Take-Home Points

• Cellular healing response differs between bony and soft tissue biceps tenodesis.
• Bony tenodesis incites an inflammatory healing response.
• Bony tenodesis healing occurs at the tendon-bone interface.
• Intrasseous bony fixation leads to tendon degeneration within the bone.
• Tendon-to-tendon tenodesis may result in regenerative tendon healing.

The long head of the biceps tendon (LHBT) is a well-established pain generator of the anterior shoulder^1,2 and may be surgically addressed in refractory cases.³ According to a recent study of 44,932 cases, biceps tenodesis rates increased 80% over just 3 years (2008-2011).⁴ Nevertheless, optimal tenodesis location and technique remain controversial. Proximal and distal tenodesis, including numerous soft-tissue and bony techniques, have been described.^5-7 Several studies have focused on the biomechanical strength of various fixation modalities.^8-14 These data highlight the ongoing evolution of our understanding of biceps-labrum complex (BLC) disease.

Over the years, tenodesis location has proved to be an important factor in outcomes.^3,15-20 Several recent studies have elucidated the role of the extra-articular LHBT and the limited capabilities of diagnostic arthroscopy.^15-17,20,21 Taylor and colleagues¹⁷ defined the bicipital tunnel as the extra-articular segment of LHBT and its fibro-osseous enclosure. The tunnel extends from the articular margin through the subpectoral region and can be divided into 3 zones: Zone 1 goes from the articular margin to the inferior margin of the subscapularis, zone 2 goes from the inferior margin of the subscapularis to the proximal margin of the pectoralis major tendon, and zone 3 is the subpectoral region. Zone 2 is often referred to as “no man’s land” for its relative invisibility from arthroscopy above and open exposure below.^17,21 Notably, a recent study reported a 47% prevalence of hidden tunnel lesions in patients with chronic BLC disease symptoms.¹⁸ Other studies have shown that standard proximal tenodesis methods often fail to address LHBT pathology in this area, leading to residual symptoms.^9,22 It is evident that tenodesis location and technique play important roles in patient outcomes. Sanders and colleagues¹⁶ found that the revision rate was significantly higher among patients who underwent biceps tenodesis without release of the bicipital tunnel sheath than among patients who underwent tenodesis with the release. Dr. O’Brien developed an alternative option: soft-tissue tenodesis with transfer of the LHBT to the conjoint tendon within the subdeltoid space.^23,24 This technique addresses intra-articular and extra-articular tunnel disease while mitigating the complications associated with bony tenodesis. Early and midterm studies have shown this to be an effective intervention for chronically symptomatic BLC disease.^25,26

Despite the abundance of literature on tenodesis techniques, no one has histologically evaluated the location-dependent healing and inflammatory responses. We conducted a study to determine the impact of tenodesis location on healing and inflammation in a rat model. We hypothesized that, compared with tendon-to-bone techniques, soft-tissue tenodesis would minimize inflammatory response and optimize healing.

Methods 

The study was approved by the Institutional Animal Care and Use Committee at the Hospital for Special Surgery. 

Animals

Biceps tenodesis was performed at 1 of 3 locations in 36 thirteen-week-old Sprague-Dawley rats (Charles River Laboratories). All rats were prepared for surgery by an experienced veterinary technician. Sedation was induced with isoflurane gas through a nose cone. 

Surgical Procedure

Animals were randomly assigned to 3 different tenodesis groups: tendon-to-bone in the bicipital groove (metaphyseal, M); tendon-to-bone in the subpectoral region (diaphyseal, D); and soft tissue-to-soft tissue transfer to the conjoint tendon (T). A standard deltopectoral approach was used to expose the biceps tendon. The tendon was tagged with a 5-0 polypropylene suture and tenotomized at the level of the bicipital groove (zone 1). All wounds were irrigated and closed with 4-0 nylon suture.

For animals undergoing tendon-to-bone metaphyseal tenodesis, a 0.045-mm Kirschner wire was used to drill bicortically into the intertubercular sulcus. Wire positioning distal to the physeal plate was confirmed with fluoroscopy. A locking stitch of 5-0 polypropylene suture was run along the free edge of the tendon. The tendon was then passed through the bone tunnel in an anterior-to-posterior direction, and the limbs of the suture were tied around the lateral cortex. 

The process was repeated for animals undergoing diaphyseal tenodesis; only the tenodesis location was different. The inferior border of the pectoralis major was identified, and a bicortical tunnel was made in the center of the diaphyseal bone. The tendon was then prepared and tenodesed to bone using the method already described.

In soft-tissue tenodesis, the conjoint tendon was identified and carefully dissected from surrounding tissues. The LHBT was then tenodesed to the attached conjoint tendon with interrupted simple stitches of 5-0 polypropylene suture.

The animals were allowed to bear weight on the operative limb immediately after surgery and without immobilization.

Specimen Harvest and Preparation

Four animals from each group were sacrificed at 6, 12, and 24 weeks. Harvested specimens were fixed in 10% neutral-buffered formalin solution. Bony specimens consisted of the upper half of the humerus and the tenodesed biceps tendon, and soft-tissue specimens consisted of the tenodesed LHBT-conjoint tendon complex. Bony specimens were decalcified in 10% ethylenediaminetetraacetic acid. All specimens were paraffin-embedded and sectioned at 7 microns.

Analysis of Cellularity

Sections were stained with hematoxylin-eosin. Overall cellularity at the tenodesis interface was quantified by averaging the nuclei count within 3 separate standardized ×20 magnification high power fields. Only nucleated cells were included in the cell count. Immunohistochemical staining with tenomodulin (Santa Cruz Laboratories, sc-49324) was performed to characterize the cell population at the interface. Deparaffinized sections underwent antigen retrieval with pronase for 30 minutes at 37°C and were incubated overnight with the anti-tenomodulin goat monoclonal antibody diluted to 1:200 in 1% phosphate-buffered saline. The prepared slides were then counterstained with methyl green. Specimens treated with tenomodulin were evaluated for presence or absence of a positive reaction at the tenodesis interface. 

Analysis of Inflammation

Inflammation at the interface was evaluated with the CD68 macrophage marker (ABcam, ab31630). Deparaffinized sections underwent antigen retrieval with pronase for 30 minutes at 37°C and were incubated overnight with anti-CD68 mouse monoclonal antibodies diluted to 1:200 in 1% phosphate-buffered saline. The prepared slides were then counterstained with neutral red. Inflammation was quantified by averaging the number of reactive cells within 3 separate standardized ×20 magnification high power fields.

Statistical Analysis

Descriptive statistics were calculated for cell and macrophage counts for each group at every time point. Two-way analysis of variance was used to compare the cell and macrophage counts between groups at each time point as well as the count differences within each group between time points. P values were Bonferroni-corrected to account for the multiple comparisons between groups. P < .05 was used to signify statistical significance.

Results

All 36 animals survived to their designated harvest time without complications. Twelve specimens were successfully harvested at 6 weeks and another 12 at 24 weeks. At 12 weeks, tenodesis failure occurred in 1 animal in group D, leaving 11 specimens for analysis.

Cellularity

Within-group analysis revealed a trend of increasing cellularity at 12 weeks followed by a decrease at 24 weeks in all 3 groups (Table 2).

Inflammatory Response 

During specimen processing, 1 group D specimen was severely degraded after pronase treatment, leaving 3 specimens for evaluation. Descriptive statistics for each group are listed in Table 3A.

At 6 weeks, mean CD68 cell count was significantly higher in group M than in group D (P = .011) and group T (P < .001) (Table 3B). Likewise, CD68 count was significantly higher in group D than in group T (P < .001). There were no differences in CD68 counts between the 2 bony tenodesis groups at 12 weeks (P = .486) or 24 weeks (P = .315). Both bony tenodesis groups, however, had persistently higher CD68 counts at 12 weeks when compared with group T (group M, P = .002; group D, P < .001). In these specimens, an inflammatory milieu characterized by a large accumulation of lymphocytes and giant cells was noted at the bone-tendon interface.

Tissue-Specific Staining

At 6 weeks, antigen retrieval resulted in severe degradation of 2 group M specimens, 2 group D specimens, and 1 group T specimen. The most notable tenomodulin reaction occurred in group T at the 6- and 12-week harvests, with the 6-week group having the most robust reaction. There was scant reaction in this group at 24 weeks.

Discussion

In this study, the healing response differed between bony and soft-tissue tenodesis techniques in a rat model. Tendon-to-bone tenodesis, both diaphyseal and metaphyseal, appeared to incite an inflammatory degenerative response, whereas tendon-to-tendon healing occurred in a more quiescent and perhaps even regenerative manner.

The early inflammatory response that occurred in the bony tenodesis groups is not unlike what occurs in fracture healing.²⁷ The reaction was even more robust at 12 weeks, signifying an ongoing inflammatory process. In this context, tendon degeneration may plausibly explain the consistent absence of mature tendon within the tunnels at all 3 time points. Some tendon degeneration may be explained by the vascular damage that occurred during surgery, but this damage was a constant factor in all 3 study groups. Interestingly, group M showed the highest early CD68 counts, consistent with this being the more biologically active region of bone.²⁸

Group T had significantly lower cell and macrophage counts throughout the study period, possibly indicating improved healing—an observation supported by a study in which the impact of macrophage depletion on bone-tendon interface healing was evaluated.²⁹ The authors found that, in suppressing macrophage activity, the morphologic and biomechanical properties at the healing interface were significantly improved.²⁹ These findings are consistent with Dr. O’Brien’s anecdotal experience with patients who previously underwent the biceps transfer; on second-look arthroscopy, there was complete seamless integration of tendon and conjoint tendon (Figure 4). 

Studies have found that the inflammatory process is closely associated with pain, and pain syndromes such as fibromyalgia.^30,31 Persistent inflammation, as seen in our bony tenodesis group, could explain the recalcitrant anterior shoulder pain that often occurs in patients after bony tenodesis of the LHBT.^2,6,19,32 

Studies have also suggested that osteoclasts at the bone-tendon interface—osteoclasts share a cell lineage with macrophages—may contribute to bone loss and tunnel widening.^33,34 Osteoclasts are expected at the bone tunnel, as fracture healing occurs at the bone-tendon interface. These osteoclasts could have contributed to the strong CD68 reaction in our bony tenodesis groups. However, CD68 historically has been described as the classic macrophage marker.³⁵ We specifically selected CD68 for this reason: Macrophages are the primary inflammatory cells involved in early healing and are key to the inflammatory process.³⁶

Results of the tenomodulin analysis suggested 2 different healing processes are occurring in the bony and tendon groups. Tenomodulin is a known tenocyte marker for developing and mature tendon in both rats and humans.^37,38 In our study, only group T had a positive tenomodulin reaction. Notably, the reaction occurred only at 6 and 12 weeks. This finding may indicate that a regenerative healing pattern becomes quiescent by 24 weeks. Indeed, it has been suggested that tenomodulin is a key regulator of tenocyte proliferation and tendon maturation.³⁹

The complete absence of tenomodulin reaction in our bony tenodesis groups in the setting of significant inflammation further supports our theory of tendon degeneration within the tunnel. One potential explanation for this finding may be that as the tendon heals to the surface of the bone, the intra-osseous tendon is no longer load-bearing and is resorbed by the body through an inflammatory response. This finding differs from those in previous studies, which have described viable tendon within the bone tunnel at all time points up to 26 weeks.⁴⁰ More recently, it has been suggested that callus formation at the external cortical tendon-bone interface is critical for healing and mechanical strength.^41,42 In addition, recent studies have found a predominantly fibroblastic healing process at the midtunnel, potentially leading to the formation of loose fibrovascular tissue at the tendon-bone interface.⁴³ These data, in concert with ours, call into question the rationale for performing intra-osseous tenodesis through bone tunnels.

Our study results, if confirmed in humans, will have significant clinical implications. If a similar effect can be confirmed in the human shoulder, one could argue that soft-tissue tenodesis may result in decreased postoperative shoulder pain. In addition, if tendon degeneration does occur within the intramedullary tunnel, surface fixation may be the better, safer alternative. Although older studies reported suboptimal strength with this type of fixation,^8,44 more recent studies have found surface fixation strength equivalent to screw fixation strength.^45,46 Such a shift in the treatment paradigm would obviate the need for violation of the humeral cortex, eliminating potential stress risers associated with screw fixation,⁴⁷ and effectively eliminating the risk of iatrogenic fracture.^48,49 It would be interesting to investigate what occurs histologically at the bone-tendon interface in surface fixation (ie, suture anchors). Would the inflammatory response at the surface be similar to the inflammatory intramedullary healing, or would it be similar to the quieter tendon-tendon healing? Answers to such questions have the potential to streamline the treatment algorithm for patients who require tenodesis.

Study Limitations

Our study had several limitations. First, as this was a basic science study using a rat model, its conclusions can only be extrapolated to humans. Second, given the nonspecific nature of the cellular analysis, we cannot draw any definitive conclusions about the cell population at the bone-tendon interface. For example, although tenomodulin is expressed by tenocytes, it is not an established specific marker for tenocytes and may be expressed by other fibroblastic cells. Still, our results provide insight into the local microenvironment and identify important differences between the tenodesis methods. Similarly, the complete absence of tendon within the bone tunnels suggests that an analysis of osteoclastic activity at the tenodesis interface may have been a valuable addition to the study. This finding, however, was unexpected, and we did not have the foresight to include it in our methods. A third limitation is that our fixation method essentially uses the suspension tenodesis method. This fixation method differs from the common fixation techniques used in the clinical setting. Testing of other fixation constructs would require a larger animal model. Furthermore, in suspension- type constructs, micromotion within the bone tunnel may independently elicit an inflammatory response. Inert suture was used in our fixation in order to reduce the risk of an iatrogenic inflammatory response. Last, it would have been valuable to perform a biomechanical analysis of the strength of each tenodesis construct. This was explored with our institution’s biomechanics team, but specimen size precluded successful analysis.

Conclusion

Our results indicated that, compared with tendon-to-tendon fixation, tendon-to-bone tenodesis produces a significantly greater inflammatory response at the tenodesis interface. An inflammatory milieu in the absence of tendon within the bony tunnel suggests intraosseous tendon degeneration. Tendon-to-tendon tenodesis, on the other hand, seems to limit the inflammatory response. In addition, a robust tenomodulin reaction in the early phases of tendon-to-tendon healing suggests regenerative healing. Our results showed a fundamental difference in the healing response between the 2 tenodesis methods. Further study is needed to evaluate the validity and applicability of our findings to the human patient population. Most important, our results underscore the need for more study to elucidate optimal tenodesis location and encourage orthopedic surgeons to reexamine current clinical practice patterns.

Take-Home Points

• Cellular healing response differs between bony and soft tissue biceps tenodesis.
• Bony tenodesis incites an inflammatory healing response.
• Bony tenodesis healing occurs at the tendon-bone interface.
• Intrasseous bony fixation leads to tendon degeneration within the bone.
• Tendon-to-tendon tenodesis may result in regenerative tendon healing.

The long head of the biceps tendon (LHBT) is a well-established pain generator of the anterior shoulder^1,2 and may be surgically addressed in refractory cases.³ According to a recent study of 44,932 cases, biceps tenodesis rates increased 80% over just 3 years (2008-2011).⁴ Nevertheless, optimal tenodesis location and technique remain controversial. Proximal and distal tenodesis, including numerous soft-tissue and bony techniques, have been described.^5-7 Several studies have focused on the biomechanical strength of various fixation modalities.^8-14 These data highlight the ongoing evolution of our understanding of biceps-labrum complex (BLC) disease.

Over the years, tenodesis location has proved to be an important factor in outcomes.^3,15-20 Several recent studies have elucidated the role of the extra-articular LHBT and the limited capabilities of diagnostic arthroscopy.^15-17,20,21 Taylor and colleagues¹⁷ defined the bicipital tunnel as the extra-articular segment of LHBT and its fibro-osseous enclosure. The tunnel extends from the articular margin through the subpectoral region and can be divided into 3 zones: Zone 1 goes from the articular margin to the inferior margin of the subscapularis, zone 2 goes from the inferior margin of the subscapularis to the proximal margin of the pectoralis major tendon, and zone 3 is the subpectoral region. Zone 2 is often referred to as “no man’s land” for its relative invisibility from arthroscopy above and open exposure below.^17,21 Notably, a recent study reported a 47% prevalence of hidden tunnel lesions in patients with chronic BLC disease symptoms.¹⁸ Other studies have shown that standard proximal tenodesis methods often fail to address LHBT pathology in this area, leading to residual symptoms.^9,22 It is evident that tenodesis location and technique play important roles in patient outcomes. Sanders and colleagues¹⁶ found that the revision rate was significantly higher among patients who underwent biceps tenodesis without release of the bicipital tunnel sheath than among patients who underwent tenodesis with the release. Dr. O’Brien developed an alternative option: soft-tissue tenodesis with transfer of the LHBT to the conjoint tendon within the subdeltoid space.^23,24 This technique addresses intra-articular and extra-articular tunnel disease while mitigating the complications associated with bony tenodesis. Early and midterm studies have shown this to be an effective intervention for chronically symptomatic BLC disease.^25,26

Despite the abundance of literature on tenodesis techniques, no one has histologically evaluated the location-dependent healing and inflammatory responses. We conducted a study to determine the impact of tenodesis location on healing and inflammation in a rat model. We hypothesized that, compared with tendon-to-bone techniques, soft-tissue tenodesis would minimize inflammatory response and optimize healing.

Methods 

The study was approved by the Institutional Animal Care and Use Committee at the Hospital for Special Surgery. 

Animals

Biceps tenodesis was performed at 1 of 3 locations in 36 thirteen-week-old Sprague-Dawley rats (Charles River Laboratories). All rats were prepared for surgery by an experienced veterinary technician. Sedation was induced with isoflurane gas through a nose cone. 

Surgical Procedure

Animals were randomly assigned to 3 different tenodesis groups: tendon-to-bone in the bicipital groove (metaphyseal, M); tendon-to-bone in the subpectoral region (diaphyseal, D); and soft tissue-to-soft tissue transfer to the conjoint tendon (T). A standard deltopectoral approach was used to expose the biceps tendon. The tendon was tagged with a 5-0 polypropylene suture and tenotomized at the level of the bicipital groove (zone 1). All wounds were irrigated and closed with 4-0 nylon suture.

For animals undergoing tendon-to-bone metaphyseal tenodesis, a 0.045-mm Kirschner wire was used to drill bicortically into the intertubercular sulcus. Wire positioning distal to the physeal plate was confirmed with fluoroscopy. A locking stitch of 5-0 polypropylene suture was run along the free edge of the tendon. The tendon was then passed through the bone tunnel in an anterior-to-posterior direction, and the limbs of the suture were tied around the lateral cortex. 

The process was repeated for animals undergoing diaphyseal tenodesis; only the tenodesis location was different. The inferior border of the pectoralis major was identified, and a bicortical tunnel was made in the center of the diaphyseal bone. The tendon was then prepared and tenodesed to bone using the method already described.

In soft-tissue tenodesis, the conjoint tendon was identified and carefully dissected from surrounding tissues. The LHBT was then tenodesed to the attached conjoint tendon with interrupted simple stitches of 5-0 polypropylene suture.

The animals were allowed to bear weight on the operative limb immediately after surgery and without immobilization.

Specimen Harvest and Preparation

Four animals from each group were sacrificed at 6, 12, and 24 weeks. Harvested specimens were fixed in 10% neutral-buffered formalin solution. Bony specimens consisted of the upper half of the humerus and the tenodesed biceps tendon, and soft-tissue specimens consisted of the tenodesed LHBT-conjoint tendon complex. Bony specimens were decalcified in 10% ethylenediaminetetraacetic acid. All specimens were paraffin-embedded and sectioned at 7 microns.

Analysis of Cellularity

Sections were stained with hematoxylin-eosin. Overall cellularity at the tenodesis interface was quantified by averaging the nuclei count within 3 separate standardized ×20 magnification high power fields. Only nucleated cells were included in the cell count. Immunohistochemical staining with tenomodulin (Santa Cruz Laboratories, sc-49324) was performed to characterize the cell population at the interface. Deparaffinized sections underwent antigen retrieval with pronase for 30 minutes at 37°C and were incubated overnight with the anti-tenomodulin goat monoclonal antibody diluted to 1:200 in 1% phosphate-buffered saline. The prepared slides were then counterstained with methyl green. Specimens treated with tenomodulin were evaluated for presence or absence of a positive reaction at the tenodesis interface. 

Analysis of Inflammation

Inflammation at the interface was evaluated with the CD68 macrophage marker (ABcam, ab31630). Deparaffinized sections underwent antigen retrieval with pronase for 30 minutes at 37°C and were incubated overnight with anti-CD68 mouse monoclonal antibodies diluted to 1:200 in 1% phosphate-buffered saline. The prepared slides were then counterstained with neutral red. Inflammation was quantified by averaging the number of reactive cells within 3 separate standardized ×20 magnification high power fields.

Statistical Analysis

Descriptive statistics were calculated for cell and macrophage counts for each group at every time point. Two-way analysis of variance was used to compare the cell and macrophage counts between groups at each time point as well as the count differences within each group between time points. P values were Bonferroni-corrected to account for the multiple comparisons between groups. P < .05 was used to signify statistical significance.

Results

All 36 animals survived to their designated harvest time without complications. Twelve specimens were successfully harvested at 6 weeks and another 12 at 24 weeks. At 12 weeks, tenodesis failure occurred in 1 animal in group D, leaving 11 specimens for analysis.

Cellularity

Within-group analysis revealed a trend of increasing cellularity at 12 weeks followed by a decrease at 24 weeks in all 3 groups (Table 2).

Inflammatory Response 

During specimen processing, 1 group D specimen was severely degraded after pronase treatment, leaving 3 specimens for evaluation. Descriptive statistics for each group are listed in Table 3A.

At 6 weeks, mean CD68 cell count was significantly higher in group M than in group D (P = .011) and group T (P < .001) (Table 3B). Likewise, CD68 count was significantly higher in group D than in group T (P < .001). There were no differences in CD68 counts between the 2 bony tenodesis groups at 12 weeks (P = .486) or 24 weeks (P = .315). Both bony tenodesis groups, however, had persistently higher CD68 counts at 12 weeks when compared with group T (group M, P = .002; group D, P < .001). In these specimens, an inflammatory milieu characterized by a large accumulation of lymphocytes and giant cells was noted at the bone-tendon interface.

Tissue-Specific Staining

At 6 weeks, antigen retrieval resulted in severe degradation of 2 group M specimens, 2 group D specimens, and 1 group T specimen. The most notable tenomodulin reaction occurred in group T at the 6- and 12-week harvests, with the 6-week group having the most robust reaction. There was scant reaction in this group at 24 weeks.

Discussion

In this study, the healing response differed between bony and soft-tissue tenodesis techniques in a rat model. Tendon-to-bone tenodesis, both diaphyseal and metaphyseal, appeared to incite an inflammatory degenerative response, whereas tendon-to-tendon healing occurred in a more quiescent and perhaps even regenerative manner.

The early inflammatory response that occurred in the bony tenodesis groups is not unlike what occurs in fracture healing.²⁷ The reaction was even more robust at 12 weeks, signifying an ongoing inflammatory process. In this context, tendon degeneration may plausibly explain the consistent absence of mature tendon within the tunnels at all 3 time points. Some tendon degeneration may be explained by the vascular damage that occurred during surgery, but this damage was a constant factor in all 3 study groups. Interestingly, group M showed the highest early CD68 counts, consistent with this being the more biologically active region of bone.²⁸

Group T had significantly lower cell and macrophage counts throughout the study period, possibly indicating improved healing—an observation supported by a study in which the impact of macrophage depletion on bone-tendon interface healing was evaluated.²⁹ The authors found that, in suppressing macrophage activity, the morphologic and biomechanical properties at the healing interface were significantly improved.²⁹ These findings are consistent with Dr. O’Brien’s anecdotal experience with patients who previously underwent the biceps transfer; on second-look arthroscopy, there was complete seamless integration of tendon and conjoint tendon (Figure 4). 

