C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

By Aly Becraft, MS; Kevin C Maki, PhD


Each year approximately 29% of heart attack (myocardial infarction) events in the USA occur in people who have previously had a heart attack.1 Even with ideal medical interventions and treatments, there is high risk of subsequent cardiac events and death in people that have suffered an acute coronary syndrome (ACS).2,3 This elevated risk may be lowered if specific biomarkers associated with future adverse cardiac events can be identified and used in long-term management following ACS. Several biomarkers of cardiovascular disease (CVD) are currently being studied, including those related to inflammation, a major contributor to the development of atherothrombosis. Well-studied inflammatory biomarkers include fibrinogen, monocyte chemotactic protein-1, tumor necrosis factor-alpha, C-reactive protein (CRP), and others.4

High-sensitivity CRP (hsCRP) measurement has become a routine and effective method for predicting risk of CVD and is also used as a prognostic marker after ACS.5 Lowered hsCRP levels in patients with chronic CVD treated with anti-inflammatory and statin therapies has been shown to improve treatment outcomes and lower risk of adverse cardiovascular events.3,6 Furthermore, other studies have reported a correlation between CRP levels and the effectiveness of statin treatment7,8 and high-dose statins have been demonstrated to accelerate decreases in hsCRP levels after ACS.9,10 While there is a substantial body of research demonstrating these associations, in order to optimize clinical use, the applications for hsCRP levels in the treatment of CVD are still being investigated.


Mani et al. recently published a secondary analysis of the Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial to assess whether longitudinal changes in hsCRP levels were associated with residual risk of cardiovascular events or death following ACS.11 This randomized, double blind, multicenter trial tested treatment of ACS with the secretory phospholipase A2 inhibitor, varespladib, in 5145 patients. Treatment began within 96 hours of an ACS. Only patients with qualifying baseline and longitudinal hsCRP levels measured at weeks 1, 2, 4, 8, and 16 weeks of the trial were used in this secondary analysis (n = 4257). The primary end point of this analysis was the association between hsCRP and a major adverse cardiac event (MACE) defined as the composite of cardiovascular death, non-fatal myocardial infarction, stroke, or hospitalization for unstable angina at 16 weeks. Secondary end points included the associations between hsCRP and individual components of the primary composite end point.11 The trial treatment had no significant effects on hsCRP level.


Analyzed patients were overweight, had a mean age of 60.3 years and 74% were male.11 Approximately 77% of the patients had hypertension, 51% had hypercholesterolemia and 65% had metabolic syndrome. In addition, 30% of patients had experienced a previous myocardial infarction, 18% had undergone percutaneous coronary intervention, and 36% of patients were using lipid-modifying therapy prior to the trial.


Of the 247 events observed in the VISTA-16 trial, 145 were included in this analysis.11 Baseline hsCRP levels following ACS were associated with higher risk for future MACE and death, as had been shown previously. Longitudinal increases in hsCRP levels were associated with significantly higher incidence of MACE [hazard ratio (HR) per SD 1.16, P < 0.001], myocardial infarction (HR 1.16, P < 0.001), all-cause death (HR 1.25, P < 0.001), and cardiovascular death (HR 1.26, P < 0.001). These relationships were not attenuated in multivariate models that adjusted for several other predictive variables and treatment assignment.  Positive associations between changes in longitudinal hsCRP levels and age (P = 0.03), body mass index (P < 0.001), hypertension (P < 0.001), congestive heart failure (P < 0.001), and active smoking (P = 0.003) were reported. 


Comment: These results suggest that measuring longitudinal changes in hsCRP levels after ACS is useful for assessing residual cardiovascular risk.  Higher baseline hsCRP after ACS and persistent hsCRP elevation were both independently associated with increased risks for MACE and individual MACE components, as well as CVD and total mortality.  Each SD increase in hsCRP during follow-up was associated with an increase of 15% in MACE, 25% in total mortality and 26% in CVD mortality.


