C-Reactive Protein Kinetics and its Prognostic Value After Transfemoral Aortic Valve Implantation

Abstract: Transcatheter aortic valve implantation (TAVI) has become an established therapeutic option in high-risk patients with severe aortic valve stenosis. The potential threat of a postinterventional infection is one of several life-threatening complications. We have analyzed C-reactive protein levels in all patients who underwent successful transfemoral aortic valve implantation between July 2009 and January 2011. CRP and leukocyte counts were measured within 24 hours prior to implantation and daily up to 14 days after implantation. Patients with CRP levels above 109 mg/L (75th percentile; normal range <5 mg/L) were additionally analyzed. We performed 215 transfemoral aortic valve implantations (Edwards and CoreValve). The mean CRP increased after TAVI with a 7.5-fold peak on day 3, and was nearly normalized on day 14. Interestingly, mean leukocyte count remained within the normal range. To identify further independent predictors for post-TAVI elevation of CRP above the 75th percentile, multivariate logistic regression analysis was performed. This showed a significant relationship for patients with elevated baseline CRP values above 11.9 mg/L, for a body mass index above 25 kg/m², for a logistic EuroSCORE ≥22% and for signs of postinterventional infection. Elevated baseline (>6.4 mg/L) and elevated peak (>102 mg/L) CRP values were associated with higher 30-day mortality. In conclusion, CRP elevation after TAVI should be expected to peak on day 3. An infection should be taken into account if CRP increases above 110 mg/L and if patients show other signs of infection. Elevated CRP at baseline and at day 3 is associated with higher 30-day mortality.

J INVASIVE CARDIOL 2012;24(6):282-286

Key words: transcatheter aortic valve implantation, aortic valve stenosis

______________________________________________

Transcatheter aortic valve implantation (TAVI) has become an established therapeutic option in high-risk patients with severe aortic valve stenosis. Both transfemoral^1-7 and transapical^8,9 aortic valve implantation have been shown to be efficient and relatively safe, considering the advanced co-morbidities of treated patient populations. Many TAVI procedures are performed in elderly patients over 80 years of age, adding to the frailty of this patient population, with slower recovery and higher prevalence of immobilizing diseases.¹⁰ Compared to surgical valve replacement (and to a lesser extent, to transapical valve implantation), transfemoral aortic valve implantation is less traumatic and less immobilizing. Nevertheless, these patients are still under significant risk for postprocedural complications. The potential threat of a postinterventional infection is one of several life-threatening conditions. Thus, understanding C-reactive protein (CRP) dynamics after TAVI and its prognostic value is very important. We have analyzed CRP levels in all patients who underwent successful transfemoral aortic valve implantation between 2009 and January 2011. CRP was measured within 24 hours before implantation and daily up to 14 days after implantation.

Methods

From July 2008 to January 2011, a total of 215 consecutive patients were successfully treated with transfemoral CoreValve (Medtronic, Inc.; n = 191) or Edwards SAPIEN XT (Edwards Lifesciences, Inc.; n = 24) implantation at our institution. All patients had symptomatic aortic stenosis with an orifice area of <1 cm², and were considered as high-risk surgical patients with either a logistic EuroSCORE¹¹ of ≥20% or specific co-morbidities that would exclude surgical therapy, such as porcelain aorta, chest radiation, or severely reduced lung capacity (obstructive pulmonary disease). Prior to TAVI, all patients received heart catheterization to verify aortic stenosis and to identify relevant coronary artery disease that would be treated by implanting stents. Furthermore, patients underwent transthoracic echocardiography, as well as electrocardiographically gated 256-slice cardiac computed tomography (Brilliance iCT; Philips Medical Systems) of the heart and computed tomography angiography of the abdominal aorta, and the pelvic and femoral arteries. Main exclusion criteria for percutaneous aortic valve implantation were an aortic annulus diameter of <19 mm or >27 mm, and access artery diameters of <6 mm. No patient had any sign of clinically relevant infection at the time of implantation, and all patients received cefuroxime for 3 days beginning with the first dose during the TAVI procedure. In patients who showed signs of infection after TAVI (36 patients), cefuroxime was continued past the 3-day limit for at least 7 days (83%). Of those patients, 67% received vancomycin in addition. The other patients either received a replacement antibiotic or a de novo antibiotic after cefuroxime had been discontinued (such as piperacillin/tacobactam or ciprofloxacin).