Studies have found that the inflammatory process is closely associated with pain, and pain syndromes such as fibromyalgia.^30,31 Persistent inflammation, as seen in our bony tenodesis group, could explain the recalcitrant anterior shoulder pain that often occurs in patients after bony tenodesis of the LHBT.^2,6,19,32 

Studies have also suggested that osteoclasts at the bone-tendon interface—osteoclasts share a cell lineage with macrophages—may contribute to bone loss and tunnel widening.^33,34 Osteoclasts are expected at the bone tunnel, as fracture healing occurs at the bone-tendon interface. These osteoclasts could have contributed to the strong CD68 reaction in our bony tenodesis groups. However, CD68 historically has been described as the classic macrophage marker.³⁵ We specifically selected CD68 for this reason: Macrophages are the primary inflammatory cells involved in early healing and are key to the inflammatory process.³⁶

Results of the tenomodulin analysis suggested 2 different healing processes are occurring in the bony and tendon groups. Tenomodulin is a known tenocyte marker for developing and mature tendon in both rats and humans.^37,38 In our study, only group T had a positive tenomodulin reaction. Notably, the reaction occurred only at 6 and 12 weeks. This finding may indicate that a regenerative healing pattern becomes quiescent by 24 weeks. Indeed, it has been suggested that tenomodulin is a key regulator of tenocyte proliferation and tendon maturation.³⁹

The complete absence of tenomodulin reaction in our bony tenodesis groups in the setting of significant inflammation further supports our theory of tendon degeneration within the tunnel. One potential explanation for this finding may be that as the tendon heals to the surface of the bone, the intra-osseous tendon is no longer load-bearing and is resorbed by the body through an inflammatory response. This finding differs from those in previous studies, which have described viable tendon within the bone tunnel at all time points up to 26 weeks.⁴⁰ More recently, it has been suggested that callus formation at the external cortical tendon-bone interface is critical for healing and mechanical strength.^41,42 In addition, recent studies have found a predominantly fibroblastic healing process at the midtunnel, potentially leading to the formation of loose fibrovascular tissue at the tendon-bone interface.⁴³ These data, in concert with ours, call into question the rationale for performing intra-osseous tenodesis through bone tunnels.

Our study results, if confirmed in humans, will have significant clinical implications. If a similar effect can be confirmed in the human shoulder, one could argue that soft-tissue tenodesis may result in decreased postoperative shoulder pain. In addition, if tendon degeneration does occur within the intramedullary tunnel, surface fixation may be the better, safer alternative. Although older studies reported suboptimal strength with this type of fixation,^8,44 more recent studies have found surface fixation strength equivalent to screw fixation strength.^45,46 Such a shift in the treatment paradigm would obviate the need for violation of the humeral cortex, eliminating potential stress risers associated with screw fixation,⁴⁷ and effectively eliminating the risk of iatrogenic fracture.^48,49 It would be interesting to investigate what occurs histologically at the bone-tendon interface in surface fixation (ie, suture anchors). Would the inflammatory response at the surface be similar to the inflammatory intramedullary healing, or would it be similar to the quieter tendon-tendon healing? Answers to such questions have the potential to streamline the treatment algorithm for patients who require tenodesis.

Study Limitations

Our study had several limitations. First, as this was a basic science study using a rat model, its conclusions can only be extrapolated to humans. Second, given the nonspecific nature of the cellular analysis, we cannot draw any definitive conclusions about the cell population at the bone-tendon interface. For example, although tenomodulin is expressed by tenocytes, it is not an established specific marker for tenocytes and may be expressed by other fibroblastic cells. Still, our results provide insight into the local microenvironment and identify important differences between the tenodesis methods. Similarly, the complete absence of tendon within the bone tunnels suggests that an analysis of osteoclastic activity at the tenodesis interface may have been a valuable addition to the study. This finding, however, was unexpected, and we did not have the foresight to include it in our methods. A third limitation is that our fixation method essentially uses the suspension tenodesis method. This fixation method differs from the common fixation techniques used in the clinical setting. Testing of other fixation constructs would require a larger animal model. Furthermore, in suspension- type constructs, micromotion within the bone tunnel may independently elicit an inflammatory response. Inert suture was used in our fixation in order to reduce the risk of an iatrogenic inflammatory response. Last, it would have been valuable to perform a biomechanical analysis of the strength of each tenodesis construct. This was explored with our institution’s biomechanics team, but specimen size precluded successful analysis.

Conclusion

Our results indicated that, compared with tendon-to-tendon fixation, tendon-to-bone tenodesis produces a significantly greater inflammatory response at the tenodesis interface. An inflammatory milieu in the absence of tendon within the bony tunnel suggests intraosseous tendon degeneration. Tendon-to-tendon tenodesis, on the other hand, seems to limit the inflammatory response. In addition, a robust tenomodulin reaction in the early phases of tendon-to-tendon healing suggests regenerative healing. Our results showed a fundamental difference in the healing response between the 2 tenodesis methods. Further study is needed to evaluate the validity and applicability of our findings to the human patient population. Most important, our results underscore the need for more study to elucidate optimal tenodesis location and encourage orthopedic surgeons to reexamine current clinical practice patterns.

Take-Home Points

• Cellular healing response differs between bony and soft tissue biceps tenodesis.
• Bony tenodesis incites an inflammatory healing response.
• Bony tenodesis healing occurs at the tendon-bone interface.
• Intrasseous bony fixation leads to tendon degeneration within the bone.
• Tendon-to-tendon tenodesis may result in regenerative tendon healing.

The long head of the biceps tendon (LHBT) is a well-established pain generator of the anterior shoulder^1,2 and may be surgically addressed in refractory cases.³ According to a recent study of 44,932 cases, biceps tenodesis rates increased 80% over just 3 years (2008-2011).⁴ Nevertheless, optimal tenodesis location and technique remain controversial. Proximal and distal tenodesis, including numerous soft-tissue and bony techniques, have been described.^5-7 Several studies have focused on the biomechanical strength of various fixation modalities.^8-14 These data highlight the ongoing evolution of our understanding of biceps-labrum complex (BLC) disease.

Over the years, tenodesis location has proved to be an important factor in outcomes.^3,15-20 Several recent studies have elucidated the role of the extra-articular LHBT and the limited capabilities of diagnostic arthroscopy.^15-17,20,21 Taylor and colleagues¹⁷ defined the bicipital tunnel as the extra-articular segment of LHBT and its fibro-osseous enclosure. The tunnel extends from the articular margin through the subpectoral region and can be divided into 3 zones: Zone 1 goes from the articular margin to the inferior margin of the subscapularis, zone 2 goes from the inferior margin of the subscapularis to the proximal margin of the pectoralis major tendon, and zone 3 is the subpectoral region. Zone 2 is often referred to as “no man’s land” for its relative invisibility from arthroscopy above and open exposure below.^17,21 Notably, a recent study reported a 47% prevalence of hidden tunnel lesions in patients with chronic BLC disease symptoms.¹⁸ Other studies have shown that standard proximal tenodesis methods often fail to address LHBT pathology in this area, leading to residual symptoms.^9,22 It is evident that tenodesis location and technique play important roles in patient outcomes. Sanders and colleagues¹⁶ found that the revision rate was significantly higher among patients who underwent biceps tenodesis without release of the bicipital tunnel sheath than among patients who underwent tenodesis with the release. Dr. O’Brien developed an alternative option: soft-tissue tenodesis with transfer of the LHBT to the conjoint tendon within the subdeltoid space.^23,24 This technique addresses intra-articular and extra-articular tunnel disease while mitigating the complications associated with bony tenodesis. Early and midterm studies have shown this to be an effective intervention for chronically symptomatic BLC disease.^25,26

Despite the abundance of literature on tenodesis techniques, no one has histologically evaluated the location-dependent healing and inflammatory responses. We conducted a study to determine the impact of tenodesis location on healing and inflammation in a rat model. We hypothesized that, compared with tendon-to-bone techniques, soft-tissue tenodesis would minimize inflammatory response and optimize healing.

Methods 

The study was approved by the Institutional Animal Care and Use Committee at the Hospital for Special Surgery. 

Animals

Biceps tenodesis was performed at 1 of 3 locations in 36 thirteen-week-old Sprague-Dawley rats (Charles River Laboratories). All rats were prepared for surgery by an experienced veterinary technician. Sedation was induced with isoflurane gas through a nose cone. 

Surgical Procedure

Animals were randomly assigned to 3 different tenodesis groups: tendon-to-bone in the bicipital groove (metaphyseal, M); tendon-to-bone in the subpectoral region (diaphyseal, D); and soft tissue-to-soft tissue transfer to the conjoint tendon (T). A standard deltopectoral approach was used to expose the biceps tendon. The tendon was tagged with a 5-0 polypropylene suture and tenotomized at the level of the bicipital groove (zone 1). All wounds were irrigated and closed with 4-0 nylon suture.

For animals undergoing tendon-to-bone metaphyseal tenodesis, a 0.045-mm Kirschner wire was used to drill bicortically into the intertubercular sulcus. Wire positioning distal to the physeal plate was confirmed with fluoroscopy. A locking stitch of 5-0 polypropylene suture was run along the free edge of the tendon. The tendon was then passed through the bone tunnel in an anterior-to-posterior direction, and the limbs of the suture were tied around the lateral cortex. 

The process was repeated for animals undergoing diaphyseal tenodesis; only the tenodesis location was different. The inferior border of the pectoralis major was identified, and a bicortical tunnel was made in the center of the diaphyseal bone. The tendon was then prepared and tenodesed to bone using the method already described.

In soft-tissue tenodesis, the conjoint tendon was identified and carefully dissected from surrounding tissues. The LHBT was then tenodesed to the attached conjoint tendon with interrupted simple stitches of 5-0 polypropylene suture.

The animals were allowed to bear weight on the operative limb immediately after surgery and without immobilization.

Specimen Harvest and Preparation

Four animals from each group were sacrificed at 6, 12, and 24 weeks. Harvested specimens were fixed in 10% neutral-buffered formalin solution. Bony specimens consisted of the upper half of the humerus and the tenodesed biceps tendon, and soft-tissue specimens consisted of the tenodesed LHBT-conjoint tendon complex. Bony specimens were decalcified in 10% ethylenediaminetetraacetic acid. All specimens were paraffin-embedded and sectioned at 7 microns.

Analysis of Cellularity

Sections were stained with hematoxylin-eosin. Overall cellularity at the tenodesis interface was quantified by averaging the nuclei count within 3 separate standardized ×20 magnification high power fields. Only nucleated cells were included in the cell count. Immunohistochemical staining with tenomodulin (Santa Cruz Laboratories, sc-49324) was performed to characterize the cell population at the interface. Deparaffinized sections underwent antigen retrieval with pronase for 30 minutes at 37°C and were incubated overnight with the anti-tenomodulin goat monoclonal antibody diluted to 1:200 in 1% phosphate-buffered saline. The prepared slides were then counterstained with methyl green. Specimens treated with tenomodulin were evaluated for presence or absence of a positive reaction at the tenodesis interface. 

Analysis of Inflammation

Inflammation at the interface was evaluated with the CD68 macrophage marker (ABcam, ab31630). Deparaffinized sections underwent antigen retrieval with pronase for 30 minutes at 37°C and were incubated overnight with anti-CD68 mouse monoclonal antibodies diluted to 1:200 in 1% phosphate-buffered saline. The prepared slides were then counterstained with neutral red. Inflammation was quantified by averaging the number of reactive cells within 3 separate standardized ×20 magnification high power fields.

Statistical Analysis

Descriptive statistics were calculated for cell and macrophage counts for each group at every time point. Two-way analysis of variance was used to compare the cell and macrophage counts between groups at each time point as well as the count differences within each group between time points. P values were Bonferroni-corrected to account for the multiple comparisons between groups. P < .05 was used to signify statistical significance.

Results

All 36 animals survived to their designated harvest time without complications. Twelve specimens were successfully harvested at 6 weeks and another 12 at 24 weeks. At 12 weeks, tenodesis failure occurred in 1 animal in group D, leaving 11 specimens for analysis.

Cellularity

Within-group analysis revealed a trend of increasing cellularity at 12 weeks followed by a decrease at 24 weeks in all 3 groups (Table 2).

Inflammatory Response 

During specimen processing, 1 group D specimen was severely degraded after pronase treatment, leaving 3 specimens for evaluation. Descriptive statistics for each group are listed in Table 3A.

At 6 weeks, mean CD68 cell count was significantly higher in group M than in group D (P = .011) and group T (P < .001) (Table 3B). Likewise, CD68 count was significantly higher in group D than in group T (P < .001). There were no differences in CD68 counts between the 2 bony tenodesis groups at 12 weeks (P = .486) or 24 weeks (P = .315). Both bony tenodesis groups, however, had persistently higher CD68 counts at 12 weeks when compared with group T (group M, P = .002; group D, P < .001). In these specimens, an inflammatory milieu characterized by a large accumulation of lymphocytes and giant cells was noted at the bone-tendon interface.

Tissue-Specific Staining

At 6 weeks, antigen retrieval resulted in severe degradation of 2 group M specimens, 2 group D specimens, and 1 group T specimen. The most notable tenomodulin reaction occurred in group T at the 6- and 12-week harvests, with the 6-week group having the most robust reaction. There was scant reaction in this group at 24 weeks.

Discussion

In this study, the healing response differed between bony and soft-tissue tenodesis techniques in a rat model. Tendon-to-bone tenodesis, both diaphyseal and metaphyseal, appeared to incite an inflammatory degenerative response, whereas tendon-to-tendon healing occurred in a more quiescent and perhaps even regenerative manner.

The early inflammatory response that occurred in the bony tenodesis groups is not unlike what occurs in fracture healing.²⁷ The reaction was even more robust at 12 weeks, signifying an ongoing inflammatory process. In this context, tendon degeneration may plausibly explain the consistent absence of mature tendon within the tunnels at all 3 time points. Some tendon degeneration may be explained by the vascular damage that occurred during surgery, but this damage was a constant factor in all 3 study groups. Interestingly, group M showed the highest early CD68 counts, consistent with this being the more biologically active region of bone.²⁸

Group T had significantly lower cell and macrophage counts throughout the study period, possibly indicating improved healing—an observation supported by a study in which the impact of macrophage depletion on bone-tendon interface healing was evaluated.²⁹ The authors found that, in suppressing macrophage activity, the morphologic and biomechanical properties at the healing interface were significantly improved.²⁹ These findings are consistent with Dr. O’Brien’s anecdotal experience with patients who previously underwent the biceps transfer; on second-look arthroscopy, there was complete seamless integration of tendon and conjoint tendon (Figure 4). 

Studies have found that the inflammatory process is closely associated with pain, and pain syndromes such as fibromyalgia.^30,31 Persistent inflammation, as seen in our bony tenodesis group, could explain the recalcitrant anterior shoulder pain that often occurs in patients after bony tenodesis of the LHBT.^2,6,19,32 

Studies have also suggested that osteoclasts at the bone-tendon interface—osteoclasts share a cell lineage with macrophages—may contribute to bone loss and tunnel widening.^33,34 Osteoclasts are expected at the bone tunnel, as fracture healing occurs at the bone-tendon interface. These osteoclasts could have contributed to the strong CD68 reaction in our bony tenodesis groups. However, CD68 historically has been described as the classic macrophage marker.³⁵ We specifically selected CD68 for this reason: Macrophages are the primary inflammatory cells involved in early healing and are key to the inflammatory process.³⁶

Results of the tenomodulin analysis suggested 2 different healing processes are occurring in the bony and tendon groups. Tenomodulin is a known tenocyte marker for developing and mature tendon in both rats and humans.^37,38 In our study, only group T had a positive tenomodulin reaction. Notably, the reaction occurred only at 6 and 12 weeks. This finding may indicate that a regenerative healing pattern becomes quiescent by 24 weeks. Indeed, it has been suggested that tenomodulin is a key regulator of tenocyte proliferation and tendon maturation.³⁹

The complete absence of tenomodulin reaction in our bony tenodesis groups in the setting of significant inflammation further supports our theory of tendon degeneration within the tunnel. One potential explanation for this finding may be that as the tendon heals to the surface of the bone, the intra-osseous tendon is no longer load-bearing and is resorbed by the body through an inflammatory response. This finding differs from those in previous studies, which have described viable tendon within the bone tunnel at all time points up to 26 weeks.⁴⁰ More recently, it has been suggested that callus formation at the external cortical tendon-bone interface is critical for healing and mechanical strength.^41,42 In addition, recent studies have found a predominantly fibroblastic healing process at the midtunnel, potentially leading to the formation of loose fibrovascular tissue at the tendon-bone interface.⁴³ These data, in concert with ours, call into question the rationale for performing intra-osseous tenodesis through bone tunnels.

Our study results, if confirmed in humans, will have significant clinical implications. If a similar effect can be confirmed in the human shoulder, one could argue that soft-tissue tenodesis may result in decreased postoperative shoulder pain. In addition, if tendon degeneration does occur within the intramedullary tunnel, surface fixation may be the better, safer alternative. Although older studies reported suboptimal strength with this type of fixation,^8,44 more recent studies have found surface fixation strength equivalent to screw fixation strength.^45,46 Such a shift in the treatment paradigm would obviate the need for violation of the humeral cortex, eliminating potential stress risers associated with screw fixation,⁴⁷ and effectively eliminating the risk of iatrogenic fracture.^48,49 It would be interesting to investigate what occurs histologically at the bone-tendon interface in surface fixation (ie, suture anchors). Would the inflammatory response at the surface be similar to the inflammatory intramedullary healing, or would it be similar to the quieter tendon-tendon healing? Answers to such questions have the potential to streamline the treatment algorithm for patients who require tenodesis.

Study Limitations

Our study had several limitations. First, as this was a basic science study using a rat model, its conclusions can only be extrapolated to humans. Second, given the nonspecific nature of the cellular analysis, we cannot draw any definitive conclusions about the cell population at the bone-tendon interface. For example, although tenomodulin is expressed by tenocytes, it is not an established specific marker for tenocytes and may be expressed by other fibroblastic cells. Still, our results provide insight into the local microenvironment and identify important differences between the tenodesis methods. Similarly, the complete absence of tendon within the bone tunnels suggests that an analysis of osteoclastic activity at the tenodesis interface may have been a valuable addition to the study. This finding, however, was unexpected, and we did not have the foresight to include it in our methods. A third limitation is that our fixation method essentially uses the suspension tenodesis method. This fixation method differs from the common fixation techniques used in the clinical setting. Testing of other fixation constructs would require a larger animal model. Furthermore, in suspension- type constructs, micromotion within the bone tunnel may independently elicit an inflammatory response. Inert suture was used in our fixation in order to reduce the risk of an iatrogenic inflammatory response. Last, it would have been valuable to perform a biomechanical analysis of the strength of each tenodesis construct. This was explored with our institution’s biomechanics team, but specimen size precluded successful analysis.

Conclusion

Our results indicated that, compared with tendon-to-tendon fixation, tendon-to-bone tenodesis produces a significantly greater inflammatory response at the tenodesis interface. An inflammatory milieu in the absence of tendon within the bony tunnel suggests intraosseous tendon degeneration. Tendon-to-tendon tenodesis, on the other hand, seems to limit the inflammatory response. In addition, a robust tenomodulin reaction in the early phases of tendon-to-tendon healing suggests regenerative healing. Our results showed a fundamental difference in the healing response between the 2 tenodesis methods. Further study is needed to evaluate the validity and applicability of our findings to the human patient population. Most important, our results underscore the need for more study to elucidate optimal tenodesis location and encourage orthopedic surgeons to reexamine current clinical practice patterns.

Take-Home Points

• TTO specifics depend on anatomy, radiographic alignment characteristics, and presence of chondral defects.
• Osteotomy and movement of the tibial tubercle can include anteriorization, anteromedialization, proximalization, medialization, or distalization.
• TTO was most commonly performed for isolated patellar instability in the presence of knee pain.
• Young women with prior surgery on the affected knee made up the primary patient population for this procedure.
• While TTO significantly improves knee pain and clinical outcome scores, >1 in 5 patients required reoperation for hardware removal.

Patellofemoral pain and patellofemoral instability are common orthopedic problems. Studies have found that 30% of patients 13 to 19 years old have patellofemoral pain and that 29 in 100,000 patients 10 to 17 years old have patellofemoral instability.^1-3 The reported rate of recurrence after nonoperative management of patellofemoral instability is 33%.⁴ Tibial tubercle osteotomy (TTO), first described by Hauser⁵ in 1938, is an effective treatment option for many patellofemoral disorders.

TTO indications include patellofemoral maltracking or malalignment, patellar instability, patellofemoral arthritis, and focal patellofemoral chondral defects.⁶ With TTO, the goal is to move the tibial tubercle in a direction that will either improve patellar tracking or offload the medial or lateral patellar facet to improve pain and function.^7,8 This action typically involves anterior, medial, lateral, or distal translation of the tibial tubercle, as posteriorization can lead to increased contact forces across the patellofemoral joint, resulting in accelerated patellofemoral wear and increased pain.⁹

We systematically reviewed the TTO literature to identify indications, clinical outcomes, complications, and reoperations. We hypothesized that the overall complication rate and the overall reoperation rate would both be <10%.

Clinical Evaluation of Patellofemoral Pathology

Patients with patellofemoral pain often report anterior knee pain, which typically begins gradually and is often activity related. Several symptoms may be present: pain with prolonged sitting with knees bent; pain on rising from a seated position; pain or crepitus with climbing stairs; and pain during repetitive activity such as running, squatting, or jumping. Location, duration, and onset of symptoms should be elicited. Patellofemoral instability can be described as dislocation events or subluxation events; number of events, mechanisms of injury, and resulting need for reduction should be documented. As age, sex, body mass index, and physical fitness are relevant to risk of recurrence, the physician should ask about general ligamentous laxity, other joint dislocations, and prior surgical intervention. Swelling or mechanical symptoms may indicate patellofemoral joint pathology.^6,10

Physical examination of patients with patellofemoral pathology begins with assessment for overall limb alignment (including resting position of patella and corresponding quadriceps angle [Q-angle]), generalized ligamentous laxity (including hypermobile joints, evaluated with Brighton criteria), overall peri-knee muscle tone and strength, effusion, and gait pattern.

Common TTO Procedures

TTO specifics depend on anatomy, radiographic alignment characteristics, and presence of chondral defects. Essentially, the patella is translated to offload the affected areas. Osteotomy and movement of the tibial tubercle can include anteriorization, anteromedialization, proximalization, medialization, or distalization.

Methods

Search Strategy and Data Collection

We searched the PubMed (Medline) database for all English-language TTO studies published between database inception and April 9, 2015. After PROSPERO registration, and following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we used the algorithm (“tibial” AND “tubercle” AND “osteotomy”) NOT (“total” AND “knee” AND “arthroplasty”) to search the literature. Inclusion criteria included level I-IV studies on TTO indications, operative findings, and outcomes. Exclusion criteria were non-English studies, unpublished studies, level V evidence, letters to the editor, editorials, review articles, basic science articles, technique articles, revision procedures, articles without clinical outcomes, and conference proceeding abstracts. Studies that reported on duplicate populations were included only with the most recent available clinical outcomes. All abstracts were reviewed in duplicate by Dr. Levy and Dr. Rao and assessed with respect to the criteria outlined. Then the same authors performed full-text reviews of eligible studies before including these studies in the systematic review.

