Aims & objectives:

    To estimate the background/residual inflammatory risk caused by hs-CRP in patients with atherosclerotic cardiovascular disease and CKD who were already on treatment, identify the clinical factors for elevated hs-CRP levels, and investigate the reasons for mortality, and MACEs associated with the progression and adverse renal events.

4. Justification for study:

Hs-CRP is a marker for future risk in patients with previous MI. Patients with previous MI 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 :

 MACE prevalence of 23%

To estimate the prevalence of MACE within 95% CI width 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 (stages 3 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 of ASCVD by one or more of the following within the last five years from the screening:

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

                                                          i.      Documented the history of MI.

                                                        ii.      Prior coronary revascularization procedure.

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

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

                                                          i.      Prior stroke of atherosclerotic origin.

                                                        ii.      Prior carotid artery revascularization procedure.

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

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

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

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

                                                      iii.       Prior peripheral artery (excluding carotid) revascularization procedure

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

·       Exclusion criteria:

                                  I.            Clinical evidence of, or suspicion of active infection, myocardial infarction, stroke, hospitalization for unstable angina pectoris, or transient ischemic attack within 30 days prior to recruitment.

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

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

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

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

                                                                         -  Blood-considered in the routine investigation

c) Statistical methods:

·       Continuous variables will be expressed as mean, SD/median, interquartile range, and qualitative variables as numbers and percentages.

·       Logistic regression will be used to find the adjusted association of study groups with MACE, adverse renal events, CKD progression, adjusting for demographic and other variables in the study.

·       All analyses will be done by using EZR software.

·       Significance will be indicated by a p-value < 0.05.

d) Tools used:

                 1. Kuppuswamy socio-economic status 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 are enrolled after providing informed consent.

•        Baseline hsCRP values are checked and recorded.

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

•        Along with the usual follow-up done in the cardiology clinic, monthly telephonic follow-up for MACE, death, and adverse renal events along with the CKD progression for every 3 months will be done along with the follow-up of baseline, 3 , 6, and 12^th months follow-up visits.

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

•        Data will be analyzed through EZR statistical software for the results.

•        Obtained results will be collected and reported.

10. Outcome measures:

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

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

•        Identifying the association of clinical and physical parameters with hs-CRP levels in patients with established ASCVD.

•        Co-relation between hs-CRP and MACE rate on total 12 months, follow-up of patients with documented ASCVD on standard medical therapy.

•        Observing the adverse renal events and progression of CKD.

11. Potential risks and benefits :

•        Risks – Risk of loss to follow-up may jeopardize the validity of outcomes.

•        Benefits – Better early detection and risk stratification among patients with ASCVD and CKD.

12. Ethical considerations and methods to address issues :

•        IEC Clearance

•        Written informed consent to be obtained from all patients.

13. Budget (give details) 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 MI survivors (>30 days) undergoing hs-CRP testing during routine check-ups in Stockholm, 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 signs of an acute sickness in combination with an active/recent malignancy, chronic infections, or immunosuppression. Inflammation was measured over a three-month period and was linked to death and MACE (composite of MI, ischemic stroke, or CV death). Most patients (66%) with lower haemoglobin, poorer eGFR, and comorbidities (e.g., heart failure, peripheral vascular disease, stroke, atrial fibrillation, diabetes mellitus, and rheumatoid illnesses) had Hs-CRP more than or 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 observed to be higher in MI patients in this investigation. This study not only identifies groups at high risk for inflammation, but it also extends the biomarker’s predictive relevance to real-world healthcare settingsCarrero et al. reported that most patients with MI exhibit elevated hsCRP levels. They identified populations at high-inflammatory risk and the prognostic validity of hsCRP from trial evidence to real-world healthcare settings.¹

During routine check-ups in Stockholm, Sweden, Fu L.E et al. investigated all the MI survivors who had hs-CRP testing > 30 days following their MI (2006-2011). Patients on antibiotics or with any acute disease, as well as active/recent malignancy, chronic infections, or immunosuppression, and their hs-CRP levels assessed during hospitalization/Emergency Department visits. Over the course of a three-month baseline period, inflammation was measured. Acute kidney injury and the study&#39;s key outcomes were CKD progression (a composite of doubling plasma creatinine, renal replacement treatment, or renal death). The lower the eGFR category, the greater the baseline hs-CRP levels. Patients with a hs-CRP of less than or equal to 2 mg/L had a greater risk of CKD development (adjusted hazard ratio: 1.42) and AKI (adjusted hazard ratio: 1.29). Regardless of baseline kidney function, increased hs-CRP was related with the later risk of AKI and progression of CKD in post-MI patients receiving normal healthcare.²

 Tonelli M 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 diabetes based on the hospital admission and insurance-claimed data, and discovered which individuals were hospitalized for MI during the hospital visit. They defined 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 per years). Patients with diabetes (without CKD) had a lower rate of MI than those with CKD (without diabetes; (p <0.0001) in patients without previous MI. Patients with diabetes had a lower rate of incident MI than those with an eGFR of 45 mL/min/1.73 m² and high proteinuria (6.6 per 1000 person-years vs. 12.4). CKD patients were at the highest risk of future CV events in this investigation.³

In the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) study, Sabatine M S et al. assessed hs-CRP levels in individuals with stable coronary artery disease. MACE events, first-time HF diagnosis, and diabetes were also monitored in these patients. Greater hs-CRP levels, even >1 mg/L, were linked to a higher risk of MACE in this investigation (hs-CRP 1−3 mg/L: adjusted hazard ratio, 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 (adjusted p <0.001) and diabetes diagnoses (adjusted p <0.001 Even after the controlled therapies and baseline variables, an elevated hs-CRP level of >1 mg/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.