All patients were informed about specific risks and alternatives of TAVI and gave informed written consent to TAVI and pre- and postinterventional monitoring (data collection). The study protocol was in accordance with the local ethics committee.

All transfemoral aortic valve implantations were performed using the 18 Fr CoreValve device or the 18/19 Fr Edwards SAPIEN XT device, as previously described.^3,5,6 In brief, first an 18 or 19 Fr delivery sheath was placed into the femoral artery, a transjugular pacemaker placed in the right ventricle, and balloon valvuloplasty performed under rapid pacing. Afterward, according to CT-measured aortic annulus diameters, a CoreValve or Edwards SAPIEN XT prosthesis was implanted. Post-interventional angiography was performed to evaluate aortic regurgitation and prosthesis position. Access site was closed using the Prostar XL 10 Fr system (Abbott Vascular). If possible, all procedures were performed under local anesthesia and light analgosedation, monitored by a cardiac anesthesiologist. A back-up cardiac surgeon and a cardiopulmonary bypass machine were available for all procedures.

Patients were transferred to our intensive care unit after the procedure (for at least 48 hours). All patients developing new grade-III atrioventricular block received a permanent pacemaker within 3 days after TAVI. Most patients were discharged after 2 weeks.

CRP was measured within 24 hours prior to transfemoral aortic valve implantation and daily up to 14 days after implantation, using the turbidimetric assay (Siemens Healthcare Diagnostics). Results were compared with daily leukocyte counts (starting within 24 hours prior to implantation). Patients with CRP levels above 109 mg/L (normal range, <5 mg/L) were additionally analyzed, according to levels above 75th percentiles and receiver operating characteristic (ROC) curve analysis.

Data are presented as mean ± standard deviation. Comparisons were performed using a paired t-test. Concerning CRP cut-off points before and after aortic valve implantation, ROC curve analysis was performed. Logistic regression analysis had been used to predict variables for increased CRP levels after TAVI and to test the predictive value of CRP on outcome. A P-value of <.05 was considered statistically significant. All statistical analyses were performed with MedCalc Version 11.6.0 for Windows (MedCalc Software).

Results

Baseline patient characteristics are shown in Table 1. Procedural data, device success, and 30-day clinical outcomes according to VARC definitions are presented in Table 2. No procedure was converted into a surgical valve replacement. Twelve patients needed a surgical access-site closure due to unsuccessful percutaneous closure of the femoral artery. Sixty patients (29.7%) received pacemaker implantation within 3 days after TAVI. Thirty-day mortality was 7.0% (n = 15). Table 3 summarizes the patient characteristics in the 30-day mortality group.

The mean CRP value of all patients prior to TAVI was 10.6 ± 12.3 mg/L, and thus above the normal range of our assay (normal range, <5 mg/L). CRP increased significantly to a peak on day 3 (79.9 ± 44 mg/L) (P<.0001), equivalent to a 7.5-fold increase of baseline values. CRP levels started decreasing on day 4, reaching nearly baseline values at day 14. Interestingly, mean leukocyte count was within the normal range throughout the entire observation period, showing no statistically significant changes (Figure 1). Median CRP at day 3 was 73.3 mg/L with an interquartile range of 44 to 108.9 mg/L. The patients who developed a CRP level above the 75th percentile (or 108.9 mg/L) were additionally analyzed.