Assessment of Study Quality

The quality of each TTO study in the review was assessed with a modified Coleman methodology score (MCMS), which ranges from 0 to 100. A study with an MCMS of <55 points is considered a poor-quality study.¹¹

Data Synthesis and Statistical Analysis

Given that most of the included studies were level IV, a formal meta-analysis was not indicated. In this article, we report categorical data as frequencies with percentages and preoperative and postoperative continuous data as means (SDs), with weighted means based on number of patients in each study, where applicable. We used 2-tailed t tests for comparisons made with the free Meta-Analysis Calculator and Grapher (http://www.healthstrategy.com/meta/meta.pl ). Statistical significance was set at P < .05. 

Results

Search Results and Included Studies

Only 1 study provided preoperative body mass index (27 kg/m2). There were 55.35% of patients who had prior surgery on the affected knee (6 studies reporting).

Preoperative Data

Preoperative pathologic, radiographic, and clinical scoring data were scarcely reported and nonuniform (Table 2). The most common pathology treated with TTO was isolated patellofemoral instability (746/1055 patients, 70.7%). The other pathologies addressed were isolated patellofemoral osteoarthritis/chondromalacia patellae (143, 13.6%), patellofemoral instability with patella alta (61, 5.8%), patellofemoral instability with patellofemoral osteoarthritis (45, 4.3%), isolated patella baja (41, 3.9%), isolated patella alta (19, 1.8%), and patellofemoral osteoarthritis with patella baja (2, 0.2%). Five hundred fifty-five patients (53%) had a preoperative complaint that included knee pain, and 809 (77%) reported preoperative patellar laxity or instability events. The imaging data reported were Q-angle, Insall-Salvati ratio, Caton-Deschamps index, Blackburne-Peel ratio, Outerbridge osteoarthritis grade, and TT-TG distance. Preoperative clinical scoring data most prominently included a visual analog scale (VAS) score of 70.50 (4 studies reporting), a Lysholm score of 59.19 (5 studies), and a Kujala score of 41.16 (4 studies). Shelbourne-Trumper and Cox-Insall scores were reported in 1 and 2 studies, respectively.

Operative Characteristics

Of the 21 studies, 12 reported only on patients who had TTO performed in isolation; in the other 9 studies, cohorts included patients who underwent concurrent procedures. In the 17 studies (856 patients) that listed numbers of patients who underwent specific concomitant procedures, 715 patients (83.5%) underwent an isolated TTO procedure, and the other 141 (16.5%) underwent either concomitant lateral femoral trochleoplasty, arthroscopic drilling of chondral lesions, patellar shaving chondroplasty, partial meniscectomy or concomitant meniscal repair, intra-articular loose body removal, and/or lateral release with or without medial plication. 

Postoperative Data

There was a cumulative total of 79 complications (8% of cohort): 17 recurrent patellar dislocations (1.9%), 4 recurrent patellar subluxations (0.4%), 10 wound complications (1.0%), 2 intraoperative complications (0.2%), 14 tibial tubercle fractures (1.3%), 19 proximal tibia fractures (1.8%), 4 cases of anterior knee pain (0.4%), 4 cases of neuropraxia (0.4%), and 5 infections (0.5%). Of note, 219 knees (21%) required reoperation, but 170 (16.3%) of these were for painful hardware removal. Sixteen knees (1.5%) required revision TTO, 1 (0.1%) required subsequent high tibial osteotomy, 2 (0.2%) underwent patellofemoral arthroplasty for advanced arthritic changes, and 5 (0.5%) underwent total knee arthroplasty for advanced arthritic changes.

Studies With TTO Performed in Isolation

Twelve studies reported outcomes of isolated TTO procedures. In the 638 patients who underwent isolated TTO, the pathologies addressed were instability/laxity (429 patients, 67%), patellofemoral osteoarthritis (74, 12%), patella alta with instability (61, 10%), patellofemoral osteoarthritis with instability (31, 5%), patella baja (24, 4%), and patella alta (19, 3%). Pain was a preoperative issue in 289 (45%) of these patients and instability in 472 (74%).

Only 2.8% of patients experienced postoperative patellar dislocation events. Of the 12 studies, 2 reported VAS scores (34-point weighted mean improvement, 65 points before surgery to 31 after surgery), 3 reported Lysholm scores (30-point improvement, from 60 to 90), and 2 reported Kujala scores (21-point improvement, from 46 to 67).

Complication rates for this isolated-TTO pooled cohort of patients were 1.2% for revision TTOs, 0.5% for wound complications, 0.8% for tibial tubercle fractures, and 1.9% for proximal tibia fractures. In total, 16% of patients required hardware removal after surgery. 

Discussion

This study found that TTO improved patient pain and clinical outcome scores despite having a high (16%) rate of reoperation for painful hardware in patients with preoperative pain or instability, or with patellofemoral osteoarthritis or aberrant patellar anatomy. This reoperation rate and the overall complication rate both exceeded our hypothesized 10% cumulative rate. However, <1% of patients required conversion to a definitive end-stage surgery (patellofemoral arthroplasty or total knee arthroplasty) by final follow-up, and the rates of comorbidities (anterior knee pain, wound infection, recurrent patellar subluxation/dislocation, tibial fracture) were relatively low.

Patellofemoral disorders are common in the general population and a frequent primary complaint on presentation to orthopedic offices. Having a thorough understanding of knee joint biomechanics is imperative when trying to determine whether surgery is appropriate for these complaints and how to proceed. Extensor mechanism abnormalities, including high lateral force vectors (or larger TT-TG distances) and excessive patellar tilt, can affect alignment and increase the risk for patellofemoral dislocations, patellofemoral anterior- based knee pains, and chondral lesions. Patella alta, an elevated patella, risks increased contact stresses between the patella and the trochlear groove³³ and decreases the osseous constraints that inhibit dislocation of the patella with physiologic flexion of the joint.³⁴ With TTO, the change in tuberosity position can alter angles in the extensor mechanism and thereby decrease joint reaction forces and patellofemoral contact area forces.^35,36

Although its use began as an option for combating patellar instability events in patients with predisposed patellofemoral kinematics,⁵ TTO has evolved in its therapeutic uses to include offloading patellar and trochlear focal chondral lesions and slowing progression of patellofemoral arthritis. Multiple iterations and modifications of the procedure have involved distal and medial transfer of the tibial tuberosity, medialization alone, concurrent anterior and medial elevation of the tuberosity, and proximal or distal transfers, depending on the pathology being corrected. Although TTO is highly versatile in treating multiple patellofemoral joint pathologies, this study found that its primary indication continues to be patellar instability, with anteromedialization as the most common direction of tubercle transfer in support of the medial structures providing the medial force vector that keeps the patella in place. These medial structures include the medial patellofemoral ligament, the vastus medialis obliquus, the medial patellotibial ligament, and the medial retinaculum. 

Also notable was the relatively high rate of reoperation after TTO. However, >75% of reoperations were performed to remove painful hardware, and the need for reoperation seemed to have no effect on the statistically significant overall preoperative-to-postoperative improvement in VAS, Lysholm, and Kujala scores. Rates of definitive surgery for end-stage patellofemoral changes, including patellofemoral arthroplasty and total knee arthroplasty, were quite low at the weighted mean follow-up of several years after surgery, suggesting a role for TTO in avoiding arthroplasty. Although the infection rate was <1%, the rate of tibial tubercle or proximal tibia fractures was a cumulative 3.1%. Patients should be counseled on this complication risk, as treatment can require cast immobilization and weight-bearing limitations.²⁴

The 69% proportion of women in the overall cohort and the mean (SD) age of 27.68 (10.45) years highlight the primary patient population that undergoes TTO. Compared with men, young women are more likely to have aberrant patellofemoral biomechanics, owing to their native anatomy, including their relatively larger Q-angle and TT-TG distance and thus increased lateral translational force vectors on the patella.³⁷ In addition, more than half of patients who are having TTO underwent previous surgery on the affected knee—an indication that TTO is still not universally considered first-line in addressing patellofemoral pathology.

Limitations of the Analysis

The limitations of this analysis derive from the limitations of the included studies, which were mostly retrospective case series with relatively short follow-up. The low MCMS (<55) of all 21 studies highlights their low quality as well. These studies showed considerable heterogeneity in their reporting of specific preoperative, intraoperative, and postoperative radiographic, physical examination, and clinical outcome scores, which may be indicative of the relatively low rate of use of TTO, a procedure originally described decades ago. These studies also showed ample heterogeneity in the specific radiographic parameters or outcome scales they used to present their data. We were therefore limited in our ability to cohesively summarize and provide cumulative data points from the patients as a unified cohort. There was substantial variety in the procedures performed, surgical techniques used, concomitant pathologies addressed at time of surgery, and diagnoses treated—indicating a performance bias. This additionally precluded any significant meta-analysis within the patient cohort. A higher quality study, a randomized controlled trial, is needed to answer more definitively and completely the questions we left unanswered, including the effect on radiographic parameters, additional clinical outcomes, and patient satisfaction.

Conclusion

TTO is most commonly performed for isolated patellar instability in the presence of knee pain. Other pathologies addressed are patellofemoral osteoarthritis, and patella alta and patella baja with and without associated knee pain. TTO significantly improves knee pain and clinical outcome scores, though 21% of patients (>1 in 5) require reoperation for hardware removal. Young women with prior surgery on the affected knee are the primary patient population.

Take-Home Points

• TTO specifics depend on anatomy, radiographic alignment characteristics, and presence of chondral defects.
• Osteotomy and movement of the tibial tubercle can include anteriorization, anteromedialization, proximalization, medialization, or distalization.
• TTO was most commonly performed for isolated patellar instability in the presence of knee pain.
• Young women with prior surgery on the affected knee made up the primary patient population for this procedure.
• While TTO significantly improves knee pain and clinical outcome scores, >1 in 5 patients required reoperation for hardware removal.

Patellofemoral pain and patellofemoral instability are common orthopedic problems. Studies have found that 30% of patients 13 to 19 years old have patellofemoral pain and that 29 in 100,000 patients 10 to 17 years old have patellofemoral instability.^1-3 The reported rate of recurrence after nonoperative management of patellofemoral instability is 33%.⁴ Tibial tubercle osteotomy (TTO), first described by Hauser⁵ in 1938, is an effective treatment option for many patellofemoral disorders.

TTO indications include patellofemoral maltracking or malalignment, patellar instability, patellofemoral arthritis, and focal patellofemoral chondral defects.⁶ With TTO, the goal is to move the tibial tubercle in a direction that will either improve patellar tracking or offload the medial or lateral patellar facet to improve pain and function.^7,8 This action typically involves anterior, medial, lateral, or distal translation of the tibial tubercle, as posteriorization can lead to increased contact forces across the patellofemoral joint, resulting in accelerated patellofemoral wear and increased pain.⁹

We systematically reviewed the TTO literature to identify indications, clinical outcomes, complications, and reoperations. We hypothesized that the overall complication rate and the overall reoperation rate would both be <10%.

Clinical Evaluation of Patellofemoral Pathology

Patients with patellofemoral pain often report anterior knee pain, which typically begins gradually and is often activity related. Several symptoms may be present: pain with prolonged sitting with knees bent; pain on rising from a seated position; pain or crepitus with climbing stairs; and pain during repetitive activity such as running, squatting, or jumping. Location, duration, and onset of symptoms should be elicited. Patellofemoral instability can be described as dislocation events or subluxation events; number of events, mechanisms of injury, and resulting need for reduction should be documented. As age, sex, body mass index, and physical fitness are relevant to risk of recurrence, the physician should ask about general ligamentous laxity, other joint dislocations, and prior surgical intervention. Swelling or mechanical symptoms may indicate patellofemoral joint pathology.^6,10

Physical examination of patients with patellofemoral pathology begins with assessment for overall limb alignment (including resting position of patella and corresponding quadriceps angle [Q-angle]), generalized ligamentous laxity (including hypermobile joints, evaluated with Brighton criteria), overall peri-knee muscle tone and strength, effusion, and gait pattern.

Common TTO Procedures

TTO specifics depend on anatomy, radiographic alignment characteristics, and presence of chondral defects. Essentially, the patella is translated to offload the affected areas. Osteotomy and movement of the tibial tubercle can include anteriorization, anteromedialization, proximalization, medialization, or distalization.

Methods

Search Strategy and Data Collection

We searched the PubMed (Medline) database for all English-language TTO studies published between database inception and April 9, 2015. After PROSPERO registration, and following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we used the algorithm (“tibial” AND “tubercle” AND “osteotomy”) NOT (“total” AND “knee” AND “arthroplasty”) to search the literature. Inclusion criteria included level I-IV studies on TTO indications, operative findings, and outcomes. Exclusion criteria were non-English studies, unpublished studies, level V evidence, letters to the editor, editorials, review articles, basic science articles, technique articles, revision procedures, articles without clinical outcomes, and conference proceeding abstracts. Studies that reported on duplicate populations were included only with the most recent available clinical outcomes. All abstracts were reviewed in duplicate by Dr. Levy and Dr. Rao and assessed with respect to the criteria outlined. Then the same authors performed full-text reviews of eligible studies before including these studies in the systematic review.

Assessment of Study Quality

The quality of each TTO study in the review was assessed with a modified Coleman methodology score (MCMS), which ranges from 0 to 100. A study with an MCMS of <55 points is considered a poor-quality study.¹¹

Data Synthesis and Statistical Analysis

Given that most of the included studies were level IV, a formal meta-analysis was not indicated. In this article, we report categorical data as frequencies with percentages and preoperative and postoperative continuous data as means (SDs), with weighted means based on number of patients in each study, where applicable. We used 2-tailed t tests for comparisons made with the free Meta-Analysis Calculator and Grapher (http://www.healthstrategy.com/meta/meta.pl ). Statistical significance was set at P < .05. 

Results

Search Results and Included Studies

Only 1 study provided preoperative body mass index (27 kg/m2). There were 55.35% of patients who had prior surgery on the affected knee (6 studies reporting).

Preoperative Data

Preoperative pathologic, radiographic, and clinical scoring data were scarcely reported and nonuniform (Table 2). The most common pathology treated with TTO was isolated patellofemoral instability (746/1055 patients, 70.7%). The other pathologies addressed were isolated patellofemoral osteoarthritis/chondromalacia patellae (143, 13.6%), patellofemoral instability with patella alta (61, 5.8%), patellofemoral instability with patellofemoral osteoarthritis (45, 4.3%), isolated patella baja (41, 3.9%), isolated patella alta (19, 1.8%), and patellofemoral osteoarthritis with patella baja (2, 0.2%). Five hundred fifty-five patients (53%) had a preoperative complaint that included knee pain, and 809 (77%) reported preoperative patellar laxity or instability events. The imaging data reported were Q-angle, Insall-Salvati ratio, Caton-Deschamps index, Blackburne-Peel ratio, Outerbridge osteoarthritis grade, and TT-TG distance. Preoperative clinical scoring data most prominently included a visual analog scale (VAS) score of 70.50 (4 studies reporting), a Lysholm score of 59.19 (5 studies), and a Kujala score of 41.16 (4 studies). Shelbourne-Trumper and Cox-Insall scores were reported in 1 and 2 studies, respectively.

Operative Characteristics

Of the 21 studies, 12 reported only on patients who had TTO performed in isolation; in the other 9 studies, cohorts included patients who underwent concurrent procedures. In the 17 studies (856 patients) that listed numbers of patients who underwent specific concomitant procedures, 715 patients (83.5%) underwent an isolated TTO procedure, and the other 141 (16.5%) underwent either concomitant lateral femoral trochleoplasty, arthroscopic drilling of chondral lesions, patellar shaving chondroplasty, partial meniscectomy or concomitant meniscal repair, intra-articular loose body removal, and/or lateral release with or without medial plication. 

Postoperative Data

There was a cumulative total of 79 complications (8% of cohort): 17 recurrent patellar dislocations (1.9%), 4 recurrent patellar subluxations (0.4%), 10 wound complications (1.0%), 2 intraoperative complications (0.2%), 14 tibial tubercle fractures (1.3%), 19 proximal tibia fractures (1.8%), 4 cases of anterior knee pain (0.4%), 4 cases of neuropraxia (0.4%), and 5 infections (0.5%). Of note, 219 knees (21%) required reoperation, but 170 (16.3%) of these were for painful hardware removal. Sixteen knees (1.5%) required revision TTO, 1 (0.1%) required subsequent high tibial osteotomy, 2 (0.2%) underwent patellofemoral arthroplasty for advanced arthritic changes, and 5 (0.5%) underwent total knee arthroplasty for advanced arthritic changes.

Studies With TTO Performed in Isolation

Twelve studies reported outcomes of isolated TTO procedures. In the 638 patients who underwent isolated TTO, the pathologies addressed were instability/laxity (429 patients, 67%), patellofemoral osteoarthritis (74, 12%), patella alta with instability (61, 10%), patellofemoral osteoarthritis with instability (31, 5%), patella baja (24, 4%), and patella alta (19, 3%). Pain was a preoperative issue in 289 (45%) of these patients and instability in 472 (74%).

Only 2.8% of patients experienced postoperative patellar dislocation events. Of the 12 studies, 2 reported VAS scores (34-point weighted mean improvement, 65 points before surgery to 31 after surgery), 3 reported Lysholm scores (30-point improvement, from 60 to 90), and 2 reported Kujala scores (21-point improvement, from 46 to 67).

Complication rates for this isolated-TTO pooled cohort of patients were 1.2% for revision TTOs, 0.5% for wound complications, 0.8% for tibial tubercle fractures, and 1.9% for proximal tibia fractures. In total, 16% of patients required hardware removal after surgery. 

Discussion

This study found that TTO improved patient pain and clinical outcome scores despite having a high (16%) rate of reoperation for painful hardware in patients with preoperative pain or instability, or with patellofemoral osteoarthritis or aberrant patellar anatomy. This reoperation rate and the overall complication rate both exceeded our hypothesized 10% cumulative rate. However, <1% of patients required conversion to a definitive end-stage surgery (patellofemoral arthroplasty or total knee arthroplasty) by final follow-up, and the rates of comorbidities (anterior knee pain, wound infection, recurrent patellar subluxation/dislocation, tibial fracture) were relatively low.

Patellofemoral disorders are common in the general population and a frequent primary complaint on presentation to orthopedic offices. Having a thorough understanding of knee joint biomechanics is imperative when trying to determine whether surgery is appropriate for these complaints and how to proceed. Extensor mechanism abnormalities, including high lateral force vectors (or larger TT-TG distances) and excessive patellar tilt, can affect alignment and increase the risk for patellofemoral dislocations, patellofemoral anterior- based knee pains, and chondral lesions. Patella alta, an elevated patella, risks increased contact stresses between the patella and the trochlear groove³³ and decreases the osseous constraints that inhibit dislocation of the patella with physiologic flexion of the joint.³⁴ With TTO, the change in tuberosity position can alter angles in the extensor mechanism and thereby decrease joint reaction forces and patellofemoral contact area forces.^35,36

Although its use began as an option for combating patellar instability events in patients with predisposed patellofemoral kinematics,⁵ TTO has evolved in its therapeutic uses to include offloading patellar and trochlear focal chondral lesions and slowing progression of patellofemoral arthritis. Multiple iterations and modifications of the procedure have involved distal and medial transfer of the tibial tuberosity, medialization alone, concurrent anterior and medial elevation of the tuberosity, and proximal or distal transfers, depending on the pathology being corrected. Although TTO is highly versatile in treating multiple patellofemoral joint pathologies, this study found that its primary indication continues to be patellar instability, with anteromedialization as the most common direction of tubercle transfer in support of the medial structures providing the medial force vector that keeps the patella in place. These medial structures include the medial patellofemoral ligament, the vastus medialis obliquus, the medial patellotibial ligament, and the medial retinaculum. 

Also notable was the relatively high rate of reoperation after TTO. However, >75% of reoperations were performed to remove painful hardware, and the need for reoperation seemed to have no effect on the statistically significant overall preoperative-to-postoperative improvement in VAS, Lysholm, and Kujala scores. Rates of definitive surgery for end-stage patellofemoral changes, including patellofemoral arthroplasty and total knee arthroplasty, were quite low at the weighted mean follow-up of several years after surgery, suggesting a role for TTO in avoiding arthroplasty. Although the infection rate was <1%, the rate of tibial tubercle or proximal tibia fractures was a cumulative 3.1%. Patients should be counseled on this complication risk, as treatment can require cast immobilization and weight-bearing limitations.²⁴

The 69% proportion of women in the overall cohort and the mean (SD) age of 27.68 (10.45) years highlight the primary patient population that undergoes TTO. Compared with men, young women are more likely to have aberrant patellofemoral biomechanics, owing to their native anatomy, including their relatively larger Q-angle and TT-TG distance and thus increased lateral translational force vectors on the patella.³⁷ In addition, more than half of patients who are having TTO underwent previous surgery on the affected knee—an indication that TTO is still not universally considered first-line in addressing patellofemoral pathology.

Limitations of the Analysis

The limitations of this analysis derive from the limitations of the included studies, which were mostly retrospective case series with relatively short follow-up. The low MCMS (<55) of all 21 studies highlights their low quality as well. These studies showed considerable heterogeneity in their reporting of specific preoperative, intraoperative, and postoperative radiographic, physical examination, and clinical outcome scores, which may be indicative of the relatively low rate of use of TTO, a procedure originally described decades ago. These studies also showed ample heterogeneity in the specific radiographic parameters or outcome scales they used to present their data. We were therefore limited in our ability to cohesively summarize and provide cumulative data points from the patients as a unified cohort. There was substantial variety in the procedures performed, surgical techniques used, concomitant pathologies addressed at time of surgery, and diagnoses treated—indicating a performance bias. This additionally precluded any significant meta-analysis within the patient cohort. A higher quality study, a randomized controlled trial, is needed to answer more definitively and completely the questions we left unanswered, including the effect on radiographic parameters, additional clinical outcomes, and patient satisfaction.

Conclusion

TTO is most commonly performed for isolated patellar instability in the presence of knee pain. Other pathologies addressed are patellofemoral osteoarthritis, and patella alta and patella baja with and without associated knee pain. TTO significantly improves knee pain and clinical outcome scores, though 21% of patients (>1 in 5) require reoperation for hardware removal. Young women with prior surgery on the affected knee are the primary patient population.

Take-Home Points

• TTO specifics depend on anatomy, radiographic alignment characteristics, and presence of chondral defects.
• Osteotomy and movement of the tibial tubercle can include anteriorization, anteromedialization, proximalization, medialization, or distalization.
• TTO was most commonly performed for isolated patellar instability in the presence of knee pain.
• Young women with prior surgery on the affected knee made up the primary patient population for this procedure.
• While TTO significantly improves knee pain and clinical outcome scores, >1 in 5 patients required reoperation for hardware removal.

Patellofemoral pain and patellofemoral instability are common orthopedic problems. Studies have found that 30% of patients 13 to 19 years old have patellofemoral pain and that 29 in 100,000 patients 10 to 17 years old have patellofemoral instability.^1-3 The reported rate of recurrence after nonoperative management of patellofemoral instability is 33%.⁴ Tibial tubercle osteotomy (TTO), first described by Hauser⁵ in 1938, is an effective treatment option for many patellofemoral disorders.

