Optimal blood metal ion thresholds for discriminating between patients with hip implants who had adverse reactions to metal debris and those patients who did not varied between the two different implant designs and were also dependent on the specific metal ion parameter used (Table III).
Compared with the other two ion parameters, cobalt concentration produced the maximum AUC of 90.5% (95% CI, 82.8% to 98.1%) for patients with BHR implants. The cobalt AUC was significantly greater than the cobalt-chromium ratio AUC (p = 0.0005) (Table III and Fig. 3), but not significantly greater than the chromium AUC (p = 0.8483). The cobalt threshold for identifying patients in the BHR group with adverse reactions to metal debris providing the optimal diagnostic test characteristics was 2.15 μg/L (88.5% sensitivity, 84.5% specificity, 34.3% positive predictive value, and 98.8% negative predictive value) (Table III, Appendix).
Compared with the other metal ion parameters, cobalt concentration produced the maximum AUC of 79.6% (95% CI, 68.8% to 90.4%) for patients with Corail-Pinnacle total hip replacements. The cobalt AUC was significantly greater than that for chromium (p = 0.0004), but not significantly different from the cobalt-chromium ratio AUC (p = 0.8139) (Table III and Fig. 4). The cobalt threshold for identifying Corail-Pinnacles with adverse reactions to metal debris providing the optimal diagnostic test characteristics was 3.57 μg/L (80.0% sensitivity, 76.2% specificity, 20.0% positive predictive value, and 98.1% negative predictive value) (Table III).
Blood metal ion thresholds for concern proposed by the United States (3 μg/L and 10 μg/L)15 and the U.K. MHRA (7 μg/L)5 were applied to the cohort and were compared with our implant-specific thresholds in terms of the diagnostic test characteristics for identifying patients with adverse reactions to metal debris and the proportion of patients with adverse reactions to metal debris who were not identified by each threshold. As our work demonstrated that cobalt alone provided optimal diagnostic test characteristic and AUC results, we only used cobalt ion data for this comparison.
Compared with fixed regulatory authority thresholds, the implant-specific thresholds for cobalt provided the optimal balance of sensitivity and specificity and higher negative predictive values, but generally lower positive predictive values (Table IV). Applying implant-specific thresholds to the cohort resulted in seven patients with adverse reactions to metal debris being missed (1.2% of the cohort [three patients in the BHR group and four patients in the Corail Pinnacle group]). More patients with adverse reactions to metal debris were missed when using fixed regulatory thresholds. With the threshold of 3 μg/L, twelve patients (2.0%) were missed; with the threshold of 7 μg/L, twenty-four patients (4.0%) were missed; and with the threshold of 10 μg/L, twenty-eight patients (4.7%) were missed. Using the regulatory authority threshold with the lowest number of missed patients (3 μg/L) resulted in 71% more missed patients with adverse reactions to metal debris compared with patients missed when using implant-specific thresholds, although this difference was not significant (p = 0.074; McNemar test). Significantly more patients with adverse reactions to metal debris were missed when using thresholds of 7 μg/L (p = 0.0001) and 10 μg/L (p = 0.0001) compared with patients missed when using implant-specific thresholds.
To our knowledge, this represents the largest study to assess whether blood metal ions could effectively identify patients with metal-on-metal hip implants with two common designs who are at risk of adverse reactions to metal debris, and it also represents the first study to formally analyze the cobalt-chromium ratio. Patients with unilateral BHR and Corail-Pinnacle hip replacements who had blood metal ions below implant-specific thresholds (2.15 μg/L for cobalt for the BHR group and 3.57 μg/L for cobalt for the Corail-Pinnacle group) were at low risk of adverse reactions to metal debris. These implant-specific thresholds were more effective compared with the fixed thresholds currently recommended5,15. Cobalt alone produced optimal results for identifying adverse reactions to metal debris in both implant systems.
The observation that implant-specific thresholds exist for identifying patients with metal-on-metal hip implants who have adverse reactions to metal debris is novel. Of the three blood metal ion parameters assessed, cobalt proved to be the best ion to test for in both the BHR group and the Corail-Pinnacle group. Our data demonstrated that cobalt ions were most effective for identifying patients at a low risk of adverse reactions to metal debris, rather than identifying patients with adverse reactions to metal debris. We consider this to be the most important finding because clinically we wish to rule out patients with this complication to allow us to focus on the subgroup of patients who may have adverse reactions to metal debris. Those asymptomatic patients above the implant-specific thresholds require cross-sectional imaging; however, those patients below the implant-specific thresholds are at a low risk of adverse reactions to metal debris. Provided that patients have normal clinical examinations and radiographs, they can be reassured and can be excluded from regular follow-up regimens5-7. In the current study, 78% of patients with BHR implants had a cobalt level below the new implant-specific threshold of 2.15 μg/L. As most patients with BHR implants are asymptomatic, even at long-term follow-up34-36, reducing follow-up regularity in this large cohort would yield substantial financial and resource savings.