To identify independent predictors for post-TAVI elevation of CRP above the 75th percentile, multivariate logistic regression analysis was performed. This showed a significant relationship for patients with elevated baseline CRP values above the ROC-derived value of 11.9 mg/L for patients with a body mass index above 25 kg/m2, for patients with a logistic EuroSCORE ≥22% and for patients with signs of postinterventional infection (fever, pulmonic infiltrates, urinary tract infection). Interestingly, permanent pacemaker implantation and surgical access-site closure was not associated with significantly elevated CRP levels. No patient showed signs of endocarditis. Table 4 shows results of univariate and multivariate regression analysis for various factors.

Since increases in CRP levels were frequently found in patients after TAVI independently of concomitant infection, we were interested in whether patients with clinical signs of infection had different CRP kinetics. Compared to patients without infection, CRP levels on day 3 after TAVI in those with infection were significantly higher (106 ± 55 mg/L vs 75 ± 41 mg/L; P=.0044). In order to analyze whether a certain cut-off value was useful to predict postinterventional infection in TAVI patients, a ROC curve analysis was performed for postprocedural infection. A CRP level above 110.9 mg/L at day 3 post TAVI was found to be a cut-off value for patients with postprocedural infection. Sensitivity was 53% and specificity was 81%, with an area under the curve (AUC) of 0.675 (P=.0024) (Figure 2A).

In order to further analyze whether CRP levels could be useful as indicators of patient outcome after TAVI, we evaluated pre- and postprocedural CRP levels with respect to postinterventional outcome. Logistic regression analysis revealed that both CRP levels (baseline and at day 3) were significant predictors of 30-day mortality after TAVI (P=.005 for baseline CRP and P=.001 for CRP at day 3). ROC curve analysis showed that preprocedural CRP levels above 6.4 mg/L were significantly associated with 30-day mortality after TAVI (sensitivity, 87%; specificity, 60%; AUC, 0.734; P=.002). Similarly, ROC curve analysis revealed that a cut-off value of 101.6 mg/L of CRP at day 3 had a sensitivity of 73%, specificity of 72%, and AUC of 0.74 for the prediction of 30-day mortality after TAVI (P=.0054) (Figure 2B).

Discussion

Transfemoral aortic valve implantation has become an established tool for the treatment of high-risk patients with severe aortic valve stenosis. These patients are at increased risk for postprocedural complications due to their above-average morbidity and age. At the same time, this patient population will not tolerate complications well. Thus, minimizing postinterventional complications is of highest priority after successful valve implantation. Since infections after TAVI could become life threatening, it is very important to understand postprocedural changes of standard laboratory data that would indicate an infection. The most common laboratory parameters that are used for infection-related monitoring are CRP and leukocyte count. This study shows that CRP increases after transfemoral aortic valve implantation with a 7.5-fold peak at day 3 and near normalization to baseline data on day 14. It also shows a lack of leukocyte count dynamics, indicating that CRP elevation after TAVI is not related to bacterial infection, rather than to inflammation. These data correlate with clinical findings on our patients. Inflammation after this procedure could have several reasons. First, the access site has to be prepared for a percutaneous closure with a 1.5 cm cut-down to the level of the femoral artery. Especially in overweight patients, this preparation can be up to 10 cm deep. Second, the shear stress of the sheath, the prosthesis on its way to the aortic valve, the balloon valvuloplasty, and the valve implantation may add to the inflammatory stimulus. Finally, baseline CRP levels are known to be significantly higher in patients with severe aortic stenosis.^12,13 Thus, these patients may be more vulnerable to further CRP elevations in stress. Our patient population had a mean CRP of 10.6 mg/L at baseline, which corresponds to a 100% elevation above the upper normal limit. Interestingly, baseline CRP also significantly predicted postprocedural CRP values.

Given the kinetics of CRP levels post TAVI — even in the absence of clinical infection — the usefulness of CRP for detection of in-hospital acquired infection may be reduced. However, we found that CRP levels above a ROC-derived cut-off value of 111 mg/L were significant predictors of clinical infection after TAVI and therefore should be considered as not related to the procedure itself.