TTO indications include patellofemoral maltracking or malalignment, patellar instability, patellofemoral arthritis, and focal patellofemoral chondral defects.⁶ With TTO, the goal is to move the tibial tubercle in a direction that will either improve patellar tracking or offload the medial or lateral patellar facet to improve pain and function.^7,8 This action typically involves anterior, medial, lateral, or distal translation of the tibial tubercle, as posteriorization can lead to increased contact forces across the patellofemoral joint, resulting in accelerated patellofemoral wear and increased pain.⁹

We systematically reviewed the TTO literature to identify indications, clinical outcomes, complications, and reoperations. We hypothesized that the overall complication rate and the overall reoperation rate would both be <10%.

Clinical Evaluation of Patellofemoral Pathology

Patients with patellofemoral pain often report anterior knee pain, which typically begins gradually and is often activity related. Several symptoms may be present: pain with prolonged sitting with knees bent; pain on rising from a seated position; pain or crepitus with climbing stairs; and pain during repetitive activity such as running, squatting, or jumping. Location, duration, and onset of symptoms should be elicited. Patellofemoral instability can be described as dislocation events or subluxation events; number of events, mechanisms of injury, and resulting need for reduction should be documented. As age, sex, body mass index, and physical fitness are relevant to risk of recurrence, the physician should ask about general ligamentous laxity, other joint dislocations, and prior surgical intervention. Swelling or mechanical symptoms may indicate patellofemoral joint pathology.^6,10

Physical examination of patients with patellofemoral pathology begins with assessment for overall limb alignment (including resting position of patella and corresponding quadriceps angle [Q-angle]), generalized ligamentous laxity (including hypermobile joints, evaluated with Brighton criteria), overall peri-knee muscle tone and strength, effusion, and gait pattern.

Common TTO Procedures

TTO specifics depend on anatomy, radiographic alignment characteristics, and presence of chondral defects. Essentially, the patella is translated to offload the affected areas. Osteotomy and movement of the tibial tubercle can include anteriorization, anteromedialization, proximalization, medialization, or distalization.

Methods

Search Strategy and Data Collection

We searched the PubMed (Medline) database for all English-language TTO studies published between database inception and April 9, 2015. After PROSPERO registration, and following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we used the algorithm (“tibial” AND “tubercle” AND “osteotomy”) NOT (“total” AND “knee” AND “arthroplasty”) to search the literature. Inclusion criteria included level I-IV studies on TTO indications, operative findings, and outcomes. Exclusion criteria were non-English studies, unpublished studies, level V evidence, letters to the editor, editorials, review articles, basic science articles, technique articles, revision procedures, articles without clinical outcomes, and conference proceeding abstracts. Studies that reported on duplicate populations were included only with the most recent available clinical outcomes. All abstracts were reviewed in duplicate by Dr. Levy and Dr. Rao and assessed with respect to the criteria outlined. Then the same authors performed full-text reviews of eligible studies before including these studies in the systematic review.

Assessment of Study Quality

The quality of each TTO study in the review was assessed with a modified Coleman methodology score (MCMS), which ranges from 0 to 100. A study with an MCMS of <55 points is considered a poor-quality study.¹¹

Data Synthesis and Statistical Analysis

Given that most of the included studies were level IV, a formal meta-analysis was not indicated. In this article, we report categorical data as frequencies with percentages and preoperative and postoperative continuous data as means (SDs), with weighted means based on number of patients in each study, where applicable. We used 2-tailed t tests for comparisons made with the free Meta-Analysis Calculator and Grapher (http://www.healthstrategy.com/meta/meta.pl ). Statistical significance was set at P < .05. 

Results

Search Results and Included Studies

Only 1 study provided preoperative body mass index (27 kg/m2). There were 55.35% of patients who had prior surgery on the affected knee (6 studies reporting).

Preoperative Data

Preoperative pathologic, radiographic, and clinical scoring data were scarcely reported and nonuniform (Table 2). The most common pathology treated with TTO was isolated patellofemoral instability (746/1055 patients, 70.7%). The other pathologies addressed were isolated patellofemoral osteoarthritis/chondromalacia patellae (143, 13.6%), patellofemoral instability with patella alta (61, 5.8%), patellofemoral instability with patellofemoral osteoarthritis (45, 4.3%), isolated patella baja (41, 3.9%), isolated patella alta (19, 1.8%), and patellofemoral osteoarthritis with patella baja (2, 0.2%). Five hundred fifty-five patients (53%) had a preoperative complaint that included knee pain, and 809 (77%) reported preoperative patellar laxity or instability events. The imaging data reported were Q-angle, Insall-Salvati ratio, Caton-Deschamps index, Blackburne-Peel ratio, Outerbridge osteoarthritis grade, and TT-TG distance. Preoperative clinical scoring data most prominently included a visual analog scale (VAS) score of 70.50 (4 studies reporting), a Lysholm score of 59.19 (5 studies), and a Kujala score of 41.16 (4 studies). Shelbourne-Trumper and Cox-Insall scores were reported in 1 and 2 studies, respectively.

Operative Characteristics

Of the 21 studies, 12 reported only on patients who had TTO performed in isolation; in the other 9 studies, cohorts included patients who underwent concurrent procedures. In the 17 studies (856 patients) that listed numbers of patients who underwent specific concomitant procedures, 715 patients (83.5%) underwent an isolated TTO procedure, and the other 141 (16.5%) underwent either concomitant lateral femoral trochleoplasty, arthroscopic drilling of chondral lesions, patellar shaving chondroplasty, partial meniscectomy or concomitant meniscal repair, intra-articular loose body removal, and/or lateral release with or without medial plication. 

Postoperative Data

There was a cumulative total of 79 complications (8% of cohort): 17 recurrent patellar dislocations (1.9%), 4 recurrent patellar subluxations (0.4%), 10 wound complications (1.0%), 2 intraoperative complications (0.2%), 14 tibial tubercle fractures (1.3%), 19 proximal tibia fractures (1.8%), 4 cases of anterior knee pain (0.4%), 4 cases of neuropraxia (0.4%), and 5 infections (0.5%). Of note, 219 knees (21%) required reoperation, but 170 (16.3%) of these were for painful hardware removal. Sixteen knees (1.5%) required revision TTO, 1 (0.1%) required subsequent high tibial osteotomy, 2 (0.2%) underwent patellofemoral arthroplasty for advanced arthritic changes, and 5 (0.5%) underwent total knee arthroplasty for advanced arthritic changes.

Studies With TTO Performed in Isolation

Twelve studies reported outcomes of isolated TTO procedures. In the 638 patients who underwent isolated TTO, the pathologies addressed were instability/laxity (429 patients, 67%), patellofemoral osteoarthritis (74, 12%), patella alta with instability (61, 10%), patellofemoral osteoarthritis with instability (31, 5%), patella baja (24, 4%), and patella alta (19, 3%). Pain was a preoperative issue in 289 (45%) of these patients and instability in 472 (74%).

Only 2.8% of patients experienced postoperative patellar dislocation events. Of the 12 studies, 2 reported VAS scores (34-point weighted mean improvement, 65 points before surgery to 31 after surgery), 3 reported Lysholm scores (30-point improvement, from 60 to 90), and 2 reported Kujala scores (21-point improvement, from 46 to 67).

Complication rates for this isolated-TTO pooled cohort of patients were 1.2% for revision TTOs, 0.5% for wound complications, 0.8% for tibial tubercle fractures, and 1.9% for proximal tibia fractures. In total, 16% of patients required hardware removal after surgery. 

Discussion

This study found that TTO improved patient pain and clinical outcome scores despite having a high (16%) rate of reoperation for painful hardware in patients with preoperative pain or instability, or with patellofemoral osteoarthritis or aberrant patellar anatomy. This reoperation rate and the overall complication rate both exceeded our hypothesized 10% cumulative rate. However, <1% of patients required conversion to a definitive end-stage surgery (patellofemoral arthroplasty or total knee arthroplasty) by final follow-up, and the rates of comorbidities (anterior knee pain, wound infection, recurrent patellar subluxation/dislocation, tibial fracture) were relatively low.

Patellofemoral disorders are common in the general population and a frequent primary complaint on presentation to orthopedic offices. Having a thorough understanding of knee joint biomechanics is imperative when trying to determine whether surgery is appropriate for these complaints and how to proceed. Extensor mechanism abnormalities, including high lateral force vectors (or larger TT-TG distances) and excessive patellar tilt, can affect alignment and increase the risk for patellofemoral dislocations, patellofemoral anterior- based knee pains, and chondral lesions. Patella alta, an elevated patella, risks increased contact stresses between the patella and the trochlear groove³³ and decreases the osseous constraints that inhibit dislocation of the patella with physiologic flexion of the joint.³⁴ With TTO, the change in tuberosity position can alter angles in the extensor mechanism and thereby decrease joint reaction forces and patellofemoral contact area forces.^35,36

Although its use began as an option for combating patellar instability events in patients with predisposed patellofemoral kinematics,⁵ TTO has evolved in its therapeutic uses to include offloading patellar and trochlear focal chondral lesions and slowing progression of patellofemoral arthritis. Multiple iterations and modifications of the procedure have involved distal and medial transfer of the tibial tuberosity, medialization alone, concurrent anterior and medial elevation of the tuberosity, and proximal or distal transfers, depending on the pathology being corrected. Although TTO is highly versatile in treating multiple patellofemoral joint pathologies, this study found that its primary indication continues to be patellar instability, with anteromedialization as the most common direction of tubercle transfer in support of the medial structures providing the medial force vector that keeps the patella in place. These medial structures include the medial patellofemoral ligament, the vastus medialis obliquus, the medial patellotibial ligament, and the medial retinaculum. 

Also notable was the relatively high rate of reoperation after TTO. However, >75% of reoperations were performed to remove painful hardware, and the need for reoperation seemed to have no effect on the statistically significant overall preoperative-to-postoperative improvement in VAS, Lysholm, and Kujala scores. Rates of definitive surgery for end-stage patellofemoral changes, including patellofemoral arthroplasty and total knee arthroplasty, were quite low at the weighted mean follow-up of several years after surgery, suggesting a role for TTO in avoiding arthroplasty. Although the infection rate was <1%, the rate of tibial tubercle or proximal tibia fractures was a cumulative 3.1%. Patients should be counseled on this complication risk, as treatment can require cast immobilization and weight-bearing limitations.²⁴

The 69% proportion of women in the overall cohort and the mean (SD) age of 27.68 (10.45) years highlight the primary patient population that undergoes TTO. Compared with men, young women are more likely to have aberrant patellofemoral biomechanics, owing to their native anatomy, including their relatively larger Q-angle and TT-TG distance and thus increased lateral translational force vectors on the patella.³⁷ In addition, more than half of patients who are having TTO underwent previous surgery on the affected knee—an indication that TTO is still not universally considered first-line in addressing patellofemoral pathology.

Limitations of the Analysis

The limitations of this analysis derive from the limitations of the included studies, which were mostly retrospective case series with relatively short follow-up. The low MCMS (<55) of all 21 studies highlights their low quality as well. These studies showed considerable heterogeneity in their reporting of specific preoperative, intraoperative, and postoperative radiographic, physical examination, and clinical outcome scores, which may be indicative of the relatively low rate of use of TTO, a procedure originally described decades ago. These studies also showed ample heterogeneity in the specific radiographic parameters or outcome scales they used to present their data. We were therefore limited in our ability to cohesively summarize and provide cumulative data points from the patients as a unified cohort. There was substantial variety in the procedures performed, surgical techniques used, concomitant pathologies addressed at time of surgery, and diagnoses treated—indicating a performance bias. This additionally precluded any significant meta-analysis within the patient cohort. A higher quality study, a randomized controlled trial, is needed to answer more definitively and completely the questions we left unanswered, including the effect on radiographic parameters, additional clinical outcomes, and patient satisfaction.

Conclusion

TTO is most commonly performed for isolated patellar instability in the presence of knee pain. Other pathologies addressed are patellofemoral osteoarthritis, and patella alta and patella baja with and without associated knee pain. TTO significantly improves knee pain and clinical outcome scores, though 21% of patients (>1 in 5) require reoperation for hardware removal. Young women with prior surgery on the affected knee are the primary patient population.

Combat veterans who have served in Iraq and Afghanistan in the post-9/11 era face unique reintegration challenges, one being the transition from driving in combat zones to driving at home.¹ Relative to previous conflicts, post-9/11 combat involves increased participation in road patrols and convoys along with more prevalent threats of improvised explosive devices (IEDs).^1,2 Roadside ambushes designed to destroy or stop vehicles became a common warfare strategy, meaning that driving became an inherently dangerous combat maneuver.³

The modern combat driving framework includes cognitive tools (eg, targeted aggression and tactical awareness) combined with specific behaviors (eg, driving unpredictably fast, using rapid lane changes, and keeping other vehicles at a distance to avoid IEDs).⁴ This framework is adaptive and lifesaving in combat zones, but it can be maladaptive and dangerous in civilian environments. Service members face difficulty in updating this cognitive framework after leaving combat zones and may continue to experience specific cognitions (eg, “the world is dangerous”; “that car holds an IED”) while driving on civilian roads.^3,5-8

The high prevalence of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) in post-9/11 veterans may complicate reintegration. Both PTSD and TBI are considered signature wounds of these conflicts.^8-11 Traumatic brain injury may be sustained as a result of blast injury or other mechanism, including a closed head injury or penetrating brain injury.¹⁰ Previous literature indicated that both PTSD and TBI across all severities are related to deficits in executive functioning, attention, and memory.^12-16

In addition to cognitive deficits, veterans with PTSD also may experience cognitive misappraisal, in which they are more likely to perceive ambiguous stimuli as threatening because of an inability to suppress trauma-related schema and associations.^5,17,18 Examples of roadside-specific trauma triggers include busy highways, traffic, loud or distracting noises, and vehicles of similar make and model as those commonly rigged with IEDs in Iraq or Afghanistan.^2,7

Blast injury, often from IEDs, is the most common cause of TBI reported in U.S. service members, so veterans that have experienced such an injury may become hyperaware of vehicles that may appear to hide IEDs.^7,19 Cognitive dysfunction and misappraisal of neutral stimuli may have an additive effect on behaviors and experiences behind the wheel.^7,15,20 As a result, veterans with comorbid PTSD and TBI may drive unsafely, self-restrict driving time, or avoid driving completely.^5,8,18

Prior research suggests that veterans with PTSD and/or TBI experience significantly higher levels of anxiety in response to common roadside stimuli (ie, an overpass or stop sign) while driving than do veterans without either PTSD or TBI.³ Cognitive behavioral therapy (CBT) interventions have been developed and systematically evaluated for treating anxiety.²¹ The goal of CBT is to identify and change dysfunctional cognitions that result in biased information processing. Cognitive restructuring, the process by which problematic cognitions (negative automatic thoughts) are identified and examined for distortions, is one method of accomplishing this goal. Distortions then are disputed and rebutted with assistance from the clinician.²² A strategy for restructuring negative automatic thoughts is coping self-instruction, which centers on identifying when negative automatic thoughts are focused on others’ behavior, accepting that their behavior cannot be changed, and using positive coping behaviors to minimize negative automatic thoughts.²³

The link between history of comorbid PTSD and TBI and combat driving, current driving anxiety, and coping strategies has not yet been extensively studied in veterans. Thus, the aim of the current study is to determine whether veterans with comorbid PTSD and TBI utilize coping self-instruction behind the wheel. Driving-specific coping self-instruction involves generating thoughts that are adaptive and accepting of others’ driving behaviors (eg, “Just turn up the radio and tune them out”). It was hypothesized that veterans with comorbid PTSD and TBI would endorse fewer coping self-instruction thoughts than would veterans without either PTSD or TBI.

Methods

The current project is part of a larger study that examines driving behaviors of post-9/11 combat veterans at the Michael J. Crescenz Veterans Affairs Medical Center in Philadelphia, Pennsylvania. Thirty-two male veterans aged between 22 and 48 years (M = 31.6, SD = 6.9) were included in the sample. Twenty-three were diagnosed with comorbid PTSD and TBI and 9 veterans with no major psychiatric or physical

Assessment

All participants completed a battery of questionnaires, including the Driver’s Angry Thoughts Questionnaire (DATQ).²³ The DATQ was used to investigate the specific thoughts that veterans experienced while driving.²³ Participants indicated on a Likert scale from 1 (not at all) to 5 (all the time) how often they experienced any of 65 thoughts while driving. Each item was categorized into 1 of 5 distinct subscales (Table 2). A frequency score was generated for each of the 5 subscales. Each subscale had good internal consistency and convergent, divergent, and predictive validity. The Coping Self-Instruction subscale, which is defined as engaging in relaxing thoughts to accept others’ driving behaviors, was of primary interest. It is a 9-item scale (frequency score can range from 9 to 45) with good reliability (α = .83).²³

Given the small and unequal sample sizes, nonparametric independent samples Mann-Whitney U-tests were selected to compare frequency of driving-related thoughts across veterans with comorbid PTSD and TBI and those of veterans without either PTSD or TBI.

Results

Descriptive statistics and results for each DATQ subscale are reported in Table 3. Group comparisons revealed that veterans with comorbid PTSD and TBI endorsed statistically significantly fewer coping self-instruction thoughts while driving (M = 11.5, SD = 7.2) than did combat veterans without either PTSD or TBI (M = 18.1, SD = 6.9; U = 56.0, P = .05). Conversely, frequency of angry thoughts were statistically significant in their difference as a function of PTSD or TBI diagnostic status.

Discussion

While driving, veterans with PTSD or TBI endorsed statistically significantly fewer coping self-instruction thoughts than did veterans without either PTSD or TBI. Prior research suggests that veterans with PTSD or TBI experience greater anxiety than do veterans without either condition while driving.^2,3 Taken together, this suggests that veterans with PTSD or TBI may lack efficient cognitive coping strategies related to the anxiety they experience while driving. Furthermore, the groups did not significantly differ in frequency of angry thoughts behind the wheel. This result was expected based on prior analyses that suggested that veterans with and without PTSD or TBI endorsed feelings of aggression, impatience, and frustration while driving at similar frequencies.³

Because all veterans in the current sample were exposed to combat, these results help to parse out the unique contribution of PTSD and TBI diagnoses on driving in civilian environments. Exposure to combat plus diagnoses of PTSD or TBI may be related to veterans’ ability to cope with typical driving situations at home. In the context of prior literature, results suggest that veterans with PTSD or TBI automatically may perceive neutral roadside stimuli as threatening, feel anxious in response to this perceived threat, and be ill-equipped to cope with this anxiety.^3,5,17,18 According to CBT models, negative automatic thoughts play a critical role in maintaining anxiety.²⁴ Particular cognitive distortions associated with PTSD symptomatology and combat driving experiences, such as misperceiving ambiguous stimuli as threatening because of an inability to suppress trauma-related schema and associations, may therefore maintain driving anxiety following military separation.

Research on CBT interventions suggests that cognitive restructuring, including coping self-instruction, are effective treatments to reduce anxiety.^22,24 The current findings suggest that combat veterans with PTSD and TBI who experience driving anxiety endorse significantly fewer coping self-instruction thoughts than do controls in response to anxiety-provoking driving situations. In fact, prior research suggests that a majority of veterans experiencing driving-related anxiety do not seek help for their symptoms, and many of those who do prefer to reach out to friends rather than mental health professionals.² However, due to their high levels of anxiety, these veterans likely would benefit from CBT interventions specifically targeted to coping strategies for civilian driving. These coping strategies should focus on recognizing that common roadside stimuli are not necessarily threatening in civilian environments. This type of cognitive restructuring may help veterans better manage anxiety while driving.

Limitations

The current study is limited by its small and unequal sample sizes and lack of a noncombat exposure comparison group. Additionally, while this study highlights a potential relationship between reduced cognitive coping strategies and behind-the-wheel anxiety in veterans with PTSD or TBI, causal inferences cannot be made. It is possible that individuals without coping strategies who are deployed to combat are more likely to develop PTSD or TBI. Being equipped with few coping strategies may then lead these veterans to experience greater anxiety while driving. Conversely, PTSD and TBI symptoms may prevent veterans from developing coping strategies over time.

Furthermore, the comorbid PTSD and TBI group was separated from the military for significantly longer than was the control group. Future studies using a longitudinal design could better examine the potential causal relationship between comorbid PTSD and TBI and coping and determine whether endorsement of coping self-instruction changes as a function of time since military separation.

Veterans in the current study report a variety of deployment experiences and locations. Methods of combat, type of vehicle, driving terrain, and prevalence of IEDs changed over the multiple post-9/11 military campaigns. Veterans who were deployed to Iraq in the mid-2000s were instructed to drive quickly and erratically to avoid IEDs and mortars, whereas veterans deployed in later years were taught to drive slowly and carefully to hunt for IEDs in heavily armored vehicles.³ Seventy-five percent of the veterans with PTSD or TBI in the current sample were deployed to Iraq in the early to mid-2000s, compared with 33% of the veterans without PTSD or TBI. Thus, the 2 groups in the current sample may have experienced different combat environments, which could impact how they perceived roadside stimuli. Future studies should recruit a larger and more balanced sample to better determine whether specific combat experiences impact coping strategies while driving.

Conclusion

To the best of the authors’ knowledge, the current study is the first to examine specific types of thoughts that veterans with and without PTSD or TBI experience while driving on civilian roads. Veterans with PTSD or TBI are not engaging in as many coping self-instruction thoughts behind the wheel, despite experiencing greater anxiety than that of veterans without either PTSD or TBI. Cognitive behavioral therapy interventions for anxiety include engaging in coping self-instruction during anxiety-provoking situations.²² Therefore, veterans with PTSD or TBI may benefit from learning targeted coping self-instruction thoughts that they can utilize when anxiety-provoking situations arise behind the wheel. Results suggest that clinicians should work with veterans with comorbid PTSD and TBI to develop specific coping self-instruction statements that they can utilize internally when faced with anxiety-provoking driving situations.

Acknowledgments
This study is the result of work supported by the Council on Brain Injury (grant #260472). The authors thank Dr. Rosette Biester for her guidance.

Combat veterans who have served in Iraq and Afghanistan in the post-9/11 era face unique reintegration challenges, one being the transition from driving in combat zones to driving at home.¹ Relative to previous conflicts, post-9/11 combat involves increased participation in road patrols and convoys along with more prevalent threats of improvised explosive devices (IEDs).^1,2 Roadside ambushes designed to destroy or stop vehicles became a common warfare strategy, meaning that driving became an inherently dangerous combat maneuver.³

The modern combat driving framework includes cognitive tools (eg, targeted aggression and tactical awareness) combined with specific behaviors (eg, driving unpredictably fast, using rapid lane changes, and keeping other vehicles at a distance to avoid IEDs).⁴ This framework is adaptive and lifesaving in combat zones, but it can be maladaptive and dangerous in civilian environments. Service members face difficulty in updating this cognitive framework after leaving combat zones and may continue to experience specific cognitions (eg, “the world is dangerous”; “that car holds an IED”) while driving on civilian roads.^3,5-8

The high prevalence of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) in post-9/11 veterans may complicate reintegration. Both PTSD and TBI are considered signature wounds of these conflicts.^8-11 Traumatic brain injury may be sustained as a result of blast injury or other mechanism, including a closed head injury or penetrating brain injury.¹⁰ Previous literature indicated that both PTSD and TBI across all severities are related to deficits in executive functioning, attention, and memory.^12-16

In addition to cognitive deficits, veterans with PTSD also may experience cognitive misappraisal, in which they are more likely to perceive ambiguous stimuli as threatening because of an inability to suppress trauma-related schema and associations.^5,17,18 Examples of roadside-specific trauma triggers include busy highways, traffic, loud or distracting noises, and vehicles of similar make and model as those commonly rigged with IEDs in Iraq or Afghanistan.^2,7

Blast injury, often from IEDs, is the most common cause of TBI reported in U.S. service members, so veterans that have experienced such an injury may become hyperaware of vehicles that may appear to hide IEDs.^7,19 Cognitive dysfunction and misappraisal of neutral stimuli may have an additive effect on behaviors and experiences behind the wheel.^7,15,20 As a result, veterans with comorbid PTSD and TBI may drive unsafely, self-restrict driving time, or avoid driving completely.^5,8,18

Prior research suggests that veterans with PTSD and/or TBI experience significantly higher levels of anxiety in response to common roadside stimuli (ie, an overpass or stop sign) while driving than do veterans without either PTSD or TBI.³ Cognitive behavioral therapy (CBT) interventions have been developed and systematically evaluated for treating anxiety.²¹ The goal of CBT is to identify and change dysfunctional cognitions that result in biased information processing. Cognitive restructuring, the process by which problematic cognitions (negative automatic thoughts) are identified and examined for distortions, is one method of accomplishing this goal. Distortions then are disputed and rebutted with assistance from the clinician.²² A strategy for restructuring negative automatic thoughts is coping self-instruction, which centers on identifying when negative automatic thoughts are focused on others’ behavior, accepting that their behavior cannot be changed, and using positive coping behaviors to minimize negative automatic thoughts.²³

The link between history of comorbid PTSD and TBI and combat driving, current driving anxiety, and coping strategies has not yet been extensively studied in veterans. Thus, the aim of the current study is to determine whether veterans with comorbid PTSD and TBI utilize coping self-instruction behind the wheel. Driving-specific coping self-instruction involves generating thoughts that are adaptive and accepting of others’ driving behaviors (eg, “Just turn up the radio and tune them out”). It was hypothesized that veterans with comorbid PTSD and TBI would endorse fewer coping self-instruction thoughts than would veterans without either PTSD or TBI.

