOS included 10,061 stable post-myocardial infarction patients with high-sensitivity CRP levels ≥2 mg/l (mean 4.2 mg/dl) despite aggressive statin use, antiplatelet agents, and renin-angiotensin inhibitors. Median LDL was 82 mg/dl. Participants were randomized to placebo or 50, 150, or 300 mg of canakinumab subcutaneously every 3 months.
- During the followup period (median 3.7 years), those on 150 mg showed a significant 15% reduction in major adverse cardiac events (MACE) (nonfatal myocardial infarction, nonfatal stroke, and CV death) and a 17% reduction in MACE+ (MACE plus unstable angina requiring urgent coronary revascularization). Virtually identical effects occurred with 300 mg (but without reaching prespecified statistical significance level of 0.01058). In patients with high-sensitivity CRP level <2 mg/l after the first dose, 26% reduction in MACE and 31% reduction in CV and all-cause mortality occurred (all p < 0.001). The risk reductions were smaller and not statistically significant in those without such a response.
- Clinicians should distinguish between patients with residual cholesterol risk and residual inflammatory risk.
- Residual inflammatory risk, defined as high-sensitivity CRP level >2 mg/l despite aggressive LDL cholesterol lowering, is common even with LDL cholesterol levels as low as 20-30 mg/dl.
- A simple method to predict long-term benefit with canakinumab is to administer a single dose and then treat long-term only those whose high-sensitivity CRP reduced >50% or to <2 mg/l on treatment.
- During canakinumab treatment, high-sensitivity CRP should be monitored because benefit tracks directly with level of high-sensitivity CRP reduction achieved.
- The benefit of canakinumab is not established in acute coronary syndrome.
- The author affirms “the inflammation hypothesis of atherothrombosis neither conflicts nor competes with the lipid hypothesis.”
- An individualized approach to therapy should be utilized. A patient may also have residual thrombotic risk, residual triglyceride risk, and/or residual lipoprotein(a) risk. For each, proven therapy exists, or major trials are in progress or planned.
Keywords: Inflammation, Thrombosis, Antibodies, Monoclonal, Biomarkers, Pharmacological, Lipoproteins, HDL, Cholesterol, LDL, Cholesterol, Myocardial Infarction, Angiotensins, Platelet Aggregation Inhibitors
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