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November 2, 2026CureusOpen Access

Residual Inflammatory Risk in Patients With Established Atherosclerotic Cardiovascular Disease and Low-Density Lipoprotein Cholesterol at Target: A Systematic Review and Meta-Analysis

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Key result

Residual inflammatory risk is linked to ~48% higher major cardiovascular events risk in patients with controlled LDL-C.

HR 1.48
95% CI 1.16-1.88
n=26,722

Why the study?

Many patients with established ASCVD who reach guideline LDL-C targets still experience recurrent events, and the prognostic impact of residual inflammatory risk (hs-CRP ≥2 mg/L) had not been quantified in this LDL-at-target population.

Does residual inflammatory risk (hs-CRP >=2 mg/L) increase the risk of major adverse cardiovascular events and mortality compared with hs-CRP <2 mg/L in patients with established ASCVD and LDL-C <70 mg/dL?

Key Points

To quantify the prognostic impact of residual inflammatory risk among patients with established atherosclerotic cardiovascular disease who achieved low-density lipoprotein cholesterol targets.
Systematic review and meta-analysis searching PubMed, Cochrane CENTRAL, and EMBASE through May 2026 for cohorts and prespecified analyses comparing hs-CRP ≥2 versus <2 mg/L in an LDL-C <70 mg/dL stratum.
Identified seven eligible studies (five contributing adjusted estimates) and pooled adjusted hazard ratios for major adverse cardiovascular events and mortality using random-effects models.
Residual inflammatory risk prevalence ranged from 29% to 47% across cohorts.
High hs-CRP was independently associated with major adverse cardiovascular events (pooled adjusted HR 1.48, 95% CI 1.16–1.88) and all-cause mortality (HR 2.13, 95% CI 1.27–3.57), with low certainty of evidence.
Associations for myocardial infarction, stroke, and repeat revascularization were not statistically significant.

Study Design

Type

Meta-Analysis (n=26,722)

Multicenter

Yes

Structured PICO

Does residual inflammatory risk (hs-CRP >=2 mg/L) increase the risk of major adverse cardiovascular events and mortality compared with hs-CRP <2 mg/L in patients with established ASCVD and LDL-C <70 mg/dL?

P

Population

26,722 adults across 5 pooled cohorts (7 eligible studies total) with established ASCVD and controlled LDL-C (<70 mg/dL), followed for a median or mean of 1 to 6 years.

E

Exposure

Residual inflammatory risk (RIR), defined as high-sensitivity C-reactive protein (hs-CRP) >=2 mg/L measured outside the acute-phase window (before the event, >=48 h after PCI, or as a delayed/persistent measurement).

C

Comparator

No residual inflammatory risk, defined as hs-CRP <2 mg/L within the same LDL-C <70 mg/dL stratum.

O

Outcome

Major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction, or stroke as defined in each study) over 1 to 4.5 years of follow-up in pooled cohorts.composite

Main Result

Hazard Ratio: 1.48 (95% CI 1.16–1.88)

Absolute Event Rate: 9.1% vs 5%

Limitations

Low certainty of evidence downgraded for residual confounding and inconsistency
Substantial statistical heterogeneity across studies (I² = 69% for MACE, 78% for all-cause mortality)
Wide 95% prediction intervals crossing unity (0.88-2.48 for MACE)
Fewer than 10 studies precluded formal funnel-plot asymmetry and Egger's tests for publication bias
Two eligible studies could not be quantitatively pooled due to incompatible referent groups or distinct stroke-cohort designs
Low GRADE certainty of evidence downgraded for residual confounding and inconsistency
Substantial statistical heterogeneity for MACE (I²=69%) and all-cause mortality (I²=78%)
95% prediction intervals crossed unity for MACE (0.88-2.48) and mortality (0.69-6.53)
Small number of pooled studies (<10) precluded formal statistical testing for publication bias
Two of seven eligible studies could not be quantitatively pooled due to differing referent groups or study endpoints

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

In patients with established ASCVD and well-controlled LDL-C (<70 mg/dL), residual inflammatory risk (hs-CRP >=2 mg/L) affects 29-47% of patients and independently predicts a 48% higher hazard of MACE and more than double the hazard of all-cause mortality.

Abstract

Intensive lowering of low-density lipoprotein cholesterol (LDL-C) reduces recurrent events in atherosclerotic cardiovascular disease (ASCVD), yet many patients who reach guideline LDL-C targets still experience events.Residual inflammatory risk (RIR), defined by high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L, is a candidate driver, but its prognostic impact has not been quantified in the LDL-at-target population.We performed the first systematic review and meta-analysis of RIR restricted to patients with established ASCVD and LDL-C <70 mg/dL.We searched PubMed, Cochrane CENTRAL, and EMBASE from inception to May 2026 for cohorts and prespecified analyses comparing hs-CRP ≥2 versus <2 mg/L within an LDL-C <70 mg/dL stratum.Adjusted hazard ratios (HRs) for major adverse cardiovascular events (MACE) and mortality were pooled using random-effects models, and certainty was rated with GRADE.Seven studies were eligible, and five contributed adjusted estimates.RIR prevalence was 29-47%.RIR was independently associated with higher hazards of MACE (pooled adjusted HR 1.48, 95% CI 1.16-1.88)and all-cause mortality (HR 2.13, 95% CI 1.27-3.57),whereas associations for myocardial infarction, stroke, and repeat revascularization were not statistically significant.Certainty of evidence was low, downgraded for residual confounding and inconsistency.Among patients with established ASCVD and well-controlled LDL-C, RIR was independently associated with higher risks of MACE and all-cause mortality, identifying inflammation as a distinct, potentially modifiable therapeutic target beyond LDL-C lowering.These hypothesisgenerating findings support trials enrolling patients with both LDL-C <70 mg/dL and hs-CRP ≥2 mg/L.The review was registered in PROSPERO (CRD420261381858).

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Cite This Study

Odugbemi et al. (2026) conducted a meta-analysis in Established atherosclerotic cardiovascular disease (ASCVD) with LDL-C at target (<70 mg/dL) (n=26,722). Residual inflammatory risk (hs-CRP >=2 mg/L) vs. No residual inflammatory risk (hs-CRP <2 mg/L) within the same LDL-C <70 mg/dL stratum was evaluated on Major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, stroke) (HR 1.48, 95% CI 1.16-1.88). Residual inflammatory risk was independently associated with higher hazards of major cardiovascular events in ASCVD patients with LDL-C </dL.

synapsesocial.com/papers/6aec1c380f6a78723039e762 https://doi.org/10.7759/cureus.119008

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