The present study adds to previous findings, such as those from the Canakinumab Antiinflammatory Thrombosis Outcome Study,12 which demonstrated similar associations between higher hsCRP levels and adverse cardiovascular outcomes and mortality and further showed that an anti-inflammatory intervention reduced MACE risk. Similarly, results from epidemiological studies have suggested that increases in serial measurement of CRP in relatively healthy populations are associated with adverse cardiovascular outcomes and increased mortality.13,14 Further study is needed to evaluate longer-term outcomes and to assess the efficacy of various treatment modalities to lower MACE and mortality incidence in those identified as having elevated residual risk after ACS due to persistent hsCRP elevation.



  1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
  3. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
  4. Dhingra R, Vasan RS. Biomarkers in cardiovascular disease: statistical assessment and section on key novel heart failure biomarkers. Trends Cardiovasc Med. 2017;27(2):123-133.
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  6. Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131.
  7. Ridker PM, Rifai N, Clearfield M, et al. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344(26):1959-1965.
  8. Ridker PM, Cannon CP, Morrow D, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20-28.
  9. Kinlay S, Schwartz GG, Olsson AG, et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline ininflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108(13):1560-1566.
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  2. Mani P, Puri R, Schwartz GG, et al. Association of initial and serial C-reactive protein levels with adverse cardiovascular events and death after acute coronary syndrome: a secondary analysis of the VISTA-16 trial. JAMA Cardiol. 2019;Epub ahead of print.
  3. Ridker PM, MacFadyen JG, Everett BM, et al. CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391(10118):319-328.
  4. Currie CJ, Poole CD, Conway P. Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality. Heart. 2008;94(4):457-462.
  5. Parrinello CM, Lutsey PL, Ballantyne CM, et al. Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality. Am Heart J. 2015;170(2):380-389.


Photo by Lucas Vasques

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

 By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 Dapagliflozin and Cardiovascular Events in the DECLARE-TIMI 58 Trial

The Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) Trial was designed to assess the safety and efficacy of dapagliflozin (10 mg/d), a selective sodium-glucose cotransporter (SGLT)-2 inhibitor, in the reduction of cardiovascular events in patients with type 2 diabetes mellitus.  This was a phase 3b, randomized, double-blinded, placebo-controlled trial in 17,160 patients ≥40 y of age with type 2 diabetes and either cardiovascular disease (CVD) or multiple CVD risk factors.  The primary efficacy endpoints were major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction or ischemic stroke) and a composite of heart failure hospitalization (HHF) or cardiovascular death.  Median follow-up was 4.5 y.  The results for the outcomes including the hazard ratios (HR) and 95% confidence intervals (CI) are shown in the table below.




(n = 8582)


(n = 8578)

HR (95% CI)



Rate/1000 patient-y






0.93 (0.84 to 1.03)





0.83 (0.73 to 0.95)





0.73 (0.61 to 0.88)

Cardiovascular death



0.98 (0.82 to 1.17)

All-cause mortality



0.93 (0.82 to 1.04)

Renal composite1



0.76 (0.67 to 0.87)

1Renal outcome was described as a 40% decrease in estimated glomerular filtration rate to <60 mL/min/1.73 m2, end-stage renal disease or death from renal or cardiovascular cause.


Conclusion:  Compared to placebo, dapagliflozin was safe and reduced the composite of cardiovascular death or HHF, but did not significantly reduce the incidence of MACE.


Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018; Epub ahead of print.



Ezetimibe and Cerebro- and Cardiovascular Events in the EWTOPIA Trial
The role of lipid-lowering therapy in elderly (≥75 y of age) Japanese men and women with elevated low-density lipoprotein cholesterol (LDL-C) levels, but no history of coronary artery disease had not been well studied previously.  The Ezetimibe Lipid Lowering Trial on Prevention of Atherosclerosis in 75 or Older (EWTOPIA 75) investigation was a prospective, multi-center, open-label, blinded endpoint, randomized controlled trial conducted between 2009-2016 in Japanese men and women whose LDL-C level was ≥140 mg/dL and who had one or more cardiovascular risk factors (diabetes, hypertension, smoking, low high-density lipoprotein cholesterol, high triglycerides, previous history of cerebral infarction or peripheral artery disease). 

