Residual Inflammatory Risk and PCI: Worthy Biomarker or Merely Something Else to Measure?

After finding a link between inflammation and MACCE, the study author endorses thinking “outside the box” to lower patient risk.

Residual Inflammatory Risk and PCI: Worthy Biomarker or Merely Something Else to Measure?

Despite having low LDL-cholesterol levels at the time of PCI, patients with a persistent residual inflammation as determined by high-sensitivity C-reactive protein (hsCRP) tests appear to have an increased risk of MACCE postprocedure.

“It is really very, very important to understand that inflammation does play a role,” senior study author Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai Hospital, New York, NY), told TCTMD. While no treatment is currently available for this cohort, “we should be thinking about those patients, survey them more closely, and understand that they're at high risk for major adverse cardiovascular and cerebrovascular events,” she suggested. “Perhaps maybe we need to take a better look and do things outside of the box for these patients—we do know diet, exercise, meditation, yoga, [and] stress reduction could have an important reduction in inflammatory response, and perhaps we need to look for other causes of inflammation in those patients to be sure [of the source].”

For the study, published in the May 21, 2019, issue of the Journal of the American College of Cardiology, Paul Guedeney, MD (Icahn School of Medicine at Mount Sinai Hospital), Mehran, and colleagues looked at 3,013 patients undergoing PCI at their institution who had baseline LDL cholesterol levels ≤ 70 mg/dL and at least two serial hsCRP measurements at least 4 weeks apart between 2009 and 2016. Patients were stratified into the following four categories according to residual inflammatory risk (RIR) status:

  • Persistent low RIR (40.7%): hsCRP ≤ 2 mg/dL at both baseline and follow-up
  • Attenuated RIR (13.7%): hsCRP > 2 mg/dL at baseline and ≤ 2 mg/dL at follow-up
  • Increased RIR (11.5%): hsCRP ≤ 2 mg/dL at baseline and > 2 mg/dL at follow-up
  • Persistent high RIR (34.1%): hsCRP > at both baseline and follow-up

Statins were used at baseline in 86.3% of all patients and were prescribed at discharge in 92.8%.

Overall MACCE, defined as the composite of all-cause death, MI, or stroke within 1 year after the second hsCRP measurement, was 106.6 per 1,000 person-years, yet the incidence rates were highest in patients with increased or persistent high RIR.

Incidence Rates per 1,000 Person-Years of Adverse Outcomes by RIR Status

 

Persistent

Low

Attenuated

Increased

Persistent

High

P Value

MACCE

64.4

96.6

138.0

152.4

< 0.001

MACCE + TVR

139.1

216.4

256.8

262.6

< 0.001

All-Cause Death

13.6

19.9

42.1

67.3

< 0.001

MI

52.7

72.4

96.2

102.4

0.009

Stent Thrombosis

2.3

3.3

4.2

4.1

< 0.001

Stroke

2.3

3.3

4.2

2.7

0.96

TVR

85.2

124.9

138.3

132.5

0.014

TLR

70.8

88.4

119.1

106.7

0.046


On multivariate analysis, the stepwise increase in MACCE risk remained from persistent low to attenuated, increased, and persistent high RIR patients. This was also observed for all-cause death, MI, and the composite of MACC and TVR.

‘A Problem of Broad Importance’

Commenting on the study in an email to TCTMD, Paul Ridker, MD (Brigham and Women's Hospital, Boston, MA), put the problem in perspective. “We can’t treat what we don’t measure,” he said. “This paper confirms that residual inflammatory risk is a major issue for clinical cardiologists and an area of unmet need that will not be solved simply by cholesterol reduction.”

Similarly, in an accompanying editorial, Brendan Everett, MD, MPH (Brigham and Women’s Hospital), writes that the confirmation of persistent high RIR as a frequent risk marker associated with adverse outcomes “suggests a problem of broad importance in patients with established coronary artery disease.”

Although the anti-inflammatory agent canakinumab (Novartis) proved effective in the CANTOS trial, the company has abandoned plans for a CV indication. Mehran, however, said she would like to see the fully human monoclonal antibody or another new drug tested in a similar “event-rich [PCI] population” to see its effect in patients who would be more prone to benefit.

“Now, obviously, the 1% fatal infection rate that we saw in CANTOS would have to be weighed against the benefit of risk reduction of MACE, and we'd have to study whether or not using an inflammasome approach—going after the inflammasome—could be an important pathway that could lead to better clinical outcomes,” she explained. “All of that is yet to be determined, but for now we know these patients are at risk. We have to survey them, we have to think about everything that we're possibly dong and do close follow-up with these patients.”

While there is not yet enough evidence to support hsCRP measurement in every PCI patient, Mehran said she would like to see it assessed more frequently in the future. “We do measure CRPs in our patients who come into our own institution as a prelab requirement because we do like to know what that status is,” she said. “We use it and gauge it as a way to understand if they have an inflammatory process and really our clinicians work very, very hard to [give] the best possible treatments for those patients.”

At the moment, cost is the biggest hurdle to routine testing of hsCRP, Mehran added. “When we show this kind of important close relationship, it could be an important biomarker to follow and to look at. I certainly want to know mine, wouldn't you want to know yours?”

The main message of this study, she concluded, is that “we can't put [inflammation] to bed, yet. It's an important aspect of what's going on with cardiovascular disease and recurrent events.”

 

Note: Mehran is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.

Sources
Disclosures
  • Guedeney reports no relevant conflicts of interest.
  • Mehran reports receiving 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; serving as a member of the executive committees for Janssen Pharmaceuticals, Bristol-Myers Squibb, and Osprey Medical; serving as a member of the data safety monitoring board of Watermark Research Partners; receiving institutional advisory board funding from Bristol-Myers Squibb and Novartis; serving as a consultant for Medscape, The Medicines Company, Boston Scientific, Merck & Company Cardiovascular Systems, Sanofi USA, Shanghai BraccoSine Pharmaceutical, and AstraZeneca; and holding equity in Claret Medical and Elixir Medical Corporation.
  • Everett reports receiving grant support from Novartis and the National Heart, Lung, and Blood Institute and serving as a consultant for Amgen, Novartis, and Roche Diagnostics.

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