Methods

The current project is part of a larger study that examines driving behaviors of post-9/11 combat veterans at the Michael J. Crescenz Veterans Affairs Medical Center in Philadelphia, Pennsylvania. Thirty-two male veterans aged between 22 and 48 years (M = 31.6, SD = 6.9) were included in the sample. Twenty-three were diagnosed with comorbid PTSD and TBI and 9 veterans with no major psychiatric or physical

Assessment

All participants completed a battery of questionnaires, including the Driver’s Angry Thoughts Questionnaire (DATQ).²³ The DATQ was used to investigate the specific thoughts that veterans experienced while driving.²³ Participants indicated on a Likert scale from 1 (not at all) to 5 (all the time) how often they experienced any of 65 thoughts while driving. Each item was categorized into 1 of 5 distinct subscales (Table 2). A frequency score was generated for each of the 5 subscales. Each subscale had good internal consistency and convergent, divergent, and predictive validity. The Coping Self-Instruction subscale, which is defined as engaging in relaxing thoughts to accept others’ driving behaviors, was of primary interest. It is a 9-item scale (frequency score can range from 9 to 45) with good reliability (α = .83).²³

Given the small and unequal sample sizes, nonparametric independent samples Mann-Whitney U-tests were selected to compare frequency of driving-related thoughts across veterans with comorbid PTSD and TBI and those of veterans without either PTSD or TBI.

Results

Descriptive statistics and results for each DATQ subscale are reported in Table 3. Group comparisons revealed that veterans with comorbid PTSD and TBI endorsed statistically significantly fewer coping self-instruction thoughts while driving (M = 11.5, SD = 7.2) than did combat veterans without either PTSD or TBI (M = 18.1, SD = 6.9; U = 56.0, P = .05). Conversely, frequency of angry thoughts were statistically significant in their difference as a function of PTSD or TBI diagnostic status.

Discussion

While driving, veterans with PTSD or TBI endorsed statistically significantly fewer coping self-instruction thoughts than did veterans without either PTSD or TBI. Prior research suggests that veterans with PTSD or TBI experience greater anxiety than do veterans without either condition while driving.^2,3 Taken together, this suggests that veterans with PTSD or TBI may lack efficient cognitive coping strategies related to the anxiety they experience while driving. Furthermore, the groups did not significantly differ in frequency of angry thoughts behind the wheel. This result was expected based on prior analyses that suggested that veterans with and without PTSD or TBI endorsed feelings of aggression, impatience, and frustration while driving at similar frequencies.³

Because all veterans in the current sample were exposed to combat, these results help to parse out the unique contribution of PTSD and TBI diagnoses on driving in civilian environments. Exposure to combat plus diagnoses of PTSD or TBI may be related to veterans’ ability to cope with typical driving situations at home. In the context of prior literature, results suggest that veterans with PTSD or TBI automatically may perceive neutral roadside stimuli as threatening, feel anxious in response to this perceived threat, and be ill-equipped to cope with this anxiety.^3,5,17,18 According to CBT models, negative automatic thoughts play a critical role in maintaining anxiety.²⁴ Particular cognitive distortions associated with PTSD symptomatology and combat driving experiences, such as misperceiving ambiguous stimuli as threatening because of an inability to suppress trauma-related schema and associations, may therefore maintain driving anxiety following military separation.

Research on CBT interventions suggests that cognitive restructuring, including coping self-instruction, are effective treatments to reduce anxiety.^22,24 The current findings suggest that combat veterans with PTSD and TBI who experience driving anxiety endorse significantly fewer coping self-instruction thoughts than do controls in response to anxiety-provoking driving situations. In fact, prior research suggests that a majority of veterans experiencing driving-related anxiety do not seek help for their symptoms, and many of those who do prefer to reach out to friends rather than mental health professionals.² However, due to their high levels of anxiety, these veterans likely would benefit from CBT interventions specifically targeted to coping strategies for civilian driving. These coping strategies should focus on recognizing that common roadside stimuli are not necessarily threatening in civilian environments. This type of cognitive restructuring may help veterans better manage anxiety while driving.

Limitations

The current study is limited by its small and unequal sample sizes and lack of a noncombat exposure comparison group. Additionally, while this study highlights a potential relationship between reduced cognitive coping strategies and behind-the-wheel anxiety in veterans with PTSD or TBI, causal inferences cannot be made. It is possible that individuals without coping strategies who are deployed to combat are more likely to develop PTSD or TBI. Being equipped with few coping strategies may then lead these veterans to experience greater anxiety while driving. Conversely, PTSD and TBI symptoms may prevent veterans from developing coping strategies over time.

Furthermore, the comorbid PTSD and TBI group was separated from the military for significantly longer than was the control group. Future studies using a longitudinal design could better examine the potential causal relationship between comorbid PTSD and TBI and coping and determine whether endorsement of coping self-instruction changes as a function of time since military separation.

Veterans in the current study report a variety of deployment experiences and locations. Methods of combat, type of vehicle, driving terrain, and prevalence of IEDs changed over the multiple post-9/11 military campaigns. Veterans who were deployed to Iraq in the mid-2000s were instructed to drive quickly and erratically to avoid IEDs and mortars, whereas veterans deployed in later years were taught to drive slowly and carefully to hunt for IEDs in heavily armored vehicles.³ Seventy-five percent of the veterans with PTSD or TBI in the current sample were deployed to Iraq in the early to mid-2000s, compared with 33% of the veterans without PTSD or TBI. Thus, the 2 groups in the current sample may have experienced different combat environments, which could impact how they perceived roadside stimuli. Future studies should recruit a larger and more balanced sample to better determine whether specific combat experiences impact coping strategies while driving.

Conclusion

To the best of the authors’ knowledge, the current study is the first to examine specific types of thoughts that veterans with and without PTSD or TBI experience while driving on civilian roads. Veterans with PTSD or TBI are not engaging in as many coping self-instruction thoughts behind the wheel, despite experiencing greater anxiety than that of veterans without either PTSD or TBI. Cognitive behavioral therapy interventions for anxiety include engaging in coping self-instruction during anxiety-provoking situations.²² Therefore, veterans with PTSD or TBI may benefit from learning targeted coping self-instruction thoughts that they can utilize when anxiety-provoking situations arise behind the wheel. Results suggest that clinicians should work with veterans with comorbid PTSD and TBI to develop specific coping self-instruction statements that they can utilize internally when faced with anxiety-provoking driving situations.

Acknowledgments
This study is the result of work supported by the Council on Brain Injury (grant #260472). The authors thank Dr. Rosette Biester for her guidance.

Combat veterans who have served in Iraq and Afghanistan in the post-9/11 era face unique reintegration challenges, one being the transition from driving in combat zones to driving at home.¹ Relative to previous conflicts, post-9/11 combat involves increased participation in road patrols and convoys along with more prevalent threats of improvised explosive devices (IEDs).^1,2 Roadside ambushes designed to destroy or stop vehicles became a common warfare strategy, meaning that driving became an inherently dangerous combat maneuver.³

The modern combat driving framework includes cognitive tools (eg, targeted aggression and tactical awareness) combined with specific behaviors (eg, driving unpredictably fast, using rapid lane changes, and keeping other vehicles at a distance to avoid IEDs).⁴ This framework is adaptive and lifesaving in combat zones, but it can be maladaptive and dangerous in civilian environments. Service members face difficulty in updating this cognitive framework after leaving combat zones and may continue to experience specific cognitions (eg, “the world is dangerous”; “that car holds an IED”) while driving on civilian roads.^3,5-8

The high prevalence of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) in post-9/11 veterans may complicate reintegration. Both PTSD and TBI are considered signature wounds of these conflicts.^8-11 Traumatic brain injury may be sustained as a result of blast injury or other mechanism, including a closed head injury or penetrating brain injury.¹⁰ Previous literature indicated that both PTSD and TBI across all severities are related to deficits in executive functioning, attention, and memory.^12-16

In addition to cognitive deficits, veterans with PTSD also may experience cognitive misappraisal, in which they are more likely to perceive ambiguous stimuli as threatening because of an inability to suppress trauma-related schema and associations.^5,17,18 Examples of roadside-specific trauma triggers include busy highways, traffic, loud or distracting noises, and vehicles of similar make and model as those commonly rigged with IEDs in Iraq or Afghanistan.^2,7

Blast injury, often from IEDs, is the most common cause of TBI reported in U.S. service members, so veterans that have experienced such an injury may become hyperaware of vehicles that may appear to hide IEDs.^7,19 Cognitive dysfunction and misappraisal of neutral stimuli may have an additive effect on behaviors and experiences behind the wheel.^7,15,20 As a result, veterans with comorbid PTSD and TBI may drive unsafely, self-restrict driving time, or avoid driving completely.^5,8,18

Prior research suggests that veterans with PTSD and/or TBI experience significantly higher levels of anxiety in response to common roadside stimuli (ie, an overpass or stop sign) while driving than do veterans without either PTSD or TBI.³ Cognitive behavioral therapy (CBT) interventions have been developed and systematically evaluated for treating anxiety.²¹ The goal of CBT is to identify and change dysfunctional cognitions that result in biased information processing. Cognitive restructuring, the process by which problematic cognitions (negative automatic thoughts) are identified and examined for distortions, is one method of accomplishing this goal. Distortions then are disputed and rebutted with assistance from the clinician.²² A strategy for restructuring negative automatic thoughts is coping self-instruction, which centers on identifying when negative automatic thoughts are focused on others’ behavior, accepting that their behavior cannot be changed, and using positive coping behaviors to minimize negative automatic thoughts.²³

The link between history of comorbid PTSD and TBI and combat driving, current driving anxiety, and coping strategies has not yet been extensively studied in veterans. Thus, the aim of the current study is to determine whether veterans with comorbid PTSD and TBI utilize coping self-instruction behind the wheel. Driving-specific coping self-instruction involves generating thoughts that are adaptive and accepting of others’ driving behaviors (eg, “Just turn up the radio and tune them out”). It was hypothesized that veterans with comorbid PTSD and TBI would endorse fewer coping self-instruction thoughts than would veterans without either PTSD or TBI.

Methods

The current project is part of a larger study that examines driving behaviors of post-9/11 combat veterans at the Michael J. Crescenz Veterans Affairs Medical Center in Philadelphia, Pennsylvania. Thirty-two male veterans aged between 22 and 48 years (M = 31.6, SD = 6.9) were included in the sample. Twenty-three were diagnosed with comorbid PTSD and TBI and 9 veterans with no major psychiatric or physical

Assessment

All participants completed a battery of questionnaires, including the Driver’s Angry Thoughts Questionnaire (DATQ).²³ The DATQ was used to investigate the specific thoughts that veterans experienced while driving.²³ Participants indicated on a Likert scale from 1 (not at all) to 5 (all the time) how often they experienced any of 65 thoughts while driving. Each item was categorized into 1 of 5 distinct subscales (Table 2). A frequency score was generated for each of the 5 subscales. Each subscale had good internal consistency and convergent, divergent, and predictive validity. The Coping Self-Instruction subscale, which is defined as engaging in relaxing thoughts to accept others’ driving behaviors, was of primary interest. It is a 9-item scale (frequency score can range from 9 to 45) with good reliability (α = .83).²³

Given the small and unequal sample sizes, nonparametric independent samples Mann-Whitney U-tests were selected to compare frequency of driving-related thoughts across veterans with comorbid PTSD and TBI and those of veterans without either PTSD or TBI.

Results

Descriptive statistics and results for each DATQ subscale are reported in Table 3. Group comparisons revealed that veterans with comorbid PTSD and TBI endorsed statistically significantly fewer coping self-instruction thoughts while driving (M = 11.5, SD = 7.2) than did combat veterans without either PTSD or TBI (M = 18.1, SD = 6.9; U = 56.0, P = .05). Conversely, frequency of angry thoughts were statistically significant in their difference as a function of PTSD or TBI diagnostic status.

Discussion

While driving, veterans with PTSD or TBI endorsed statistically significantly fewer coping self-instruction thoughts than did veterans without either PTSD or TBI. Prior research suggests that veterans with PTSD or TBI experience greater anxiety than do veterans without either condition while driving.^2,3 Taken together, this suggests that veterans with PTSD or TBI may lack efficient cognitive coping strategies related to the anxiety they experience while driving. Furthermore, the groups did not significantly differ in frequency of angry thoughts behind the wheel. This result was expected based on prior analyses that suggested that veterans with and without PTSD or TBI endorsed feelings of aggression, impatience, and frustration while driving at similar frequencies.³

Because all veterans in the current sample were exposed to combat, these results help to parse out the unique contribution of PTSD and TBI diagnoses on driving in civilian environments. Exposure to combat plus diagnoses of PTSD or TBI may be related to veterans’ ability to cope with typical driving situations at home. In the context of prior literature, results suggest that veterans with PTSD or TBI automatically may perceive neutral roadside stimuli as threatening, feel anxious in response to this perceived threat, and be ill-equipped to cope with this anxiety.^3,5,17,18 According to CBT models, negative automatic thoughts play a critical role in maintaining anxiety.²⁴ Particular cognitive distortions associated with PTSD symptomatology and combat driving experiences, such as misperceiving ambiguous stimuli as threatening because of an inability to suppress trauma-related schema and associations, may therefore maintain driving anxiety following military separation.

Research on CBT interventions suggests that cognitive restructuring, including coping self-instruction, are effective treatments to reduce anxiety.^22,24 The current findings suggest that combat veterans with PTSD and TBI who experience driving anxiety endorse significantly fewer coping self-instruction thoughts than do controls in response to anxiety-provoking driving situations. In fact, prior research suggests that a majority of veterans experiencing driving-related anxiety do not seek help for their symptoms, and many of those who do prefer to reach out to friends rather than mental health professionals.² However, due to their high levels of anxiety, these veterans likely would benefit from CBT interventions specifically targeted to coping strategies for civilian driving. These coping strategies should focus on recognizing that common roadside stimuli are not necessarily threatening in civilian environments. This type of cognitive restructuring may help veterans better manage anxiety while driving.

Limitations

The current study is limited by its small and unequal sample sizes and lack of a noncombat exposure comparison group. Additionally, while this study highlights a potential relationship between reduced cognitive coping strategies and behind-the-wheel anxiety in veterans with PTSD or TBI, causal inferences cannot be made. It is possible that individuals without coping strategies who are deployed to combat are more likely to develop PTSD or TBI. Being equipped with few coping strategies may then lead these veterans to experience greater anxiety while driving. Conversely, PTSD and TBI symptoms may prevent veterans from developing coping strategies over time.

Furthermore, the comorbid PTSD and TBI group was separated from the military for significantly longer than was the control group. Future studies using a longitudinal design could better examine the potential causal relationship between comorbid PTSD and TBI and coping and determine whether endorsement of coping self-instruction changes as a function of time since military separation.

Veterans in the current study report a variety of deployment experiences and locations. Methods of combat, type of vehicle, driving terrain, and prevalence of IEDs changed over the multiple post-9/11 military campaigns. Veterans who were deployed to Iraq in the mid-2000s were instructed to drive quickly and erratically to avoid IEDs and mortars, whereas veterans deployed in later years were taught to drive slowly and carefully to hunt for IEDs in heavily armored vehicles.³ Seventy-five percent of the veterans with PTSD or TBI in the current sample were deployed to Iraq in the early to mid-2000s, compared with 33% of the veterans without PTSD or TBI. Thus, the 2 groups in the current sample may have experienced different combat environments, which could impact how they perceived roadside stimuli. Future studies should recruit a larger and more balanced sample to better determine whether specific combat experiences impact coping strategies while driving.

Conclusion

To the best of the authors’ knowledge, the current study is the first to examine specific types of thoughts that veterans with and without PTSD or TBI experience while driving on civilian roads. Veterans with PTSD or TBI are not engaging in as many coping self-instruction thoughts behind the wheel, despite experiencing greater anxiety than that of veterans without either PTSD or TBI. Cognitive behavioral therapy interventions for anxiety include engaging in coping self-instruction during anxiety-provoking situations.²² Therefore, veterans with PTSD or TBI may benefit from learning targeted coping self-instruction thoughts that they can utilize when anxiety-provoking situations arise behind the wheel. Results suggest that clinicians should work with veterans with comorbid PTSD and TBI to develop specific coping self-instruction statements that they can utilize internally when faced with anxiety-provoking driving situations.

Acknowledgments
This study is the result of work supported by the Council on Brain Injury (grant #260472). The authors thank Dr. Rosette Biester for her guidance.

SAN ANTONIO – Skip the perioperative aromatase inhibitor (AI) therapy in women with early stage hormone receptor-positive breast cancer, because it doesn’t make a difference in either time to recurrence or overall survival, British investigators advise.

Among nearly 4,500 women enrolled in the POETIC trial, time to recurrence (TTR) and overall survival (OS) were similar whether patients received AI therapy within 2 weeks of surgery or did not, reported John Robertson, MD, from the University of Nottingham, England, and his colleagues.

“There is no evidence of improved clinical outcome with perioperative aromatase inhibitor therapy,” he said at the San Antonio Breast Cancer Symposium.

The trial wasn’t all for naught, however, because it also provided further evidence that measuring Ki67 levels at baseline and at 2 weeks of therapy offer significant and independent prognostic information.

“If your baseline Ki67 is low, the prognosis is good, suggesting no need for 2 weeks of AI treatment and a second Ki67 measurement,” Dr. Robertson said.

However, if the Ki67 level is 10% or higher at baseline, a Ki67 measure after 2 weeks of AI therapy can be used to guide additional therapy.

“If the 2-week Ki67 is low, patients will do relatively well, with 8.4% recurrences, and may need no additional treatment beyond standard of care. If, however, your Ki67 at 2 weeks remains high, you have a poor prognosis with an almost 20% 5-year recurrence risk, and those patients should be considered for additional chemotherapy, and/or for trials looking at new agents,” he said.

POETIC was a randomized phase 3 trial in postmenopausal women with newly diagnosed estrogen– and progesterone receptor–positive invasive breast cancer. Patients were randomized on a 2:1 basis, respectively, to either perioperative therapy with an AI (letrozole or anastrozole) for 2 weeks, surgery, and an additional 2 weeks of AI treatment, or to surgery with no perioperative therapy within a 2-week window. Patients could receive further treatment in accordance with local practice.

Of 4,486 patients randomized, 4,480 were available for analysis, including 2,528 with both baseline and 2-week Ki67 in the perioperative therapy arm, and 678 with paired Ki67 readings in the no-therapy arm.

For the primary endpoint of TTR, the curves were superimposable, with 5-year TTR of 90.9% in the perioperative AI groups, and 90.3% in the no perioperative AI group, translating into an absolute difference of only 0.52%.

Similarly, there were no differences in OS at 5 years, at 89.0% vs. 89.5%, respectively (absolute difference, 0.51%), with survival curves virtually indistinguishable from one another.

The events contributing to TTR, including local or distant recurrence and breast cancer deaths were equally distributed between the trial arms.

For patients with high baseline Ki67 values (10% or greater) at both baseline and after 2 weeks of perioperative AI therapy, the 5-year absolute risk for recurrence was 19.6%, compared with 8.9% for those with high baseline but low 2-week Ki67 levels, and 4.5% for those with low levels at both time points. The hazard ratio for patients with high Ki67 at both time points was 2.22 (P less than .001).

The POETIC trial was supported by Cancer Research UK. Dr. Robertson did not report disclosure information.

SOURCE: Robertson J et al., Abstract GS1-03

SAN ANTONIO – Skip the perioperative aromatase inhibitor (AI) therapy in women with early stage hormone receptor-positive breast cancer, because it doesn’t make a difference in either time to recurrence or overall survival, British investigators advise.

Among nearly 4,500 women enrolled in the POETIC trial, time to recurrence (TTR) and overall survival (OS) were similar whether patients received AI therapy within 2 weeks of surgery or did not, reported John Robertson, MD, from the University of Nottingham, England, and his colleagues.

“There is no evidence of improved clinical outcome with perioperative aromatase inhibitor therapy,” he said at the San Antonio Breast Cancer Symposium.

The trial wasn’t all for naught, however, because it also provided further evidence that measuring Ki67 levels at baseline and at 2 weeks of therapy offer significant and independent prognostic information.

“If your baseline Ki67 is low, the prognosis is good, suggesting no need for 2 weeks of AI treatment and a second Ki67 measurement,” Dr. Robertson said.

However, if the Ki67 level is 10% or higher at baseline, a Ki67 measure after 2 weeks of AI therapy can be used to guide additional therapy.

“If the 2-week Ki67 is low, patients will do relatively well, with 8.4% recurrences, and may need no additional treatment beyond standard of care. If, however, your Ki67 at 2 weeks remains high, you have a poor prognosis with an almost 20% 5-year recurrence risk, and those patients should be considered for additional chemotherapy, and/or for trials looking at new agents,” he said.

POETIC was a randomized phase 3 trial in postmenopausal women with newly diagnosed estrogen– and progesterone receptor–positive invasive breast cancer. Patients were randomized on a 2:1 basis, respectively, to either perioperative therapy with an AI (letrozole or anastrozole) for 2 weeks, surgery, and an additional 2 weeks of AI treatment, or to surgery with no perioperative therapy within a 2-week window. Patients could receive further treatment in accordance with local practice.

Of 4,486 patients randomized, 4,480 were available for analysis, including 2,528 with both baseline and 2-week Ki67 in the perioperative therapy arm, and 678 with paired Ki67 readings in the no-therapy arm.

For the primary endpoint of TTR, the curves were superimposable, with 5-year TTR of 90.9% in the perioperative AI groups, and 90.3% in the no perioperative AI group, translating into an absolute difference of only 0.52%.

Similarly, there were no differences in OS at 5 years, at 89.0% vs. 89.5%, respectively (absolute difference, 0.51%), with survival curves virtually indistinguishable from one another.

The events contributing to TTR, including local or distant recurrence and breast cancer deaths were equally distributed between the trial arms.