The primary endpoint was MACE, defined as a composite of sudden cardiac death, myocardial infarction, coronary revascularization, and/or stroke.  Secondary outcomes included cardiac events, cerebrovascular events, and all-cause mortality.  Eligible patients were randomized to either an ezetimibe group (10 mg/d plus dietary counseling; n = 1716) or a control group (dietary counseling alone; n = 1695).  LDL-C levels were reduced significantly more among patients taking ezetimibe (from 161 to 120 mg/dL) compared to subjects in the control group (from 162 to 131 mg/dL) (p < 0.001 for interaction).  The results for the outcomes are shown in the table below.



HR (95% CI)



0.66 (0.50 to 0.86)


Cardiac events

0.60 (0.37 to 0.98)


Cerebrovascular events

0.78 (0.55 to 1.11)


All-cause mortality

1.09 (0.89 to 1.34)


Conclusions:  In an elderly (≥75 y) Japanese population, ezetimibe (10 mg/d) plus dietary counseling compared to dietary counseling alone for primary prevention (elevated LDL-C, no history of CVD), was shown to help prevent cerebro- and cardiovascular events. 


Kumbhani DJ.  Ezetimibe in prevention of cerebro- and cardiovascular events in middle- to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol – EWTOPIA 75.   https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/08/22/56/ewtopia75#references-for-article.

Ouchi Y. Ezetimibe in prevention of cerebro- and cardiovascular events in middle-to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol: a multicenter, randomized, controlled, open-label trial. Presented at AHA 2018. November 10, 2018. Chicago, IL.



The Cardiovascular Inflammation Reduction Trial (CIRT): Low Dose Methotrexate for the Prevention of Atherosclerotic Events
CIRT was a randomized, double-blind trial of low-dose methotrexate (LD-MTX; target dose 15-20 mg/week) or placebo in patients with a prior myocardial infarction or multi-vessel coronary disease who also had either type 2 diabetes or metabolic syndrome.  It was designed to investigate whether inhibiting inflammation with LD-MTX might provide a similar cardiovascular benefit to that shown previously by treatment with canakinumab, an anti-inflammatory agent.  At the outset of CIRT, the primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death.  Towards the end of the trial, but before the trial was unblinded, hospitalization for unstable angina that led to urgent revascularization was added to the composite primary endpoint.

Eligible patients were randomly assigned to either LD-MTX (n = 2391) or placebo (n = 2395), and all patients also received 1 mg folate/day.  The trial was stopped after a median follow-up of 2.3 years (maximum 5.1 years) because it had crossed a pre-specified boundary for futility for both the original and final endpoints, and due to the lack of evidence for a reduction in C-reactive protein (CRP) with LD-MTX.  Median changes in inflammatory markers from enrollment to eight months in the LD-MTX and placebo groups, respectively, were 0.09 and 0.05 mg/L for CRP, -0.24 and -0.31 pg/mL for interleukin (IL)-1ß and 0.30 and 0.04 pg/mL for IL-6 (all p >0.05).  Results for the cardiovascular endpoints are shown below.




(n = 2391)


(n = 2395)

HR (95% CI)



Rate/100 patient-y



Original MACE



1.01 (0.82 to 1.25)


Final MACE



0.96 (0.79 to 1.16)


Conclusions:  In patients with prior myocardial infarction or multivessel CVD with either type 2 diabetes or metabolic syndrome, LD-MTX did not reduce inflammatory markers or cardiovascular events when compared to placebo.


Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2018; Epub ahead of print.

Photo by Aaron Bean