Association of high sensitivity C-reactive protein in an established atherosclerotic cardiovascular disease with chronic kidney disease: A prospective cohort study

Aims & objectives:Toestimate the background/residual inflammatory risk caused by hs-CRP in patientswith atherosclerotic cardiovascular disease and CKD who were already ontreatment, identify the clinical factors for elevated hs-CRP levels, andinvestigate the reasons for mortality, and MACEs associated with the progressionand adverse renal events.

4. Justification for study:Hs-CRPis a marker for future risk in patients with previous MI. Patients with previousMI and CKD are at increased risk for future MACE. By assessing hs-CRP levels,we plan to identify the highest-risk subset of people with previous MI and CKD.

5. Departments involved: Department of Cardiology, KMC Manipal

6. Study period: 3 years

7. Sample size :MACEprevalence of 23%

To estimate the prevalence of MACE within 95% CIwidth of 0.06

Margin of error = 3%

13% relative precision

1.96×1.96×0.761×0.239/0.0009 = 776 patients

 Adding 10% non-responsive samples

The final sample size is 776+78 = 854 patients.

 8. Materials and methods:

a)Inclusion and exclusion criteria:

·      Inclusion criteria:

o   CKD (stages3 and 4) defined as baseline eGFR > 15 and < 60 mL/min/1.73 m2(using the chronic kidney disease epidemiology collaboration (CKD-EPI)creatinine equation).

o   Evidence ofASCVD by one or more of the following within the last five years from thescreening:

1.     Coronaryheart disease is defined as at least one of the following:

i.     Documentedthe history of MI.

ii.     Priorcoronary revascularization procedure.

iii.      â‰¥ 50% stenosis in major epicardial coronaryartery documented by cardiac catheterization or CT coronary angiography.

2.     Cerebrovasculardisease is defined as at least one of the following:

i.     Priorstroke of atherosclerotic origin.

ii.     Priorcarotid artery revascularization procedure.

iii.      â‰¥ 50% stenosis in carotid artery documented byX-ray angiography, MR angiography, CT angiography or Doppler ultrasound.

3.     Symptomaticperipheral artery disease (PAD) defined as at least one of the following:

i.     Intermittentclaudication with an ankle-brachial index (ABI) ≤ 0.90 at rest

ii.     Intermittentclaudication with a ≥ 50% stenosis in peripheral artery (excluding carotid)documented by X-ray angiography, MR angiography, CT angiography or Dopplerultrasound

iii.      Prior peripheral artery (excluding carotid)revascularization procedure

iv.     Lowerextremity amputation at or above ankle due to atherosclerotic disease(excluding e.g., trauma or osteomyelitis).

·      Exclusion criteria:

I.           Clinical evidence of, or suspicion of activeinfection, myocardial infarction, stroke, hospitalization for unstable anginapectoris, or transient ischemic attack within 30 days prior to recruitment.

II.           Planned coronary, carotid, or peripheral arteryrevascularization known on the day of screening.

III.           Major cardiac surgical, non-cardiac surgical, ormajor endoscopic procedure (thoracoscopic or laparoscopic) within the past 30days prior to recruitment or any major surgical procedure planned at the timeof recruitment.

IV.           hs-CRP levels of more than 20 are excluded andreassessed later about including patients in the study.

b) biological materials required (type - blood,tissue etc., and quantity):

-  Blood-considered in the routineinvestigation

 c)Statistical methods:

·      Continuousvariables will be expressed as mean, SD/median, interquartile range, and qualitativevariables as numbers and percentages.

·      Logisticregression will be used to find the adjusted association of study groups withMACE, adverse renal events, CKD progression, adjusting for demographic andother variables in the study.

·      Allanalyses will be done by using EZR software.

·      Significancewill be indicated by a p-value < 0.05.

d) Tools used:

1. Kuppuswamy socio-economicstatus scale – It is noncommercial-Free to use

attachment added.

2.  Manipal scale for cardiac drug compliance(MSCDC)- Approval Obtained-

attachment added

9.Detailed description of procedure / processes:

•       IEC Clearance

•       Patients who meet inclusion/exclusion criteria areenrolled after providing informed consent.

•       Baseline hsCRP values are checked and recorded.

•       Patients will be observed for MACE, progression ofCKD with elevated and normal levels of hs-CRP who are on standard medicaltherapy.

•       Alongwith the usual follow-up done in the cardiology clinic, monthly telephonicfollow-up for MACE, death, and adverse renal events along with the CKDprogression for every 3 months will be done along with the follow-up ofbaseline, 3 , 6, and 12th months follow-up visits.

•       Socioeconomic status and drug compliance of the patientsalso will be observed and documented.

•       Data will be analyzed through EZR statistical softwarefor the results.

•       Obtainedresults will be collected and reported.

10. Outcome measures:

•       Prevalenceof elevated hs-CRP levels in established ASCVD and CKD.

•       Identifyingthe relationship between raised levels of hs-CRP and other biochemical parametersamong the sub-group population with established ASCVD.

•       Identifyingthe association of clinical and physical parameters with hs-CRP levels in patientswith established ASCVD.

•       Co-relationbetween hs-CRP and MACE rate on total 12 months, follow-up of patients with documentedASCVD on standard medical therapy.

•       Observingthe adverse renal events and progression of CKD.