For patients with high baseline Ki67 values (10% or greater) at both baseline and after 2 weeks of perioperative AI therapy, the 5-year absolute risk for recurrence was 19.6%, compared with 8.9% for those with high baseline but low 2-week Ki67 levels, and 4.5% for those with low levels at both time points. The hazard ratio for patients with high Ki67 at both time points was 2.22 (P less than .001).

The POETIC trial was supported by Cancer Research UK. Dr. Robertson did not report disclosure information.

SOURCE: Robertson J et al., Abstract GS1-03

SAN ANTONIO – Skip the perioperative aromatase inhibitor (AI) therapy in women with early stage hormone receptor-positive breast cancer, because it doesn’t make a difference in either time to recurrence or overall survival, British investigators advise.

Among nearly 4,500 women enrolled in the POETIC trial, time to recurrence (TTR) and overall survival (OS) were similar whether patients received AI therapy within 2 weeks of surgery or did not, reported John Robertson, MD, from the University of Nottingham, England, and his colleagues.

“There is no evidence of improved clinical outcome with perioperative aromatase inhibitor therapy,” he said at the San Antonio Breast Cancer Symposium.

The trial wasn’t all for naught, however, because it also provided further evidence that measuring Ki67 levels at baseline and at 2 weeks of therapy offer significant and independent prognostic information.

“If your baseline Ki67 is low, the prognosis is good, suggesting no need for 2 weeks of AI treatment and a second Ki67 measurement,” Dr. Robertson said.

However, if the Ki67 level is 10% or higher at baseline, a Ki67 measure after 2 weeks of AI therapy can be used to guide additional therapy.

“If the 2-week Ki67 is low, patients will do relatively well, with 8.4% recurrences, and may need no additional treatment beyond standard of care. If, however, your Ki67 at 2 weeks remains high, you have a poor prognosis with an almost 20% 5-year recurrence risk, and those patients should be considered for additional chemotherapy, and/or for trials looking at new agents,” he said.

POETIC was a randomized phase 3 trial in postmenopausal women with newly diagnosed estrogen– and progesterone receptor–positive invasive breast cancer. Patients were randomized on a 2:1 basis, respectively, to either perioperative therapy with an AI (letrozole or anastrozole) for 2 weeks, surgery, and an additional 2 weeks of AI treatment, or to surgery with no perioperative therapy within a 2-week window. Patients could receive further treatment in accordance with local practice.

Of 4,486 patients randomized, 4,480 were available for analysis, including 2,528 with both baseline and 2-week Ki67 in the perioperative therapy arm, and 678 with paired Ki67 readings in the no-therapy arm.

For the primary endpoint of TTR, the curves were superimposable, with 5-year TTR of 90.9% in the perioperative AI groups, and 90.3% in the no perioperative AI group, translating into an absolute difference of only 0.52%.

Similarly, there were no differences in OS at 5 years, at 89.0% vs. 89.5%, respectively (absolute difference, 0.51%), with survival curves virtually indistinguishable from one another.

The events contributing to TTR, including local or distant recurrence and breast cancer deaths were equally distributed between the trial arms.

For patients with high baseline Ki67 values (10% or greater) at both baseline and after 2 weeks of perioperative AI therapy, the 5-year absolute risk for recurrence was 19.6%, compared with 8.9% for those with high baseline but low 2-week Ki67 levels, and 4.5% for those with low levels at both time points. The hazard ratio for patients with high Ki67 at both time points was 2.22 (P less than .001).

The POETIC trial was supported by Cancer Research UK. Dr. Robertson did not report disclosure information.

SOURCE: Robertson J et al., Abstract GS1-03

SAN ANTONIO – Increasing the dose intensity of adjuvant chemotherapy for breast cancer by spacing cycles more closely or by giving drugs sequentially instead of concurrently improves outcomes, confirms a meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Study details

“We know that adjuvant chemotherapy can really help reduce recurrence and prevent breast cancer death. It reduces breast cancer death by about a third,” Mr. Gray noted, giving some background to the analysis. “We are still looking at ways to improve that even further. One of the approaches, which is based on cytokinetic modeling, is to try and increase the dose intensity of the chemotherapy.”

For the meta-analysis, the investigators identified trials that achieved dose intensification by reducing the interval between treatment cycles (a dose-dense approach) and/or by giving drugs sequentially rather than concurrently (allowing delivery of higher doses of each drug).

In all, seven trials, which included 10,004 women in total, tested chemotherapy given every 2 weeks (dose-dense chemotherapy) versus the same chemotherapy given every 3 weeks. Results showed that the former approach netted significantly lower risks of recurrence (rate ratio [RR], 0.83; P = .00004) and breast cancer mortality (RR, 0.86; P = .004), Mr. Gray reported. Absolute gains at 10 years were 4.3% and 2.8%, respectively. Findings were similar after adding five more trials, with another 5,508 women, that had some differences in chemotherapy treatments between arms.

Six trials, which included 11,028 women in total, tested sequential chemotherapy every 3 weeks versus concurrent chemotherapy every 3 weeks. Results showed similarly that the former strategy yielded lower risks of recurrence (RR, 0.87; P = .0006) and breast cancer death (RR, 0.89; P = .03). Absolute gains at 10 years were 3.2% and 2.1%, respectively.

Another six trials, which included a total of 6,532 women, tested sequential chemotherapy given every 2 weeks versus concurrent chemotherapy given every 3 weeks. Results here showed once again that the former yielded lower risks of recurrence (RR, 0.82; P = .0001) and breast cancer mortality (RR, 0.82; P = .001). Absolute gains at 10 years were 4.5% and 3.9%, respectively.

Finally, a pooled analysis of all trials showed that dose intensification reduced the risk of recurrence (RR, 0.85; P less than .00001) and breast cancer mortality (RR, 0.87; P less than .00001). Absolute gains at 10 years were 3.6% and 2.7%, respectively.

“That 13% reduction in breast cancer mortality may seem relatively modest, but given that taxane and anthracycline on a standard schedule reduces your chance of breast cancer death by a third, if you then reduce that by another 15%, then you have got almost 50% of breast cancer deaths by dose-dense taxane and anthracycline chemotherapy,” Mr. Gray pointed out. “So these little step-by-step improvements, it’s really important to identify them, and you get incremental gains which result in breast cancer deaths being about half of what they were 25 or 30 years ago.”

The proportional reduction in risk was similar whether tumors were ER positive or negative, but additional follow-up, especially for the positive tumors, will be important. “We do need longer follow-up in these trials, and sadly, many of the funding bodies are not providing funding for long-term follow-up,” he commented. “This is really valuable information, and we should be following these women up further, out to 20 years, given the long natural history of breast cancer.”

In terms of safety, the dose-intensification strategies were actually associated with lower risks of death without recurrence (RR, 0.85; P less than .02) and all-cause mortality (RR, 0.87; P less than .00001). Findings were similar when analyses focused on the first year of treatment.

Tolerability and toxicities of dose-intense regimens relative to standard regimens were not evaluated by the meta-analysis because these outcomes were reported differently across trials, according to Mr. Gray. However, the investigators did perform a systematic review of health-related quality of life studies that will be part of the final manuscript.

“We found surprisingly little extra toxicity” with the dose intensification, he reported. “It’s not very much considering the extra benefits we are getting. And when you know you are getting more benefit, it makes it easy to tolerate a drug.”

“In the U.S., people have moved toward the accelerated chemotherapy much more than they have in Europe. I think people have the mindset, ‘Well, we’ve always done it this way,’ ” Mr. Gray concluded. “This evidence being so clear and definite will help change that mindset. I wouldn’t be surprised if practice in the U.K. and many other parts of Europe doesn’t switch as a result of these very definite findings.” 

SAN ANTONIO – Increasing the dose intensity of adjuvant chemotherapy for breast cancer by spacing cycles more closely or by giving drugs sequentially instead of concurrently improves outcomes, confirms a meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Study details

“We know that adjuvant chemotherapy can really help reduce recurrence and prevent breast cancer death. It reduces breast cancer death by about a third,” Mr. Gray noted, giving some background to the analysis. “We are still looking at ways to improve that even further. One of the approaches, which is based on cytokinetic modeling, is to try and increase the dose intensity of the chemotherapy.”

For the meta-analysis, the investigators identified trials that achieved dose intensification by reducing the interval between treatment cycles (a dose-dense approach) and/or by giving drugs sequentially rather than concurrently (allowing delivery of higher doses of each drug).

In all, seven trials, which included 10,004 women in total, tested chemotherapy given every 2 weeks (dose-dense chemotherapy) versus the same chemotherapy given every 3 weeks. Results showed that the former approach netted significantly lower risks of recurrence (rate ratio [RR], 0.83; P = .00004) and breast cancer mortality (RR, 0.86; P = .004), Mr. Gray reported. Absolute gains at 10 years were 4.3% and 2.8%, respectively. Findings were similar after adding five more trials, with another 5,508 women, that had some differences in chemotherapy treatments between arms.

Six trials, which included 11,028 women in total, tested sequential chemotherapy every 3 weeks versus concurrent chemotherapy every 3 weeks. Results showed similarly that the former strategy yielded lower risks of recurrence (RR, 0.87; P = .0006) and breast cancer death (RR, 0.89; P = .03). Absolute gains at 10 years were 3.2% and 2.1%, respectively.

Another six trials, which included a total of 6,532 women, tested sequential chemotherapy given every 2 weeks versus concurrent chemotherapy given every 3 weeks. Results here showed once again that the former yielded lower risks of recurrence (RR, 0.82; P = .0001) and breast cancer mortality (RR, 0.82; P = .001). Absolute gains at 10 years were 4.5% and 3.9%, respectively.

Finally, a pooled analysis of all trials showed that dose intensification reduced the risk of recurrence (RR, 0.85; P less than .00001) and breast cancer mortality (RR, 0.87; P less than .00001). Absolute gains at 10 years were 3.6% and 2.7%, respectively.

“That 13% reduction in breast cancer mortality may seem relatively modest, but given that taxane and anthracycline on a standard schedule reduces your chance of breast cancer death by a third, if you then reduce that by another 15%, then you have got almost 50% of breast cancer deaths by dose-dense taxane and anthracycline chemotherapy,” Mr. Gray pointed out. “So these little step-by-step improvements, it’s really important to identify them, and you get incremental gains which result in breast cancer deaths being about half of what they were 25 or 30 years ago.”

The proportional reduction in risk was similar whether tumors were ER positive or negative, but additional follow-up, especially for the positive tumors, will be important. “We do need longer follow-up in these trials, and sadly, many of the funding bodies are not providing funding for long-term follow-up,” he commented. “This is really valuable information, and we should be following these women up further, out to 20 years, given the long natural history of breast cancer.”

In terms of safety, the dose-intensification strategies were actually associated with lower risks of death without recurrence (RR, 0.85; P less than .02) and all-cause mortality (RR, 0.87; P less than .00001). Findings were similar when analyses focused on the first year of treatment.

Tolerability and toxicities of dose-intense regimens relative to standard regimens were not evaluated by the meta-analysis because these outcomes were reported differently across trials, according to Mr. Gray. However, the investigators did perform a systematic review of health-related quality of life studies that will be part of the final manuscript.

“We found surprisingly little extra toxicity” with the dose intensification, he reported. “It’s not very much considering the extra benefits we are getting. And when you know you are getting more benefit, it makes it easy to tolerate a drug.”

“In the U.S., people have moved toward the accelerated chemotherapy much more than they have in Europe. I think people have the mindset, ‘Well, we’ve always done it this way,’ ” Mr. Gray concluded. “This evidence being so clear and definite will help change that mindset. I wouldn’t be surprised if practice in the U.K. and many other parts of Europe doesn’t switch as a result of these very definite findings.” 

SAN ANTONIO – Increasing the dose intensity of adjuvant chemotherapy for breast cancer by spacing cycles more closely or by giving drugs sequentially instead of concurrently improves outcomes, confirms a meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Study details

“We know that adjuvant chemotherapy can really help reduce recurrence and prevent breast cancer death. It reduces breast cancer death by about a third,” Mr. Gray noted, giving some background to the analysis. “We are still looking at ways to improve that even further. One of the approaches, which is based on cytokinetic modeling, is to try and increase the dose intensity of the chemotherapy.”

For the meta-analysis, the investigators identified trials that achieved dose intensification by reducing the interval between treatment cycles (a dose-dense approach) and/or by giving drugs sequentially rather than concurrently (allowing delivery of higher doses of each drug).

In all, seven trials, which included 10,004 women in total, tested chemotherapy given every 2 weeks (dose-dense chemotherapy) versus the same chemotherapy given every 3 weeks. Results showed that the former approach netted significantly lower risks of recurrence (rate ratio [RR], 0.83; P = .00004) and breast cancer mortality (RR, 0.86; P = .004), Mr. Gray reported. Absolute gains at 10 years were 4.3% and 2.8%, respectively. Findings were similar after adding five more trials, with another 5,508 women, that had some differences in chemotherapy treatments between arms.

Six trials, which included 11,028 women in total, tested sequential chemotherapy every 3 weeks versus concurrent chemotherapy every 3 weeks. Results showed similarly that the former strategy yielded lower risks of recurrence (RR, 0.87; P = .0006) and breast cancer death (RR, 0.89; P = .03). Absolute gains at 10 years were 3.2% and 2.1%, respectively.

Another six trials, which included a total of 6,532 women, tested sequential chemotherapy given every 2 weeks versus concurrent chemotherapy given every 3 weeks. Results here showed once again that the former yielded lower risks of recurrence (RR, 0.82; P = .0001) and breast cancer mortality (RR, 0.82; P = .001). Absolute gains at 10 years were 4.5% and 3.9%, respectively.

Finally, a pooled analysis of all trials showed that dose intensification reduced the risk of recurrence (RR, 0.85; P less than .00001) and breast cancer mortality (RR, 0.87; P less than .00001). Absolute gains at 10 years were 3.6% and 2.7%, respectively.

“That 13% reduction in breast cancer mortality may seem relatively modest, but given that taxane and anthracycline on a standard schedule reduces your chance of breast cancer death by a third, if you then reduce that by another 15%, then you have got almost 50% of breast cancer deaths by dose-dense taxane and anthracycline chemotherapy,” Mr. Gray pointed out. “So these little step-by-step improvements, it’s really important to identify them, and you get incremental gains which result in breast cancer deaths being about half of what they were 25 or 30 years ago.”

The proportional reduction in risk was similar whether tumors were ER positive or negative, but additional follow-up, especially for the positive tumors, will be important. “We do need longer follow-up in these trials, and sadly, many of the funding bodies are not providing funding for long-term follow-up,” he commented. “This is really valuable information, and we should be following these women up further, out to 20 years, given the long natural history of breast cancer.”

In terms of safety, the dose-intensification strategies were actually associated with lower risks of death without recurrence (RR, 0.85; P less than .02) and all-cause mortality (RR, 0.87; P less than .00001). Findings were similar when analyses focused on the first year of treatment.

Tolerability and toxicities of dose-intense regimens relative to standard regimens were not evaluated by the meta-analysis because these outcomes were reported differently across trials, according to Mr. Gray. However, the investigators did perform a systematic review of health-related quality of life studies that will be part of the final manuscript.

“We found surprisingly little extra toxicity” with the dose intensification, he reported. “It’s not very much considering the extra benefits we are getting. And when you know you are getting more benefit, it makes it easy to tolerate a drug.”

“In the U.S., people have moved toward the accelerated chemotherapy much more than they have in Europe. I think people have the mindset, ‘Well, we’ve always done it this way,’ ” Mr. Gray concluded. “This evidence being so clear and definite will help change that mindset. I wouldn’t be surprised if practice in the U.K. and many other parts of Europe doesn’t switch as a result of these very definite findings.” 

Adolescents are one of the highest risk groups for HIV, but they often don’t want to talk about it. They also don’t want to get tested—of 40% of high school students who had had intercourse, only 10% had been tested, according to a CDC study.

Are online forums the solution? They offer anonymity along with information, and many adolescents—if not most—are used to getting information from social media. Researchers from University of California in Davis, say there’s a real need for a reliable source of advice on the subject for that audience. Most online forums for adolescent message boards and websites revolve around pregnancy and birth control rather than STDs.

The researchers noted that higher levels of stigma surrounding HIV correlate with lower levels of HIV testing. Even the testing is stigmatized, because many people feel just getting the test creates the impression that they are promiscuous, for instance. They also fear what the test may tell them and that it might be used against them in employment or health insurance.

The researchers analyzed 201 threads and 319 posts. Among 7 forums, 2 (POZ, MedHelp) were monitored by counselors, and 4 (DailyStrength, eHealth Forum, HealingWell, and HealthBoards) were monitored by members. One (The Body) was monitored by counselors and members.

In 13 threads, users displayed a “self-stigmatizing attitude” toward HIV testing, mainly because of the fear of being diagnosed. Others feared losing employment or having relationships affected. Notably, no adolescents asked about HIV testing in the forums targeted at their age groups. It is important to increase the visibility of HIV-related resources in adolescents’ forums, the researchers say; the lack of available information online may “perpetuate the taboo among this population by conveying a deeper stigma toward HIV.”

The study showed that the level of stigmatization differed significantly based on who monitored the session: The threads maintained by members had fewer stigmatized posts. The researchers suggest that if health care professionals get more involved by collaborating with forums to provide more content and framing HIV testing as a regular preventive checkup, they may reduce the stigma. Health care professionals also may be able to identify those who suspect they have HIV and encourage them to get tested. Health care professionals also can initiate threads that invite open discussion of HIV-related topics in sexual education forums devoted to adolescents. The researchers say breaking the online silence will lead more people to timely testing.

Source:

Ho CL, Pan W, Taylor LD. J Psychosoc Nurs Ment Health Serv. 2017;55(12):34-43.

doi: 10.3928/02793695-20170905-01.

Adolescents are one of the highest risk groups for HIV, but they often don’t want to talk about it. They also don’t want to get tested—of 40% of high school students who had had intercourse, only 10% had been tested, according to a CDC study.

Are online forums the solution? They offer anonymity along with information, and many adolescents—if not most—are used to getting information from social media. Researchers from University of California in Davis, say there’s a real need for a reliable source of advice on the subject for that audience. Most online forums for adolescent message boards and websites revolve around pregnancy and birth control rather than STDs.

The researchers noted that higher levels of stigma surrounding HIV correlate with lower levels of HIV testing. Even the testing is stigmatized, because many people feel just getting the test creates the impression that they are promiscuous, for instance. They also fear what the test may tell them and that it might be used against them in employment or health insurance.

The researchers analyzed 201 threads and 319 posts. Among 7 forums, 2 (POZ, MedHelp) were monitored by counselors, and 4 (DailyStrength, eHealth Forum, HealingWell, and HealthBoards) were monitored by members. One (The Body) was monitored by counselors and members.

In 13 threads, users displayed a “self-stigmatizing attitude” toward HIV testing, mainly because of the fear of being diagnosed. Others feared losing employment or having relationships affected. Notably, no adolescents asked about HIV testing in the forums targeted at their age groups. It is important to increase the visibility of HIV-related resources in adolescents’ forums, the researchers say; the lack of available information online may “perpetuate the taboo among this population by conveying a deeper stigma toward HIV.”

The study showed that the level of stigmatization differed significantly based on who monitored the session: The threads maintained by members had fewer stigmatized posts. The researchers suggest that if health care professionals get more involved by collaborating with forums to provide more content and framing HIV testing as a regular preventive checkup, they may reduce the stigma. Health care professionals also may be able to identify those who suspect they have HIV and encourage them to get tested. Health care professionals also can initiate threads that invite open discussion of HIV-related topics in sexual education forums devoted to adolescents. The researchers say breaking the online silence will lead more people to timely testing.

Source:

Ho CL, Pan W, Taylor LD. J Psychosoc Nurs Ment Health Serv. 2017;55(12):34-43.

doi: 10.3928/02793695-20170905-01.

Adolescents are one of the highest risk groups for HIV, but they often don’t want to talk about it. They also don’t want to get tested—of 40% of high school students who had had intercourse, only 10% had been tested, according to a CDC study.

Are online forums the solution? They offer anonymity along with information, and many adolescents—if not most—are used to getting information from social media. Researchers from University of California in Davis, say there’s a real need for a reliable source of advice on the subject for that audience. Most online forums for adolescent message boards and websites revolve around pregnancy and birth control rather than STDs.

The researchers noted that higher levels of stigma surrounding HIV correlate with lower levels of HIV testing. Even the testing is stigmatized, because many people feel just getting the test creates the impression that they are promiscuous, for instance. They also fear what the test may tell them and that it might be used against them in employment or health insurance.

The researchers analyzed 201 threads and 319 posts. Among 7 forums, 2 (POZ, MedHelp) were monitored by counselors, and 4 (DailyStrength, eHealth Forum, HealingWell, and HealthBoards) were monitored by members. One (The Body) was monitored by counselors and members.

In 13 threads, users displayed a “self-stigmatizing attitude” toward HIV testing, mainly because of the fear of being diagnosed. Others feared losing employment or having relationships affected. Notably, no adolescents asked about HIV testing in the forums targeted at their age groups. It is important to increase the visibility of HIV-related resources in adolescents’ forums, the researchers say; the lack of available information online may “perpetuate the taboo among this population by conveying a deeper stigma toward HIV.”

The study showed that the level of stigmatization differed significantly based on who monitored the session: The threads maintained by members had fewer stigmatized posts. The researchers suggest that if health care professionals get more involved by collaborating with forums to provide more content and framing HIV testing as a regular preventive checkup, they may reduce the stigma. Health care professionals also may be able to identify those who suspect they have HIV and encourage them to get tested. Health care professionals also can initiate threads that invite open discussion of HIV-related topics in sexual education forums devoted to adolescents. The researchers say breaking the online silence will lead more people to timely testing.

Source:

Ho CL, Pan W, Taylor LD. J Psychosoc Nurs Ment Health Serv. 2017;55(12):34-43.

doi: 10.3928/02793695-20170905-01.

in the bone marrow

New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.

Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).

And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.

Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.

“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”

Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.

Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).

The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.

When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.

The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.

“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”

in the bone marrow

New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.

Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).

And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.

Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.

“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”

Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.

Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).

The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.

When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.

The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.

“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”

in the bone marrow

New research suggests a 2-drug combination might improve hematopoietic stem cell transplant (HSCT) for donors and recipients.

Researchers found that a single dose of the drugs provides HSC mobilization that rivals 5-day treatment with granulocyte colony-stimulating factor (G-CSF).

And the combination mobilizes HSCs that have higher engraftment efficiency than HSCs mobilized by G-CSF.

Jonathan Hoggatt, PhD, of Massachusetts General Hospital in Boston, and his colleagues reported these findings in Cell.

“Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes,” Dr Hoggatt said. “So in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard 5-day protocol. This means less pain, time off work, and lifestyle disruption for the donor, more convenience for the clinical staff, and more predictability for the harvesting procedure.”

Dr Hoggatt and his colleagues have investigated ways to enhance HSC donation for several years. In a previous study, the researchers found that a CXCR2 agonist called GRO-beta induced rapid movement of HSCs from the marrow into the blood in animal models.

Initial experiments in the current study revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing HSCs. Therefore, the team tried combining GRO-beta with the CXCR4 antagonist AMD3100 (plerixafor).

The researchers found that simultaneous administration of both drugs rapidly (within 15 minutes) produced a quantity of HSCs equal to that provided by the 5-day G-CSF protocol.

When transplanted in mice, the HSCs mobilized by AMD3100 and GRO-beta prompted faster reconstitution of bone marrow and recovery of immune cell populations than HSCs mobilized by G-CSF.

The HSCs mobilized by AMD3100 and GRO-beta showed patterns of gene expression similar to those of fetal HSCs.

“These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells,” Dr Hoggatt said. “Finding that they express genes similar to those of fetal liver HSCs . . . suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now, we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans.”

