Consecutive patients undergoing first time implantation of either a single or dual chamber ICD at the Cleveland Clinic Foundation between October 2002 and October 2003 were prospectively studied. Patients undergoing ICD implantation at the clinic routinely have blood drawn the day before implant for basic haematological and biochemical analyses. Therefore, obtaining BNP and CRP concentrations did not require a separate visit or blood sampling for the patient. All included patients had (1) presence of structural heart disease, (2) either primary or secondary prevention indications for ICD implantation, and (3) serum biomarker concentrations determined from blood drawn the day before implantation. Exclusion criteria were patients having an existing ICD, implantation of a biventricular ICD, a separate pacing indication, residence too remote to attend follow up in a Cleveland Clinic Health System device clinic, or presence of any of the following conditions within 60 days of implantation: decompensated heart failure, acute coronary syndrome, major surgery, or systemic infection. Baseline demographic data, clinical characteristics, ECG, and an echocardiogram were collected within one month before implantation for included patients. NYHA class was assessed on the day before ICD implantation. All patients gave informed consent for the blood tests and procedures and all data were collected in accordance with institutional ethics review board guidelines at the Cleveland Clinic Foundation.
Patients had their venous blood samples drawn from a forearm vein for both BNP and ultrasensitive CRP concentrations on the day before ICD implantation. All blood samples were drawn in the morning after an overnight fast. CRP concentrations were assayed by immunonephelometry with the Dade Behring BNIII analyser protocol (Dade Behring, Deerfield, Illinois, USA; detection limit 0.175 mg/l, upper measurement limit 24 mg/l, expected reference interval < 0.5–2.0 mg/l, coefficient of variation 7.6%) on non‐EDTA serum separated samples. BNP concentrations were determined according to the manufacturer's specifications with the Biosite Diagnostics assay (Biosite Diagnostics, San Diego, California, USA; detection limit < 5 ng/l, upper measurement limit 5000 ng/l, expected reference interval 5–100 ng/l, coefficient of variation 10.1%) on samples collected in EDTA tubes. Samples were analysed by personnel blinded to the patients' clinical data.
End point and follow up
Patients were followed up after implantation in a Cleveland Clinic Health System device clinic at six weeks, three months, and every six months thereafter (our routine follow up schedule). They were also asked to call the device clinic within 72 hours of an ICD discharge to make an appointment for a visit. At each visit the patient was clinically assessed and the device was interrogated. Occurrence of an ICD shock or antitachycardia pacing was confirmed in all cases by device interrogation. The attending staff electrophysiologist in the clinic then analysed the stored electrograms to determine whether the shock or antitachycardia pacing occurred appropriately for the treatment of either sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Another electrophysiologist blinded to the first staff member's interpretation also confirmed the appropriateness of the ICD therapy. Both had to agree in their interpretation of the event for the event to be included as an appropriate ICD therapy. Both electrophysiologists were blinded to the patient's BNP and CRP results.
The end point of the study was the occurrence of any appropriate ICD delivered therapy, whether shock or antitachycardia pacing. Inappropriate ICD therapies (caused by supraventricular tachycardia, device malfunction, etc) were not included for analysis. The mean (SD) follow up time for patients was 13.1 (5.2) months.
All data are reported as mean (SD) for continuous variables and number of patients (%) for categorical variables unless otherwise indicated. BNP and CRP concentrations are expressed as median (interquartile range). Univariate analyses were carried out by the unpaired, independent samples t test for continuous variables and the χ2 test for categorical variables. However, since the distributions of BNP and CRP concentrations were skewed, these variables were compared by the Mann‐Whitney U test. The incidence of ICD therapy over time was compared between categories of BNP by the Kaplan‐Meier method for time to event curves and the log rank test for comparison. All multivariate analyses by Cox regression analysis with a determination of a hazard ratio and its 95% confidence interval (CI) for each variable in the model. Forward, stepwise regression was initially performed to identify those variables that most affected the hazard ratio of BNP, with a cut off p < 0.10 for entry into the model. Separate forced entry regression analyses were performed to adjust the hazard ratio of BNP for these and other potential confounding variables. Univariate Cox regression with BNP or BNP quartile used as the only variable was also performed to determine an unadjusted hazard ratio. We also divided the population into increasing quartiles with respect to BNP. The hazard ratios of ICD shock were calculated for quartiles two through four compared with the lowest (first) quartile in unadjusted and adjusted analyses. To test for trend, univariate Cox regression was performed by treating quartile as a continuous variable and by using the median value of each quartile. Similar multivariate and quartile analyses were performed for CRP as was described for BNP. A probability value of p < 0.05 was considered significant for all statistical determinations. All data were analysed with SPSS software version 11.0 (SPSS Inc, Chicago, Illinois, USA).