11. Potential risks and benefits : •       Risks – Risk of loss to follow-upmay jeopardize the validity of outcomes. •       Benefits – Better early detectionand risk stratification among patients with ASCVD and CKD.12. Ethical considerations and methods to addressissues :•       IEC Clearance•       Written informed consent to be obtainedfrom all patients. **13. Budget (givedetails) and proposed funding source:**Funded by Nova Nordisk, India PVT LTD- 3,41,600 Rs - attachment added

 14. Review of literature(within 1000 words):

All the MIsurvivors (>30 days) undergoing hs-CRP testing during routine check-ups inStockholm, Sweden were included in a study done by Carrero J.J et al.from the year 2006−2011. During hospitalization/Emergency Department visits,hs-CRP levels were tested, and followed up on any ongoing antibiotics or signsof an acute sickness in combination with an active/recent malignancy, chronicinfections, or immunosuppression. Inflammation was measured over a three-monthperiod and was linked to death and MACE (composite of MI, ischemic stroke, orCV death). Most patients (66%) with lower haemoglobin, poorer eGFR, andcomorbidities (e.g., heart failure, peripheral vascular disease, stroke, atrialfibrillation, diabetes mellitus, and rheumatoid illnesses) had Hs-CRP more thanor equal to 2 mg/L. They were at a higher risk of MACEs (hazard ratio: 1.28)and death (hazard ratio: 1.42). They had a greater risk of MACEs (hazard ratio:1.28) and death (hazard ratio: 1.42). The levels of hs-CRP were observedto be higher in MI patients in this investigation. This study not onlyidentifies groups at high risk for inflammation, but it also extends thebiomarker’s predictive relevance to real-world healthcare settingsCarrero etal. reported that most patients with MI exhibit elevated hsCRP levels. Theyidentified populations at high-inflammatory risk and the prognostic validity ofhsCRP from trial evidence to real-world healthcare settings.1

Duringroutine check-ups in Stockholm, Sweden, Fu L.E et al. investigated all the MI survivorswho had hs-CRP testing > 30 days following their MI (2006-2011). Patients onantibiotics or with any acute disease, as well as active/recent malignancy,chronic infections, or immunosuppression, and their hs-CRP levels assessedduring hospitalization/Emergency Department visits. Over the course of athree-month baseline period, inflammation was measured. Acute kidney injury andthe study's key outcomes were CKD progression (a composite of doublingplasma creatinine, renal replacement treatment, or renal death). The lower theeGFR category, the greater the baseline hs-CRP levels. Patients with a hs-CRPof less than or equal to 2 mg/L had a greater risk of CKD development (adjustedhazard ratio: 1.42) and AKI (adjusted hazard ratio: 1.29). Regardless ofbaseline kidney function, increased hs-CRP was related with the later risk of AKIand progression of CKD in post-MI patients receiving normal healthcare.2

TonelliM et al.investigated GFR and proteinuria in a population-based cohort in Alberta, Canada.They classified the participants using a proper criterion having MI or diabetesbased on the hospital admission and insurance-claimed data, and discoveredwhich individuals were hospitalized for MI during the hospital visit. Theydefined chronic renal disease as having an eGFR of 15−59.9 mL/min/1.73 m2.The unadjusted rate of MI was more in patients with previous MI (18.5 per 1000 peryears). Patients with diabetes (without CKD) had a lower rate of MI than thosewith CKD (without diabetes; (p <0.0001) in patients without previousMI. Patients with diabetes had a lower rate of incident MI than those with aneGFR of 45 mL/min/1.73 m2 and high proteinuria (6.6 per 1000person-years vs. 12.4). CKD patients were at the highest risk of future CVevents in this investigation.3

In the Prevention of Events withAngiotensin-Converting Enzyme Inhibition (PEACE) study, Sabatine M S etal. assessed hs-CRP levels in individuals with stable coronary arterydisease. MACE events, first-time HF diagnosis, and diabetes were also monitoredin these patients. Greater hs-CRP levels, even >1 mg/L, were linked to ahigher risk of MACE in this investigation (hs-CRP 1−3 mg/L: adjusted hazardratio, 1.39; p =0.016; hs-CRP >3 mg/L: adjusted hazard ratio, 1.52; p=0.003). Increased hs-CRP levels were also alone predicting of new HF (adjustedp <0.001) and diabetes diagnoses (adjusted p <0.001 Even after thecontrolled therapies and baseline variables, an elevated hs-CRP level of >1mg/L is a significant predictor of MACE in a stable CAD.4

15. References:

1. Carrero JJ, Andersson Franko M, Obergfell A, Gabrielsen A, Jernberg T. hsCRP Level and the Risk of Death or Recurrent Cardiovascular Events in Patients with Myocardial Infarction: a Healthcare-Based Study. J Am Heart Assoc. 2019 Jun 4;8(11):e012638. doi: 10.1161/JAHA.119.012638.
2. Fu EL, Franko MA, Obergfell A, Dekker FW, Gabrielsen A, Jernberg T, Carrero JJ. High-sensitivity C-reactive protein and the risk of chronic kidney disease progression or acute kidney injury in post-myocardial infarction patients. Am Heart J. 2019 Oct;216:20-29. doi: 10.1016/j.ahj.2019.06.019.
3. Tonelli M, Sacks F, Pfeffer M, Jhangri GS, Curhan G, Cholesterol, et al. Biomarkers of inflammation and progression of chronic kidney disease.Kidney Int. 2005;68(1):237-45.
4. Sabatine MS, Morrow DA, Jablonski KA, Rice MM, Warnica JW, Domanski MJ, Hsia J, Gersh BJ, Rifai N, Ridker PM, Pfeffer MA, Braunwald E; PEACE Investigators. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation. 2007 Mar 27;115(12):1528-36. Doi: .1161/CIRCULATIONAHA.106.649939. Epub 2007 Mar 19. PMID: 17372173.