Image by Kevin MacKenzie

Researchers have found evidence to suggest that pharmacomechanical catheter-directed thrombolysis is largely inappropriate as first-line treatment for patients with acute proximal deep vein thrombosis (DVT).

The team found that anticoagulation plus pharmacomechanical thrombolysis was no more effective than anticoagulation alone for preventing post-thrombotic syndrome (PTS).

Additionally, patients who received pharmacomechanical thrombolysis had a higher risk of major bleeding.

The researchers reported these findings in NEJM.

The trial, known as the ATTRACT study, was designed to determine whether performing pharmacomechanical thrombolysis as part of initial treatment for patients with DVT would reduce the number of patients who later develop PTS.

“The clinical research in deep vein thrombosis and post-thrombotic syndrome is very important to the clinical community and of interest to the National Heart, Lung, and Blood Institute [NHLBI],” said Andrei Kindzelski, MD, PhD, the NHLBI program officer for the ATTRACT trial.

“This landmark study, conducted at 56 clinical sites, demonstrated, in an unbiased manner, no benefits of catheter-directed thrombolysis as a first-line deep vein thrombosis treatment, enabling patients to avoid an unnecessary medical procedure. At the same time, ATTRACT identified a potential future research need in more targeted use of catheter-directed thrombolysis in specific patient groups.”

The study included 692 patients who were randomized to receive anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis.

Anticoagulation consisted of unfractionated heparin, enoxaparin, dalteparin, or tinzaparin for at least 5 days, overlapped with long-term warfarin, as well as the prescription of elastic compression stockings.

Pharmacomechanical thrombolysis consisted of catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting.

Results

The study’s primary outcome was the development of PTS between 6 and 24 months of follow-up.

There was no significant difference in PTS incidence between the treatment arms. PTS occurred in 47% (157/336) of patients in the pharmacomechanical-thrombolysis group and 48% (171/355) of patients in the control group (risk ratio=0.96, P=0.56).

Pharmacomechanical thrombolysis did reduce the severity of PTS, however. The incidence of moderate-to-severe PTS was 24% in the control group and 18% in the pharmacomechanical-thrombolysis group (risk ratio=0.73; P=0.04).

Severity scores for PTS were significantly lower in the pharmacomechanical-thrombolysis group than the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for each time point).

There was no significant difference between the treatment arms in the incidence of recurrent venous thromboembolism (VTE) over the 24-month follow-up period. Recurrent VTE was observed in 12% of patients in the pharmacomechanical-thrombolysis group and 8% of controls (P=0.09).

On the other hand, there was a significant increase in the incidence of major bleeding within 10 days in the pharmacomechanical-thrombolysis group. The incidence was 1.7% (n=6) in the pharmacomechanical thrombolysis group and 0.3% (n=1) in the control group (P=0.049).

“None of us was surprised to find that this treatment [pharmacomechanical thrombolysis] is riskier than blood-thinning drugs alone,” said study author Suresh Vedantham, MD, of Washington University School of Medicine in St. Louis, Missouri.

“To justify that extra risk, we would have had to show a dramatic improvement in long-term outcomes, and the study didn’t show that. We saw some improvement in disease severity but not enough to justify the risks for most patients.”

While the results indicate that most patients should not undergo pharmacomechanical thrombolysis, the data also hint that the benefits may outweigh the risks in some patients, such as those with exceptionally large clots.

“This is the first large, rigorous study to examine the ability of imaging-guided treatment to address post-thrombotic syndrome,” Dr Vedantham said. “This study will advance patient care by helping many people avoid an unnecessary procedure.”

“The findings are also interesting because there is the suggestion that at least some patients may have benefited. Sorting that out is going to be very important.”

For now, pharmacomechanical thrombolysis should be reserved for use as a second-line treatment for some carefully selected patients who are experiencing particularly severe limitations of leg function from DVT and who are not responding to anticoagulation alone, Dr Vedantham added.

This research was sponsored by NHLBI. Additional funding was provided by Boston Scientific, Covidien (now Medtronic), and Genentech, which provided recombinant tissue plasminogen activator for the study. Compression stockings were donated by BSN Medical.

Image by Kevin MacKenzie

Researchers have found evidence to suggest that pharmacomechanical catheter-directed thrombolysis is largely inappropriate as first-line treatment for patients with acute proximal deep vein thrombosis (DVT).

The team found that anticoagulation plus pharmacomechanical thrombolysis was no more effective than anticoagulation alone for preventing post-thrombotic syndrome (PTS).

Additionally, patients who received pharmacomechanical thrombolysis had a higher risk of major bleeding.

The researchers reported these findings in NEJM.

The trial, known as the ATTRACT study, was designed to determine whether performing pharmacomechanical thrombolysis as part of initial treatment for patients with DVT would reduce the number of patients who later develop PTS.

“The clinical research in deep vein thrombosis and post-thrombotic syndrome is very important to the clinical community and of interest to the National Heart, Lung, and Blood Institute [NHLBI],” said Andrei Kindzelski, MD, PhD, the NHLBI program officer for the ATTRACT trial.

“This landmark study, conducted at 56 clinical sites, demonstrated, in an unbiased manner, no benefits of catheter-directed thrombolysis as a first-line deep vein thrombosis treatment, enabling patients to avoid an unnecessary medical procedure. At the same time, ATTRACT identified a potential future research need in more targeted use of catheter-directed thrombolysis in specific patient groups.”

The study included 692 patients who were randomized to receive anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis.

Anticoagulation consisted of unfractionated heparin, enoxaparin, dalteparin, or tinzaparin for at least 5 days, overlapped with long-term warfarin, as well as the prescription of elastic compression stockings.

Pharmacomechanical thrombolysis consisted of catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting.

Results

The study’s primary outcome was the development of PTS between 6 and 24 months of follow-up.

There was no significant difference in PTS incidence between the treatment arms. PTS occurred in 47% (157/336) of patients in the pharmacomechanical-thrombolysis group and 48% (171/355) of patients in the control group (risk ratio=0.96, P=0.56).

Pharmacomechanical thrombolysis did reduce the severity of PTS, however. The incidence of moderate-to-severe PTS was 24% in the control group and 18% in the pharmacomechanical-thrombolysis group (risk ratio=0.73; P=0.04).

Severity scores for PTS were significantly lower in the pharmacomechanical-thrombolysis group than the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for each time point).

There was no significant difference between the treatment arms in the incidence of recurrent venous thromboembolism (VTE) over the 24-month follow-up period. Recurrent VTE was observed in 12% of patients in the pharmacomechanical-thrombolysis group and 8% of controls (P=0.09).

On the other hand, there was a significant increase in the incidence of major bleeding within 10 days in the pharmacomechanical-thrombolysis group. The incidence was 1.7% (n=6) in the pharmacomechanical thrombolysis group and 0.3% (n=1) in the control group (P=0.049).

“None of us was surprised to find that this treatment [pharmacomechanical thrombolysis] is riskier than blood-thinning drugs alone,” said study author Suresh Vedantham, MD, of Washington University School of Medicine in St. Louis, Missouri.

“To justify that extra risk, we would have had to show a dramatic improvement in long-term outcomes, and the study didn’t show that. We saw some improvement in disease severity but not enough to justify the risks for most patients.”

While the results indicate that most patients should not undergo pharmacomechanical thrombolysis, the data also hint that the benefits may outweigh the risks in some patients, such as those with exceptionally large clots.

“This is the first large, rigorous study to examine the ability of imaging-guided treatment to address post-thrombotic syndrome,” Dr Vedantham said. “This study will advance patient care by helping many people avoid an unnecessary procedure.”

“The findings are also interesting because there is the suggestion that at least some patients may have benefited. Sorting that out is going to be very important.”

For now, pharmacomechanical thrombolysis should be reserved for use as a second-line treatment for some carefully selected patients who are experiencing particularly severe limitations of leg function from DVT and who are not responding to anticoagulation alone, Dr Vedantham added.

This research was sponsored by NHLBI. Additional funding was provided by Boston Scientific, Covidien (now Medtronic), and Genentech, which provided recombinant tissue plasminogen activator for the study. Compression stockings were donated by BSN Medical.

Image by Kevin MacKenzie

Researchers have found evidence to suggest that pharmacomechanical catheter-directed thrombolysis is largely inappropriate as first-line treatment for patients with acute proximal deep vein thrombosis (DVT).

The team found that anticoagulation plus pharmacomechanical thrombolysis was no more effective than anticoagulation alone for preventing post-thrombotic syndrome (PTS).

Additionally, patients who received pharmacomechanical thrombolysis had a higher risk of major bleeding.

The researchers reported these findings in NEJM.

The trial, known as the ATTRACT study, was designed to determine whether performing pharmacomechanical thrombolysis as part of initial treatment for patients with DVT would reduce the number of patients who later develop PTS.

“The clinical research in deep vein thrombosis and post-thrombotic syndrome is very important to the clinical community and of interest to the National Heart, Lung, and Blood Institute [NHLBI],” said Andrei Kindzelski, MD, PhD, the NHLBI program officer for the ATTRACT trial.

“This landmark study, conducted at 56 clinical sites, demonstrated, in an unbiased manner, no benefits of catheter-directed thrombolysis as a first-line deep vein thrombosis treatment, enabling patients to avoid an unnecessary medical procedure. At the same time, ATTRACT identified a potential future research need in more targeted use of catheter-directed thrombolysis in specific patient groups.”

The study included 692 patients who were randomized to receive anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis.

Anticoagulation consisted of unfractionated heparin, enoxaparin, dalteparin, or tinzaparin for at least 5 days, overlapped with long-term warfarin, as well as the prescription of elastic compression stockings.

Pharmacomechanical thrombolysis consisted of catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting.

Results

The study’s primary outcome was the development of PTS between 6 and 24 months of follow-up.

There was no significant difference in PTS incidence between the treatment arms. PTS occurred in 47% (157/336) of patients in the pharmacomechanical-thrombolysis group and 48% (171/355) of patients in the control group (risk ratio=0.96, P=0.56).

Pharmacomechanical thrombolysis did reduce the severity of PTS, however. The incidence of moderate-to-severe PTS was 24% in the control group and 18% in the pharmacomechanical-thrombolysis group (risk ratio=0.73; P=0.04).

Severity scores for PTS were significantly lower in the pharmacomechanical-thrombolysis group than the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for each time point).

There was no significant difference between the treatment arms in the incidence of recurrent venous thromboembolism (VTE) over the 24-month follow-up period. Recurrent VTE was observed in 12% of patients in the pharmacomechanical-thrombolysis group and 8% of controls (P=0.09).

On the other hand, there was a significant increase in the incidence of major bleeding within 10 days in the pharmacomechanical-thrombolysis group. The incidence was 1.7% (n=6) in the pharmacomechanical thrombolysis group and 0.3% (n=1) in the control group (P=0.049).

“None of us was surprised to find that this treatment [pharmacomechanical thrombolysis] is riskier than blood-thinning drugs alone,” said study author Suresh Vedantham, MD, of Washington University School of Medicine in St. Louis, Missouri.

“To justify that extra risk, we would have had to show a dramatic improvement in long-term outcomes, and the study didn’t show that. We saw some improvement in disease severity but not enough to justify the risks for most patients.”

While the results indicate that most patients should not undergo pharmacomechanical thrombolysis, the data also hint that the benefits may outweigh the risks in some patients, such as those with exceptionally large clots.

“This is the first large, rigorous study to examine the ability of imaging-guided treatment to address post-thrombotic syndrome,” Dr Vedantham said. “This study will advance patient care by helping many people avoid an unnecessary procedure.”

“The findings are also interesting because there is the suggestion that at least some patients may have benefited. Sorting that out is going to be very important.”

For now, pharmacomechanical thrombolysis should be reserved for use as a second-line treatment for some carefully selected patients who are experiencing particularly severe limitations of leg function from DVT and who are not responding to anticoagulation alone, Dr Vedantham added.

This research was sponsored by NHLBI. Additional funding was provided by Boston Scientific, Covidien (now Medtronic), and Genentech, which provided recombinant tissue plasminogen activator for the study. Compression stockings were donated by BSN Medical.

Photo from NIAID

An experimental Zika vaccine is safe and induces an immune response in healthy adults, according to research published in The Lancet.

Investigators tested 2 potential Zika vaccines, VRC5288 and VRC5283, in a pair of phase 1 trials.

Both vaccines were considered well-tolerated, but one of them, VRC5283, induced a greater immune response than the other.

Both vaccines were developed by investigators at the National Institute of Allergy and Infectious Diseases (NIAID).

Now, NIAID is leading an international effort to evaluate VRC5283 in a phase 2/2b trial.

“Following early reports that Zika infection during pregnancy can lead to birth defects, NIAID scientists rapidly created one of the first investigational Zika vaccines using a DNA-based platform and began initial studies in healthy adults less than 1 year later,” said NIAID Director Anthony S. Fauci, MD.

To create their vaccines, the investigators inserted into plasmids genes that encode proteins found on the surface of the Zika virus.

The team developed 2 different plasmids for clinical testing: VRC5288 (Zika virus and Japanese encephalitis virus chimera) and VRC5283 (wild-type Zika virus).

In August 2016, NIAID initiated a phase 1 trial of the VRC5288 plasmid in 80 healthy volunteers ages 18 to 35. Subjects received a 4 mg dose via a needle and syringe injection in the arm muscle.

They received doses of VRC5288 at 0 and 8 weeks; 0 and 12 weeks; 0, 4, and 8 weeks; or 0, 4, and 20 weeks.

In December 2016, NIAID initiated a separate trial testing the VRC5283 plasmid. This study enrolled 45 healthy volunteers ages 18 to 50.

Subjects in this trial received 4 mg doses of VRC5283 at 0, 4, and 8 weeks. They were vaccinated in 3 different ways—via single-dose needle and syringe injection in 1 arm, via split-dose needle and syringe injection in each arm, or via needle-free injection in each arm.

Safety

The vaccinations were considered safe and well-tolerated in both trials, although some participants experienced mild to moderate reactions.

Local reactions (with VRC5288 and VRC5283, respectively) included pain/tenderness (mild—46% and 73%, moderate—0% and 7%), mild swelling (1% and 7%), and mild redness (6% and 2%).

Systemic reactions (with VRC5288 and VRC5283, respectively)  included malaise (mild—25% and 33%, moderate—3% and 4%), myalgia (mild—18% and 13%, moderate—4% and 7%), headache (mild—19% and 29%, moderate—4% and 4%), chills (mild—6% and 2%, moderate—1% and 2%), nausea (mild—8% and 4%, moderate—1% and 0%), and joint pain (mild—5% and 16%, moderate—0% and 2%).

Immunogenicity

The investigators analyzed blood samples from all subjects 4 weeks after their final vaccinations.

The team found that 60% to 89% of subjects generated a neutralizing antibody response to VRC5288, and 77% to 100% of subjects generated a neutralizing antibody response to VRC5283.

Subjects who received VRC5283 via the needle-free injector all generated a neutralizing antibody response and had the highest levels of neutralizing antibodies.

Subjects who received VRC5283 in a split-dose administered to both arms had more robust immune responses than those receiving the full dose in 1 arm.

“NIAID has begun phase 2 testing of this candidate to determine if it can prevent Zika virus infection, and the promising phase 1 data . . . support its continued development,” Dr Fauci said.

Photo from NIAID

An experimental Zika vaccine is safe and induces an immune response in healthy adults, according to research published in The Lancet.

Investigators tested 2 potential Zika vaccines, VRC5288 and VRC5283, in a pair of phase 1 trials.

Both vaccines were considered well-tolerated, but one of them, VRC5283, induced a greater immune response than the other.

Both vaccines were developed by investigators at the National Institute of Allergy and Infectious Diseases (NIAID).

Now, NIAID is leading an international effort to evaluate VRC5283 in a phase 2/2b trial.

“Following early reports that Zika infection during pregnancy can lead to birth defects, NIAID scientists rapidly created one of the first investigational Zika vaccines using a DNA-based platform and began initial studies in healthy adults less than 1 year later,” said NIAID Director Anthony S. Fauci, MD.

To create their vaccines, the investigators inserted into plasmids genes that encode proteins found on the surface of the Zika virus.

The team developed 2 different plasmids for clinical testing: VRC5288 (Zika virus and Japanese encephalitis virus chimera) and VRC5283 (wild-type Zika virus).

In August 2016, NIAID initiated a phase 1 trial of the VRC5288 plasmid in 80 healthy volunteers ages 18 to 35. Subjects received a 4 mg dose via a needle and syringe injection in the arm muscle.

They received doses of VRC5288 at 0 and 8 weeks; 0 and 12 weeks; 0, 4, and 8 weeks; or 0, 4, and 20 weeks.

In December 2016, NIAID initiated a separate trial testing the VRC5283 plasmid. This study enrolled 45 healthy volunteers ages 18 to 50.

Subjects in this trial received 4 mg doses of VRC5283 at 0, 4, and 8 weeks. They were vaccinated in 3 different ways—via single-dose needle and syringe injection in 1 arm, via split-dose needle and syringe injection in each arm, or via needle-free injection in each arm.

Safety

The vaccinations were considered safe and well-tolerated in both trials, although some participants experienced mild to moderate reactions.

Local reactions (with VRC5288 and VRC5283, respectively) included pain/tenderness (mild—46% and 73%, moderate—0% and 7%), mild swelling (1% and 7%), and mild redness (6% and 2%).

Systemic reactions (with VRC5288 and VRC5283, respectively)  included malaise (mild—25% and 33%, moderate—3% and 4%), myalgia (mild—18% and 13%, moderate—4% and 7%), headache (mild—19% and 29%, moderate—4% and 4%), chills (mild—6% and 2%, moderate—1% and 2%), nausea (mild—8% and 4%, moderate—1% and 0%), and joint pain (mild—5% and 16%, moderate—0% and 2%).

Immunogenicity

The investigators analyzed blood samples from all subjects 4 weeks after their final vaccinations.

The team found that 60% to 89% of subjects generated a neutralizing antibody response to VRC5288, and 77% to 100% of subjects generated a neutralizing antibody response to VRC5283.

Subjects who received VRC5283 via the needle-free injector all generated a neutralizing antibody response and had the highest levels of neutralizing antibodies.

Subjects who received VRC5283 in a split-dose administered to both arms had more robust immune responses than those receiving the full dose in 1 arm.

“NIAID has begun phase 2 testing of this candidate to determine if it can prevent Zika virus infection, and the promising phase 1 data . . . support its continued development,” Dr Fauci said.

Photo from NIAID

An experimental Zika vaccine is safe and induces an immune response in healthy adults, according to research published in The Lancet.

Investigators tested 2 potential Zika vaccines, VRC5288 and VRC5283, in a pair of phase 1 trials.

Both vaccines were considered well-tolerated, but one of them, VRC5283, induced a greater immune response than the other.

Both vaccines were developed by investigators at the National Institute of Allergy and Infectious Diseases (NIAID).

Now, NIAID is leading an international effort to evaluate VRC5283 in a phase 2/2b trial.

“Following early reports that Zika infection during pregnancy can lead to birth defects, NIAID scientists rapidly created one of the first investigational Zika vaccines using a DNA-based platform and began initial studies in healthy adults less than 1 year later,” said NIAID Director Anthony S. Fauci, MD.

To create their vaccines, the investigators inserted into plasmids genes that encode proteins found on the surface of the Zika virus.

The team developed 2 different plasmids for clinical testing: VRC5288 (Zika virus and Japanese encephalitis virus chimera) and VRC5283 (wild-type Zika virus).

In August 2016, NIAID initiated a phase 1 trial of the VRC5288 plasmid in 80 healthy volunteers ages 18 to 35. Subjects received a 4 mg dose via a needle and syringe injection in the arm muscle.

They received doses of VRC5288 at 0 and 8 weeks; 0 and 12 weeks; 0, 4, and 8 weeks; or 0, 4, and 20 weeks.

In December 2016, NIAID initiated a separate trial testing the VRC5283 plasmid. This study enrolled 45 healthy volunteers ages 18 to 50.

Subjects in this trial received 4 mg doses of VRC5283 at 0, 4, and 8 weeks. They were vaccinated in 3 different ways—via single-dose needle and syringe injection in 1 arm, via split-dose needle and syringe injection in each arm, or via needle-free injection in each arm.

Safety

The vaccinations were considered safe and well-tolerated in both trials, although some participants experienced mild to moderate reactions.

Local reactions (with VRC5288 and VRC5283, respectively) included pain/tenderness (mild—46% and 73%, moderate—0% and 7%), mild swelling (1% and 7%), and mild redness (6% and 2%).

Systemic reactions (with VRC5288 and VRC5283, respectively)  included malaise (mild—25% and 33%, moderate—3% and 4%), myalgia (mild—18% and 13%, moderate—4% and 7%), headache (mild—19% and 29%, moderate—4% and 4%), chills (mild—6% and 2%, moderate—1% and 2%), nausea (mild—8% and 4%, moderate—1% and 0%), and joint pain (mild—5% and 16%, moderate—0% and 2%).

Immunogenicity

The investigators analyzed blood samples from all subjects 4 weeks after their final vaccinations.

The team found that 60% to 89% of subjects generated a neutralizing antibody response to VRC5288, and 77% to 100% of subjects generated a neutralizing antibody response to VRC5283.

Subjects who received VRC5283 via the needle-free injector all generated a neutralizing antibody response and had the highest levels of neutralizing antibodies.

Subjects who received VRC5283 in a split-dose administered to both arms had more robust immune responses than those receiving the full dose in 1 arm.

“NIAID has begun phase 2 testing of this candidate to determine if it can prevent Zika virus infection, and the promising phase 1 data . . . support its continued development,” Dr Fauci said.

Dana, an adult nurse practitioner, has been working for two years at a large, suburban primary care practice owned by the regional hospital system. She sees too many patients per day, never has enough time to chart properly, and is concerned by the expanding role of the medical assistants. She sees salary postings on social media and feels she is underpaid. She fantasizes about owning her own practice but would settle for making more money. She’s heard that some NPs have profit-sharing, but she’s not exactly sure what that means.

Kelsey, a PA, is looking for his first job out of school. He’s been offered a full-time, salaried position with benefits at an urgent care center, but he doesn’t know if this is a good deal for him or not. The family physicians there make $85,000 more per year than the PAs, although the roles are quite similar.

DOWN TO BUSINESS

The US health care crisis is, fundamentally, a financial crisis; our system is comprised of both for-profit and not-for-profit (NFP) businesses. Every day, NPs and PAs are making decisions that affect their job satisfaction, performance, and retention. Many lack confidence in their ability to make good decisions about their salaries, because they don’t understand the business of health care.¹ To survive and thrive, NPs and PAs must understand the basics of the business end.²

So, what qualifies as a business? Any commercial, retail, or professional entity that earns and spends money. It doesn’t matter if it is a for-profit or NFP organization; it can’t survive unless it makes more money than it spends. How that money is earned varies, from selling services and/or goods to receiving grants, income from interest or rentals, or government subsidies.

The major difference between a for-profit and a NFP organization is who controls the money.³ The owners of a for-profit company control the profits, which may be split among the owners or reinvested in the company. A NFP business may use its profits to provide charity care, offset losses of other programs, or invest in capital improvements (eg, new building, equipment). How the profits are to be used is outlined in the business goals or the mission statement of the entity. There are also federal and state regulations for both types of businesses; visit the Internal Revenue Service website for details (www.irs.gov/charities-non-profits; www.irs.gov/businesses/small-businesses-self-employed).

HOW YOU GET PAID FOR SERVICES

As a PA or NP, you generate income for your employer regardless of whether you work for a for-profit or NFP business. Your patients are billed for services rendered.