Our study has not systematically analyzed the onset of fever in post-TAVI patients. Fever would have been inferior to our laboratory analysis, since all patients received paracetamol or metamizole at least during the first 2 days after implantation, to achieve sufficient analgesia at the access site and to enable early mobilization. Both substances are antipyretic. Also, we did not perform routine procalcitonin measurements on all patients. Only patients who did show clinical signs of infection, combined with CRP elevation, were considered for additional procalcitonin measurements. We did not include additional inflammatory markers in our study (such as TNF-alpha or MCP-1), since the aim was to investigate the post-TAVI dynamics with parameters that are routinely used in clinical practice.

Two different systems were used in this study (CoreValve and Edwards SAPIEN XT). Since CoreValve implantations were predominant, a comparison between these two systems relating CRP kinetics would not be statistically sound. However, looking at the data, no trend is visible.

Finally, our analysis in over 200 patients post TAVI showed that CRP levels on baseline and post TAVI (at the peak time point at day 3) were significantly related to short-term mortality in our patient cohort. The prognostic value of CRP in patients with aortic stenosis has been described before.¹² However, although CRP levels were elevated in almost all patients post TAVI, values above 100 mg/L at day 3 post TAVI (and therefore well above the average increase of CRP in the absence of infection), were significantly associated with short-term mortality and might therefore be useful to discriminate between patients with adverse outcomes.

References

1. Buellesfeld L, Wenaweser P, Gerckens U, et al. Transcatheter aortic valve implantation: predictors of procedural success — the Siegburg-Bern experience. Eur Heart J. 2010;31(8):984-991.
2. De Jaegere PP, Piazza N, Galema TW, et al. Early echocardiographic evaluation following percutaneous implantation with the self-expanding CoreValve Revalving System aortic valve bioprosthesis. EuroIntervention. 2008;4(3):351-357.
3. Piazza N, Grube E, Gerckens U, et al. Procedural and 30-day outcomes following transcatheter aortic valve implantation using the third generation (18 Fr) corevalve revalving system: results from the multicentre, expanded evaluation registry 1-year following CE mark approval. EuroIntervention. 2008;4(2):242-249.
4. Zajarias A, Cribier AG. Outcomes and safety of percutaneous aortic valve replacement. J Am Coll Cardiol. 2009;53(20):1829-1836.
5. Grube E, Schuler G, Buellesfeld L, et al. Percutaneous aortic valve replacement for severe aortic stenosis in high-risk patients using the second- and current third-generation self-expanding CoreValve prosthesis: device success and 30-day clinical outcome. J Am Coll Cardiol. 2007;50(1):69-76.
6. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597-1607.
7. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198.
8. Rodés-Cabau J, Webb JG, Cheung A, et al. Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk acute and late outcomes of the multicenter Canadian experience. J Am Coll Cardiol. 2010;55(11):1080-1090.
9. Rodés-Cabau J, Dumont E, De LaRochellière R, et al. Feasibility and initial results of percutaneous aortic valve implantation including selection of the transfemoral or transapical approach in patients with severe aortic stenosis. Am J Cardiol. 2008;102(9):1240-1246.
10. Bekeredjian R, Krumsdorf U, Chorianopoulos E, et al. Usefulness of percutaneous aortic valve implantation to improve quality of life in patients >80 years of age. Am J Cardiol. 2010;106(12):1777-1781.
11. Nashef SA, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9-11.
12. Imai K, Okura H, Kume T, et al. C-reactive protein predicts severity, progression, and prognosis of asymptomatic aortic valve stenosis. Am Heart J. 2008;156(4):713-718.
13. Galante A, Pietroiusti A, Vellini M, et al. C-reactive protein is increased in patients with degenerative aortic valvular stenosis. J Am Coll Cardiol. 2001;38(4):1078-1082.

______________________________________________

From the ¹Department of Cardiology and ²Department of Cardiothoracic Surgery, University of Heidelberg, Heidelberg, Germany.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted November 3, 2011, provisional acceptance given December 1, 2011, final version accepted February 27, 2012.
Address for correspondence: Raffi Bekeredjian, MD, Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Email: raffi.bekeredjian@med.uni-heidelberg.de