Low LDL-C but High hsCRP Linked to Increased Events After PCI

Debra L Beck

May 14, 2019

Patients undergoing percutaneous coronary intervention (PCI) who had well-controlled LDL cholesterol (LDL-C) but persistently elevated high-sensitivity C-reactive protein (hsCRP) concentrations had a more than twofold greater risk for major adverse cardiac and cerebrovascular events, compared with those with low LDL-C and low hsCRP levels, a new study shows.

"What we wanted to do was to really understand what happens to people who have a low baseline level of LDL-C but persistent elevation of CRP, and what we saw over a 1-year follow-up was a stepwise increase in major adverse cardiovascular and cerebrovascular events," senior author Roxana Mehran, MD, Mount Sinai Hospital, New York City, told theheart.org | Medscape Cardiology.

When patients were categorized according to their serial hsCRP levels, with high hsCRP defined as at least 2 mg/L, a stepwise increase in the primary end point of major adverse cardiac and cerebrovascular accident (MACCE), defined as death, myocardial infarction, or stroke, within 1 year of the second hsCRP measurement was noted.

The study, published in the May 21 issue of the Journal of the American College of Cardiology, was a retrospective analysis of a prospective PCI registry from Mount Sinai Hospital.

The researchers looked at all patients who underwent PCI between January 2009 and December 2016 at their institution (n = 22,799). They separated out the 3013 patients who had both a baseline LDL-C of 70 mg/dL or less and at least two hsCRP measurements taken at least 4 weeks apart.

After adjustment for possible confounders and using those with persistent low residual inflammatory risk as the reference groups, the presence of persistent high residual inflammation was associated with a 2.10-fold increased risk for MACCE (< .001).

"I think what we're saying here is 'let's not put inflammation to bed,'" said Mehran. "It is a really important issue and we need to go after it and figure it out."

Residual Risk

The term residual inflammatory risk has worked its way into the lexicon on the tail of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) trial, presented in 2017 at the European Society of Cardiology meeting. CANTOS demonstrated that RIR (hsCRP ≥ 2 mg/L) can be successfully treated with canakinumab, a monoclonal antibody targeting interleukin (IL)-1ß, a key cytokine in the inflammatory pathway.

Commenting on this new study in an email, CANTOS principal investigator Paul Ridker, MD, Brigham and Women's Hospital, Harvard Medical School, Boston, said: "Residual inflammatory risk is a major challenge for our patients that cannot simply be addressed with further lipid reduction. As demonstrated here and in multiple other settings, the first step is to measure inflammation itself. Only then can we begin to formulate a targeted treatment plan."

Mehran noted that although her institution routinely measures hsCRP in PCI patients, many do not.

Brendan Everett, MD, also from Brigham and Woman's Hospital, and author of an editorial accompanying the current publication, explained the rationale behind targeting residual risks.

"What Paul Ridker has done — and many people I think agree with this approach, which is why it's become more widespread — is try to parse the residual risk that we know exists in individuals with recurrent atherosclerotic events into its underlying pathophysiologic causes. So, you can have residual cholesterol risk, or residual blood pressure risk, or residual inflammatory risk, and what we see is that these are likely different pathophysiologic pathways and require different therapeutic approaches," he said.

The presence of subclinical inflammation (defined as hsCRP ≥ 2 mg/L) and its associated risk for recurrent events has been shown in several randomized trials, including PROVE-IT TIMI 22, IMPROVE-IT, and SPIRE-1/SPIRE-2, explains Everett in his editorial.

In those trials, the prevalence of an elevated hsCRP and a LDL-C level below 70 mg/dL ranged from 29% to 37%. Even in FOURIER, where median achieved LDL-C was 30 mg/dL, hsCRP was useful for risk-stratifying patients, with higher event rates seen in those with the highest hsCRP concentrations, he noted.

At this time, it's unclear how to best treat subclinical vascular inflammation. Plans to market canakinumab as a treatment for residual inflammatory risk hit a snag last year when the US Food and Drug Administration failed to award canakinumab a cardiovascular indication. The drug is currently indicated for the treatment of rare autoimmune disease.

"I think it is frustrating to many of us who work in this field that canakinumab has not been approved and may not be further pursued for a cardiovascular indication by Novartis, because I think it's clear that there seems to be a subset of patients — not all patients — but a subset of patients that would benefit from having access to that therapy," said Everett in an interview.

He also noted, however, that the evidence for diet and exercise to lower CRP is solid. "All the things with respect to behaviors that you think would be benefits for cardiovascular health do in fact have a beneficial effect on C-reactive protein," he said.

Added Mehran: "This would be the target population for canakinumab, but the drug is not available so for now it's really about diet, exercise, continued medical surveillance, and really, really tight control of all risk factors."

"I've also been talking to my patients a lot about meditation, yoga, relaxation techniques, less time on TV and social media, and more self-reflection, all of which are things we now have an important impact on the inflammatory process," she said.

Mehran added that the infection risk seen in the CANTOS trial is something she would weigh carefully should the drug ever become available for cardiovascular prevention.

Mehran has received institutional research grant support from Eli Lilly/Daiichi-Sankyo, Bristol-Myers Squibb, AstraZeneca, The Medicines Company, OrbusNeich, Bayer, CSL Behring, Abbott Laboratories, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, AUM Cardiovascular, and Beth Israel Deaconess Medical Center; is a member of the executive committees for Janssen Pharmaceuticals, Bristol-Myers Squibb, and Osprey Medical; is a member of the data safety monitoring board of Watermark Research Partners; has received institutional (payment to institution) advisory board funding from Bristol-Myers Squibb and Novartis; has served as a consultant for Medscape, The Medicines Company, Boston Scientific, Merck & Company Cardiovascular Systems, Sanofi USA, Shanghai BraccoSine Pharmaceutical, and AstraZeneca; and holds equity in Claret Medical and Elixir Medical Corporation.

Ridker has served as a consultant to Novartis and is listed as a coinventor on patents held by Brigham and Woman's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens.

Everett has received grant support from Novartis and has served as a consultant for Amgen, Novartis, and Roche Diagnostics.

J Am Coll Cardiol. 2019;73:2401-2409, 2410-2412. Abstract, Editorial

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