If you work for a fee-for-service or NFP practice with insurance contracts, the bill gets coded and electronically submitted for payment. Each insurer, whether private or government (ie, Medicare or Medicaid), has established what they will reimburse you for that service. The reimbursement rate is part of your contract with that insurer. Rates are determined based on your profession, licensure, geographic locale, type of facility, and the market rate. An insurance representative would be able to tell you your reimbursement rate for the most common procedure codes you use. (Your employer has this information but may or may not share it with you.) Medicare rates can be found online at www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched/.

If you work for a direct-pay practice, you collect what you bill directly from the patient, often at the time of the visit. A direct-pay practice does not have insurance contracts and does not bill insurers for patients who have insurance; rather, they provide a billing statement with procedure and diagnostic codes and NPI numbers to the patient, who can submit it directly to their insurer. If the insurer accepts out-of-network providers (those with whom they have no contract), they will reimburse the patient directly.

If you work in a fee-for-service or NFP practice, you may see patients who do not have insurance or who have very high deductibles and pay cash for their services. This does not make it a direct-pay practice. Also, by law, fee-for-service and NFP practices can only have one fee schedule for the entire practice. So, you can’t charge one patient $55 for a flu shot and another patient $25. These practices can offer discounts for cash payments at the time of service, to help reduce the set fees, if they choose.

TALKIN’ ’BOUT YOUR (REVENUE) GENERATION

To know how much you can negotiate for your salary and benefits—your total compensation package (of which benefits is often about 30%)—it is critical to know how much revenue you can generate for your employer.⁴ How can you figure this out?

If you are already working, you can ask your practice manager for some data. In some practices, this information is readily shared, perhaps as a means to boost productivity and even allow comparison between employees. If your practice manager is not forthcoming, you can collect the relevant information yourself. It may be challenging, but it is vital information to have. You need to know how many patients you see per day (keep a log for a month), what their payment source is (specific insurer or self-pay), and what the reimbursement rates are. Although reimbursement rates are deemed confidential per your insurance contract and therefore can’t be shared, you can find Medicare and Medicaid rates online. You can also call the provider representative from each insurer and ask for your reimbursement rates for your five or so most commonly used codes.

Another consideration is payment received (ie, not just what you charge). Do all patients pay everything they owe? Not always. Understand the difference between what you bill, what is allowed, and what you collect. The percentage of what is not collected is called the uncollectable rate. Factor that in.

Furthermore, how much do you contribute to the organization by testing? Dana works for a primary care clinic within a hospital system. Let’s assume her practice doesn’t offer colonoscopies or mammograms; how many referrals does she make to the hospital system for these tests? While she may not know the hospital’s profit margin on them, she can figure out how many she orders in a year. And what about the PA who works for a surgeon? Does he or she do the post-surgical checks? How much time does that save the surgeon, who can be providing higher revenue–producing services with the time saved? That contributes to the income of the practice, too! These are points you can make to justify your salary.

MIX IT UP

There is another major consideration for computing your financial contribution to the practice: understanding case mix. Let’s say your most common visit is billed as a 99213 and you charge $100 for this visit. You use this code 50 times in a week. Do you collect $100 x 50 or $5,000 per week? If you have a direct-pay practice and you collect all of it, yes, you will. If your practice accepts insurance, the number of patients you see with different insurers is called your case mix.

Let’s look at the impact of case mix on what you generate. ­Remember, it will take you about the same amount of time and effort to see these patients regardless of their insurer. Ask your practice manager what your case mix is. If he/she is not willing to share this information, you can get an estimate by looking at the demographics of your patient community. How many are older than 65? How many are on public assistance? Community needs assessments will provide you with this data; you can also check the patient’s chart or ask what insurance they have and add this to your log.

How much will you generate by seeing 50 patients in a week for a 99213 for which you charge $100? Let’s start with sample (not actual) base rates to illustrate the concept: $65 for Medicare, $35 for Medicaid, $82 for third-party private insurance, and $100 for self-pay.

Now let’s explore how case mix impacts revenue, with three different scenarios (see charts). In Scenario 1, 50% of your patients have Medicare, 30% have Medicaid, 16% have third-party private insurance, and 4% pay cash (self-pay). In Scenario 2, 26% have Medicare, 0% have Medicaid, 64% have private insurance, and 10% self-pay. In Scenario 3, your practice is a direct-pay practice with 100% self-payers and a 0% uncollectable rate.

In Scenario 1, with a case mix of 80% of your patient payments from Medicare or Medicaid, you generate $3,006 per week. If you see patients 48 weeks per year, you generate $144,288. In Scenario 2, with a case mix of 74% of your patient payments from private insurance, you generate $3,969 per week. In a year, you generate $190,512. And in Scenario 3, with 100% direct-pay patients, you generate $5,000 per week or $240,000 per year.

This example illustrates how case mix influences health care business, based on the current US reimbursement system. If you work for a practice that serves mostly Medicare and Medicaid patients, you do not command the same salary as an NP or PA who works for a direct-pay practice or one with a majority of privately insured patients.

OVERHEAD, OR IN OVER YOUR HEAD?

Now you have a better understanding of what your worth is to a practice. But what does it cost a practice to employ you? What’s your practice’s overhead?

Overhead includes the cost of processing claims; salaries and benefits; physician collaboration, if needed; rent, utilities, insurance, and depreciation. Overhead rates can range from 20% to 50%—meaning, if you generate $225,000 in revenue, it costs $45,000 to $112,500 to employ you. That leaves $112,500 (with higher overhead) to $180,000 (with lower overhead) for your salary. This revenue generation is an average: Many clinicians generate more than $225,000, while new graduates often generate less.

But in addition to generating more revenue, it can be beneficial to examine what you can do to help decrease the practice overhead. Because the bulk of overhead costs is salary, consider how many full-time-equivalent employees are needed to support you. Some NPs and PAs work with a full-time medical assistant or nurse, while others function very efficiently without one.

While providers like Dana and Kelsey can’t control what their practices pay for rent, utilities, or staffing, they can suggest improvements. Suggestions about scheduling, decreasing no-show rates, and improving recalls, immunization rates, and follow-up visits can all help increase revenue by decreasing day-to-day operating costs.

CONCLUSION

Most NPs and PAs went into their profession to help people—but that altruistic goal doesn’t mean you have to undervalue your own worth. Understanding the basic business of health care can help you negotiate your salary, maximize your income, and create new revenue models for patient care. While this may seem daunting to anyone who went to nursing or medical school, there are great resources to help you educate yourself on the essentials of health care business (see box).

Understanding the infrastructure of the health care system will help NPs and PAs become leaders who can impact health care change. These basic business skills are necessary to ensure fair and full compensation for the roles they play. 

Dana, an adult nurse practitioner, has been working for two years at a large, suburban primary care practice owned by the regional hospital system. She sees too many patients per day, never has enough time to chart properly, and is concerned by the expanding role of the medical assistants. She sees salary postings on social media and feels she is underpaid. She fantasizes about owning her own practice but would settle for making more money. She’s heard that some NPs have profit-sharing, but she’s not exactly sure what that means.

Kelsey, a PA, is looking for his first job out of school. He’s been offered a full-time, salaried position with benefits at an urgent care center, but he doesn’t know if this is a good deal for him or not. The family physicians there make $85,000 more per year than the PAs, although the roles are quite similar.

DOWN TO BUSINESS

The US health care crisis is, fundamentally, a financial crisis; our system is comprised of both for-profit and not-for-profit (NFP) businesses. Every day, NPs and PAs are making decisions that affect their job satisfaction, performance, and retention. Many lack confidence in their ability to make good decisions about their salaries, because they don’t understand the business of health care.¹ To survive and thrive, NPs and PAs must understand the basics of the business end.²

So, what qualifies as a business? Any commercial, retail, or professional entity that earns and spends money. It doesn’t matter if it is a for-profit or NFP organization; it can’t survive unless it makes more money than it spends. How that money is earned varies, from selling services and/or goods to receiving grants, income from interest or rentals, or government subsidies.

The major difference between a for-profit and a NFP organization is who controls the money.³ The owners of a for-profit company control the profits, which may be split among the owners or reinvested in the company. A NFP business may use its profits to provide charity care, offset losses of other programs, or invest in capital improvements (eg, new building, equipment). How the profits are to be used is outlined in the business goals or the mission statement of the entity. There are also federal and state regulations for both types of businesses; visit the Internal Revenue Service website for details (www.irs.gov/charities-non-profits; www.irs.gov/businesses/small-businesses-self-employed).

HOW YOU GET PAID FOR SERVICES

As a PA or NP, you generate income for your employer regardless of whether you work for a for-profit or NFP business. Your patients are billed for services rendered.

If you work for a fee-for-service or NFP practice with insurance contracts, the bill gets coded and electronically submitted for payment. Each insurer, whether private or government (ie, Medicare or Medicaid), has established what they will reimburse you for that service. The reimbursement rate is part of your contract with that insurer. Rates are determined based on your profession, licensure, geographic locale, type of facility, and the market rate. An insurance representative would be able to tell you your reimbursement rate for the most common procedure codes you use. (Your employer has this information but may or may not share it with you.) Medicare rates can be found online at www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched/.

If you work for a direct-pay practice, you collect what you bill directly from the patient, often at the time of the visit. A direct-pay practice does not have insurance contracts and does not bill insurers for patients who have insurance; rather, they provide a billing statement with procedure and diagnostic codes and NPI numbers to the patient, who can submit it directly to their insurer. If the insurer accepts out-of-network providers (those with whom they have no contract), they will reimburse the patient directly.

If you work in a fee-for-service or NFP practice, you may see patients who do not have insurance or who have very high deductibles and pay cash for their services. This does not make it a direct-pay practice. Also, by law, fee-for-service and NFP practices can only have one fee schedule for the entire practice. So, you can’t charge one patient $55 for a flu shot and another patient $25. These practices can offer discounts for cash payments at the time of service, to help reduce the set fees, if they choose.

TALKIN’ ’BOUT YOUR (REVENUE) GENERATION

To know how much you can negotiate for your salary and benefits—your total compensation package (of which benefits is often about 30%)—it is critical to know how much revenue you can generate for your employer.⁴ How can you figure this out?

If you are already working, you can ask your practice manager for some data. In some practices, this information is readily shared, perhaps as a means to boost productivity and even allow comparison between employees. If your practice manager is not forthcoming, you can collect the relevant information yourself. It may be challenging, but it is vital information to have. You need to know how many patients you see per day (keep a log for a month), what their payment source is (specific insurer or self-pay), and what the reimbursement rates are. Although reimbursement rates are deemed confidential per your insurance contract and therefore can’t be shared, you can find Medicare and Medicaid rates online. You can also call the provider representative from each insurer and ask for your reimbursement rates for your five or so most commonly used codes.

Another consideration is payment received (ie, not just what you charge). Do all patients pay everything they owe? Not always. Understand the difference between what you bill, what is allowed, and what you collect. The percentage of what is not collected is called the uncollectable rate. Factor that in.

Furthermore, how much do you contribute to the organization by testing? Dana works for a primary care clinic within a hospital system. Let’s assume her practice doesn’t offer colonoscopies or mammograms; how many referrals does she make to the hospital system for these tests? While she may not know the hospital’s profit margin on them, she can figure out how many she orders in a year. And what about the PA who works for a surgeon? Does he or she do the post-surgical checks? How much time does that save the surgeon, who can be providing higher revenue–producing services with the time saved? That contributes to the income of the practice, too! These are points you can make to justify your salary.

MIX IT UP

There is another major consideration for computing your financial contribution to the practice: understanding case mix. Let’s say your most common visit is billed as a 99213 and you charge $100 for this visit. You use this code 50 times in a week. Do you collect $100 x 50 or $5,000 per week? If you have a direct-pay practice and you collect all of it, yes, you will. If your practice accepts insurance, the number of patients you see with different insurers is called your case mix.

Let’s look at the impact of case mix on what you generate. ­Remember, it will take you about the same amount of time and effort to see these patients regardless of their insurer. Ask your practice manager what your case mix is. If he/she is not willing to share this information, you can get an estimate by looking at the demographics of your patient community. How many are older than 65? How many are on public assistance? Community needs assessments will provide you with this data; you can also check the patient’s chart or ask what insurance they have and add this to your log.

How much will you generate by seeing 50 patients in a week for a 99213 for which you charge $100? Let’s start with sample (not actual) base rates to illustrate the concept: $65 for Medicare, $35 for Medicaid, $82 for third-party private insurance, and $100 for self-pay.

Now let’s explore how case mix impacts revenue, with three different scenarios (see charts). In Scenario 1, 50% of your patients have Medicare, 30% have Medicaid, 16% have third-party private insurance, and 4% pay cash (self-pay). In Scenario 2, 26% have Medicare, 0% have Medicaid, 64% have private insurance, and 10% self-pay. In Scenario 3, your practice is a direct-pay practice with 100% self-payers and a 0% uncollectable rate.

In Scenario 1, with a case mix of 80% of your patient payments from Medicare or Medicaid, you generate $3,006 per week. If you see patients 48 weeks per year, you generate $144,288. In Scenario 2, with a case mix of 74% of your patient payments from private insurance, you generate $3,969 per week. In a year, you generate $190,512. And in Scenario 3, with 100% direct-pay patients, you generate $5,000 per week or $240,000 per year.

This example illustrates how case mix influences health care business, based on the current US reimbursement system. If you work for a practice that serves mostly Medicare and Medicaid patients, you do not command the same salary as an NP or PA who works for a direct-pay practice or one with a majority of privately insured patients.

OVERHEAD, OR IN OVER YOUR HEAD?

Now you have a better understanding of what your worth is to a practice. But what does it cost a practice to employ you? What’s your practice’s overhead?

Overhead includes the cost of processing claims; salaries and benefits; physician collaboration, if needed; rent, utilities, insurance, and depreciation. Overhead rates can range from 20% to 50%—meaning, if you generate $225,000 in revenue, it costs $45,000 to $112,500 to employ you. That leaves $112,500 (with higher overhead) to $180,000 (with lower overhead) for your salary. This revenue generation is an average: Many clinicians generate more than $225,000, while new graduates often generate less.

But in addition to generating more revenue, it can be beneficial to examine what you can do to help decrease the practice overhead. Because the bulk of overhead costs is salary, consider how many full-time-equivalent employees are needed to support you. Some NPs and PAs work with a full-time medical assistant or nurse, while others function very efficiently without one.

While providers like Dana and Kelsey can’t control what their practices pay for rent, utilities, or staffing, they can suggest improvements. Suggestions about scheduling, decreasing no-show rates, and improving recalls, immunization rates, and follow-up visits can all help increase revenue by decreasing day-to-day operating costs.

CONCLUSION

Most NPs and PAs went into their profession to help people—but that altruistic goal doesn’t mean you have to undervalue your own worth. Understanding the basic business of health care can help you negotiate your salary, maximize your income, and create new revenue models for patient care. While this may seem daunting to anyone who went to nursing or medical school, there are great resources to help you educate yourself on the essentials of health care business (see box).

Understanding the infrastructure of the health care system will help NPs and PAs become leaders who can impact health care change. These basic business skills are necessary to ensure fair and full compensation for the roles they play. 

Dana, an adult nurse practitioner, has been working for two years at a large, suburban primary care practice owned by the regional hospital system. She sees too many patients per day, never has enough time to chart properly, and is concerned by the expanding role of the medical assistants. She sees salary postings on social media and feels she is underpaid. She fantasizes about owning her own practice but would settle for making more money. She’s heard that some NPs have profit-sharing, but she’s not exactly sure what that means.

Kelsey, a PA, is looking for his first job out of school. He’s been offered a full-time, salaried position with benefits at an urgent care center, but he doesn’t know if this is a good deal for him or not. The family physicians there make $85,000 more per year than the PAs, although the roles are quite similar.

DOWN TO BUSINESS

The US health care crisis is, fundamentally, a financial crisis; our system is comprised of both for-profit and not-for-profit (NFP) businesses. Every day, NPs and PAs are making decisions that affect their job satisfaction, performance, and retention. Many lack confidence in their ability to make good decisions about their salaries, because they don’t understand the business of health care.¹ To survive and thrive, NPs and PAs must understand the basics of the business end.²

So, what qualifies as a business? Any commercial, retail, or professional entity that earns and spends money. It doesn’t matter if it is a for-profit or NFP organization; it can’t survive unless it makes more money than it spends. How that money is earned varies, from selling services and/or goods to receiving grants, income from interest or rentals, or government subsidies.

The major difference between a for-profit and a NFP organization is who controls the money.³ The owners of a for-profit company control the profits, which may be split among the owners or reinvested in the company. A NFP business may use its profits to provide charity care, offset losses of other programs, or invest in capital improvements (eg, new building, equipment). How the profits are to be used is outlined in the business goals or the mission statement of the entity. There are also federal and state regulations for both types of businesses; visit the Internal Revenue Service website for details (www.irs.gov/charities-non-profits; www.irs.gov/businesses/small-businesses-self-employed).

HOW YOU GET PAID FOR SERVICES

As a PA or NP, you generate income for your employer regardless of whether you work for a for-profit or NFP business. Your patients are billed for services rendered.

If you work for a fee-for-service or NFP practice with insurance contracts, the bill gets coded and electronically submitted for payment. Each insurer, whether private or government (ie, Medicare or Medicaid), has established what they will reimburse you for that service. The reimbursement rate is part of your contract with that insurer. Rates are determined based on your profession, licensure, geographic locale, type of facility, and the market rate. An insurance representative would be able to tell you your reimbursement rate for the most common procedure codes you use. (Your employer has this information but may or may not share it with you.) Medicare rates can be found online at www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched/.

If you work for a direct-pay practice, you collect what you bill directly from the patient, often at the time of the visit. A direct-pay practice does not have insurance contracts and does not bill insurers for patients who have insurance; rather, they provide a billing statement with procedure and diagnostic codes and NPI numbers to the patient, who can submit it directly to their insurer. If the insurer accepts out-of-network providers (those with whom they have no contract), they will reimburse the patient directly.

If you work in a fee-for-service or NFP practice, you may see patients who do not have insurance or who have very high deductibles and pay cash for their services. This does not make it a direct-pay practice. Also, by law, fee-for-service and NFP practices can only have one fee schedule for the entire practice. So, you can’t charge one patient $55 for a flu shot and another patient $25. These practices can offer discounts for cash payments at the time of service, to help reduce the set fees, if they choose.

TALKIN’ ’BOUT YOUR (REVENUE) GENERATION

To know how much you can negotiate for your salary and benefits—your total compensation package (of which benefits is often about 30%)—it is critical to know how much revenue you can generate for your employer.⁴ How can you figure this out?

If you are already working, you can ask your practice manager for some data. In some practices, this information is readily shared, perhaps as a means to boost productivity and even allow comparison between employees. If your practice manager is not forthcoming, you can collect the relevant information yourself. It may be challenging, but it is vital information to have. You need to know how many patients you see per day (keep a log for a month), what their payment source is (specific insurer or self-pay), and what the reimbursement rates are. Although reimbursement rates are deemed confidential per your insurance contract and therefore can’t be shared, you can find Medicare and Medicaid rates online. You can also call the provider representative from each insurer and ask for your reimbursement rates for your five or so most commonly used codes.

Another consideration is payment received (ie, not just what you charge). Do all patients pay everything they owe? Not always. Understand the difference between what you bill, what is allowed, and what you collect. The percentage of what is not collected is called the uncollectable rate. Factor that in.

Furthermore, how much do you contribute to the organization by testing? Dana works for a primary care clinic within a hospital system. Let’s assume her practice doesn’t offer colonoscopies or mammograms; how many referrals does she make to the hospital system for these tests? While she may not know the hospital’s profit margin on them, she can figure out how many she orders in a year. And what about the PA who works for a surgeon? Does he or she do the post-surgical checks? How much time does that save the surgeon, who can be providing higher revenue–producing services with the time saved? That contributes to the income of the practice, too! These are points you can make to justify your salary.

MIX IT UP

There is another major consideration for computing your financial contribution to the practice: understanding case mix. Let’s say your most common visit is billed as a 99213 and you charge $100 for this visit. You use this code 50 times in a week. Do you collect $100 x 50 or $5,000 per week? If you have a direct-pay practice and you collect all of it, yes, you will. If your practice accepts insurance, the number of patients you see with different insurers is called your case mix.

Let’s look at the impact of case mix on what you generate. ­Remember, it will take you about the same amount of time and effort to see these patients regardless of their insurer. Ask your practice manager what your case mix is. If he/she is not willing to share this information, you can get an estimate by looking at the demographics of your patient community. How many are older than 65? How many are on public assistance? Community needs assessments will provide you with this data; you can also check the patient’s chart or ask what insurance they have and add this to your log.

How much will you generate by seeing 50 patients in a week for a 99213 for which you charge $100? Let’s start with sample (not actual) base rates to illustrate the concept: $65 for Medicare, $35 for Medicaid, $82 for third-party private insurance, and $100 for self-pay.

Now let’s explore how case mix impacts revenue, with three different scenarios (see charts). In Scenario 1, 50% of your patients have Medicare, 30% have Medicaid, 16% have third-party private insurance, and 4% pay cash (self-pay). In Scenario 2, 26% have Medicare, 0% have Medicaid, 64% have private insurance, and 10% self-pay. In Scenario 3, your practice is a direct-pay practice with 100% self-payers and a 0% uncollectable rate.

In Scenario 1, with a case mix of 80% of your patient payments from Medicare or Medicaid, you generate $3,006 per week. If you see patients 48 weeks per year, you generate $144,288. In Scenario 2, with a case mix of 74% of your patient payments from private insurance, you generate $3,969 per week. In a year, you generate $190,512. And in Scenario 3, with 100% direct-pay patients, you generate $5,000 per week or $240,000 per year.

This example illustrates how case mix influences health care business, based on the current US reimbursement system. If you work for a practice that serves mostly Medicare and Medicaid patients, you do not command the same salary as an NP or PA who works for a direct-pay practice or one with a majority of privately insured patients.

OVERHEAD, OR IN OVER YOUR HEAD?

Now you have a better understanding of what your worth is to a practice. But what does it cost a practice to employ you? What’s your practice’s overhead?

Overhead includes the cost of processing claims; salaries and benefits; physician collaboration, if needed; rent, utilities, insurance, and depreciation. Overhead rates can range from 20% to 50%—meaning, if you generate $225,000 in revenue, it costs $45,000 to $112,500 to employ you. That leaves $112,500 (with higher overhead) to $180,000 (with lower overhead) for your salary. This revenue generation is an average: Many clinicians generate more than $225,000, while new graduates often generate less.

But in addition to generating more revenue, it can be beneficial to examine what you can do to help decrease the practice overhead. Because the bulk of overhead costs is salary, consider how many full-time-equivalent employees are needed to support you. Some NPs and PAs work with a full-time medical assistant or nurse, while others function very efficiently without one.

While providers like Dana and Kelsey can’t control what their practices pay for rent, utilities, or staffing, they can suggest improvements. Suggestions about scheduling, decreasing no-show rates, and improving recalls, immunization rates, and follow-up visits can all help increase revenue by decreasing day-to-day operating costs.

CONCLUSION

Most NPs and PAs went into their profession to help people—but that altruistic goal doesn’t mean you have to undervalue your own worth. Understanding the basic business of health care can help you negotiate your salary, maximize your income, and create new revenue models for patient care. While this may seem daunting to anyone who went to nursing or medical school, there are great resources to help you educate yourself on the essentials of health care business (see box).

Understanding the infrastructure of the health care system will help NPs and PAs become leaders who can impact health care change. These basic business skills are necessary to ensure fair and full compensation for the roles they play.