Our implant-specific thresholds are lower than those previously proposed for a range of poorly functioning metal-on-metal hip designs (3.5 to 7 μg/L)10-14. These implant-specific thresholds provide more balanced sensitivity and specificity compared with those in previous studies, which showed good specificity but poor sensitivity10,13,14. We consider the definition used for failure to be the main factor explaining these observed differences between studies. The definition of failure in previous reports had included both symptomatic patients, regardless of cause, and patients with implants revised for reasons other than adverse reactions to metal debris10,13,14. Our definition for identifying metal-on-metal hip replacement-related complications was more robust; therefore, the implant-specific thresholds are specific for adverse reactions to metal debris.
The application of fixed metal ion thresholds recommended by U.S. and U.K. authorities5,15 missed more patients with hip implants who had adverse reactions to metal debris compared with patients missed when using implant-specific thresholds. The fixed thresholds of 7 μg/L (the U.K. threshold and also recommended recently by Hart et al. in patients with ASR hip implants)14 and 10 μg/L (the U.S. upper threshold) missed significantly more patients with hip implants who had adverse reactions to metal debris compared with implant-specific thresholds. When using 3 μg/L (the U.S. lower threshold), the difference was not significant; however, this “low-risk” threshold15 missed 71% more patients with hip implants who had adverse reactions to metal debris compared with patients missed when implant-specific thresholds were used. We consider this difference clinically important given the potentially destructive nature of adverse reactions to metal debris and poor outcomes reported following revision of both metal-on-metal hip resurfacings and stemmed total hip replacements4. It is important not to miss patients with this potentially destructive condition; therefore, minimizing the false-negative rate is clinically beneficial. Although current guidelines recommend using fixed blood metal ion thresholds5,15, we observed that implant-specific thresholds provided more accurate information for the two implant systems assessed in this study. In light of these findings, it is hoped that implant-specific thresholds will be developed for other implant designs in the future.
Of the three blood metal ion parameters investigated, cobalt was the best ion to test for in both the BHR implant group and the Corail-Pinnacle implant group. Differences in chromium and the cobalt-chromium ratio between arthroplasties are likely to relate to implant design, with previous studies demonstrating that wear debris and/or corrosion at the taper-head junction in metal-on-metal total hip replacements produces cobalt preferentially over chromium37-39. Our data suggest that measuring blood chromium in patients with unilateral BHR and Corail-Pinnacle replacements provides no additional information compared with cobalt alone. Given the financial burden associated with follow-up for patients with metal-on-metal implants40, we recommend measuring only blood cobalt, which confirms the recommendations of others6. Sampling cobalt alone would save one-third of blood test costs at our laboratory (saving $15.40 per test).
This study had limitations. The proposed implant-specific thresholds only apply to patients with unilateral BHR and Corail-Pinnacle implants. These two implant groups were also heterogeneous given the different patient selection criteria described for each procedure20-22. Furthermore, this was a cross-sectional study with blood metal ions sampled once. Although we cannot make recommendations regarding intervals for repeat blood testing, current evidence suggests that annual blood sampling would be the most frequent for asymptomatic patients with metal-on-metal total hip replacements41; however, patients with BHR implants who have low initial ion levels are unlikely to need repeat testing within this time frame, if at all, provided that they are asymptomatic42. It is also recognized that there is currently a lack of interlaboratory standardization for blood metal ion analysis that may limit the generalizability of our findings. Finally, in line with current recommendations5,6 and other centers13,43,44, not all asymptomatic patients underwent cross-sectional imaging. Only asymptomatic patients with blood metal ions of >7 μg/L underwent such imaging. Although this reflects modern follow-up programs in which resources must be rationalized, some asymptomatic patients not undergoing cross-sectional imaging may have had silent adverse reactions to metal debris, although they would have been classified as patients without adverse reactions to metal debris. However, this effect was mitigated by including patients with adverse reactions to metal debris on imaging but still under surveillance as arthroplasty failures.
In conclusion, patients who underwent metal-on-metal hip arthroplasty with unilateral BHR and Corail-Pinnacle implants and who had blood metal ions below our proposed implant-specific thresholds were at a low risk of adverse reactions to metal debris. These implant-specific thresholds could be used to rationalize follow-up resources in asymptomatic patients with these two implant designs. Analysis of cobalt alone is acceptable for both implant systems. Fixed blood metal ion thresholds currently recommended by regulatory authorities5,15 were associated with an increased risk of missing patients who have adverse reactions to metal debris. Implant-specific thresholds were therefore more effective for identifying patients with unilateral BHR and Corail-Pinnacle implants who were at risk of adverse reactions to metal debris and required further investigation.
A description of an analysis of the male and female cohorts in the BHR group and a table showing a summary of the ROC analysis for cobalt in patients with the BHR implant stratified by sex are available with the online version of this article as a data supplement at jbjs.org.
Investigation performed at the Royal Orthopaedic Hospital, Birmingham, United Kingdom
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