The rate of total hip arthroplasty (THA) is rising and demand is expected to increase by 174% to 572,000 by 2030.¹ The rate of periprosthetic fracture around primary THA is frequently reported at around 1%,^2-4 though a recent study of over 32,000 THAs quotes the 20-year probability of periprosthetic fracture at 3.5%.⁵ Revision THA is also increasing in frequency and associated rates of periprosthetic fracture range from 1.5% to 7.8% following revision THA,^3,4,6 with the probability of fracture at 20 years of 11%.⁷ Projection models predict that the number of periprosthetic fractures will rise by 4.6% per decade over the next 30 years.⁸

Broadly, treatment options include open reduction internal fixation (ORIF), revision THA, and combined approaches. The Vancouver classification, based on fracture location, stem stability, and bone loss, is often used to guide fracture treatment, with stable implants treated with ORIF and unstable implants requiring revision arthroplasty.

Fixation strategies for treatment of periprosthetic fracture around a well-fixed arthroplasty stem have evolved over time, and there continue to be a variety of available internal fixation options with no clear consensus on the optimal strategy.⁹ Rates of reoperation following ORIF of periprosthetic femur fracture are reported from 13% to 23%,^8,10-12 confirming that there remains room for improvement in management of these injuries.

Locking Plate Fixation

Early fixation strategies included allograft and cables alone as well as nonlocked plate and cerclage constructs. In response to the complication and reoperation rate for nonlocked plate constructs, reported at 33%,¹³ locking plates were introduced as a treatment option, allowing for both improved osseous vascularity and added screw options.¹⁴ When compared to the traditional nonlocked Ogden construct, locking plate constructs are more resistant to axial and torsional load.¹⁵ Clinically, the relative risk of nonunion after nonlocking plate fixation is reported at 11.9 times that of fixation with locking plate technology.¹⁶

Successful use of lateral locking plate fixation for treatment of this injury has been reported on in several clinical series.^17-20 Froberg and colleagues¹² evaluated 60 Vancouver B1 and C fractures treated by locking plate osteosynthesis and reported no nonunions, an improvement from previous constructs. However, 8 out of 60 patients with 2-year follow-up required reoperation—4 for infection, 3 for refracture, and 1 for stem loosening—making it clear that the locking plate alone was not a panacea.

With locking plate fixation a mainstay of modern treatment of periprosthetic femur fractures, many questions still remain.

Proximal Fixation

Even with the introduction of locked plates, treatment success after ORIF of Vancouver B1 fractures relies on adequate proximal fixation. Options for proximal fixation around the stem include cerclage wires or cables, unicortical locked screws, obliquely directed bicortical screws, and use of the locking attachment plate to insert bicortical locked screws. These strategies can be used in the presence of cemented or uncemented stems, with biomechanical evidence that screw fixation through the cement mantle does not cause failure.²¹

Several biomechanical studies address the stiffness and strength of varying proximal fixation strategies. While early fixation relied heavily on cables, the use of cables alone as proximal fixation has been linked to significantly higher rates of failure when compared to other constructs in a large clinical series.¹¹ Multiple biomechanical studies have shown that newer methods of proximal fixation provide more rigid constructs.^22,23

Unicortical locked screws appear to outperform cables biomechanically. The use of unicortical screws in lieu of or in addition to cables provides added resistance to lateral bending as well as torsion when compared to cables alone.²⁴ A second group found that unicortical locked screws alone were superior to combined fixation with cerclage wires and unicortical locked screws.²⁵

Added stability can be demonstrated by bicortical fixation strategies, which offer increased rigidity when compared to cables or unicortical screws.²² In vitro work has shown enhanced fixation stability with bicortical screw fixation using the locking attachment plate when compared to cerclage wires alone.^23,26 Clinically, some authors have demonstrated success with the use of reversed distal femoral locking plates in order to enhance proximal locking options and allow for bicortical fixation around the stem.¹⁹ As noted above, the data favor the opinion that clinical failure rates with cerclage wires alone are high, and biomechanically, bicortical fixation around the femoral stem appears to be superior to unicortical locked screw fixation or cerclage wires. If rigid proximal fixation is desired, an effort should be made to obtain bicortical fixation around the femoral stem.

Allograft

Allograft strut, either alone or in addition to plate osteosynthesis, has long been used in treatment of periprosthetic fractures. Proponents of this technique cite improved biomechanical stability¹⁷ and allograft incorporation resulting in restoration of bone stock.

Early treatment of periprosthetic femur fractures consisted solely of allograft and cable fixation, but data on the technique is limited. A small series reported reasonable success, with only 2 out of 19 patients developing nonunion.²⁷ More recently Haddad and colleagues²⁸ reported malunions in 3 out of 19 patients treated with allograft and cables alone. Allograft alone has been largely abandoned in favor of plate fixation, and biomechanical evidence shows that plate and screw or cerclage constructs are more resistant to torsion and lateral bending than allograft with cables alone.²⁹

However, the role of allograft in treatment of periprosthetic femur fractures is not clearly defined. Some authors advocate routinely supplementing plate fixation with allograft^28,30 and others go as far as to suggest superior union rates of strut allograft augmented plate fixation when compared to plate fixation alone for periprosthetic fractures around a stable femoral stem.³¹ However, in that series, the failure rate of 5/11 patients treated with plate alone is higher than current series,¹² and others have demonstrated good success without allograft, even with nonlocked plates.³²

As recently as 2016, a lateral locking plate supplemented with allograft has been described as a successful technique, with no nonunions reported in a small series.³⁰ However, without a comparison group, it is unclear what role the allograft plays in success in that construct.

Despite some proposed benefits, the additional soft tissue stripping required to place allograft has raised the question of delayed healing and increased infection rate as a result of this technique. A systematic review by Moore and colleagues³³ looking at the use of allograft strut in Vancouver B1 fractures found increased time to union (4.4 vs 6.6 months) and deep infection rate (3.8% vs 8.3%) with the use of allograft strut, leading them to recommend cautious use of allograft when treating Vancouver B1 fractures.

With improved fixation strategies available, the role of allograft may be best reserved for patients with inadequate bone stock.

Dual Plate Fixation

Dual plate fixation has been proposed as one mechanism to increase construct strength. A periprosthetic fracture model has shown that, biomechanically, orthogonal plates have higher bending stiffness, torsional stiffness, cycles to failure, and load to failure when compared to a single lateral plate with use of a locking attachment plate proximally.³⁴ Choi and colleagues³⁵ compared lateral locking plates alone, lateral locking plates with allograft, and lateral locking plates with an orthogonal anterior plate and found the addition of an anterior plate resulted in the strongest construct.

Clinically, Müller and colleagues³⁶ reported on a series of 10 patients treated with orthogonal (anterior and lateral) plating for periprosthetic femur fractures, including 3 nonunions. In their series, there was 1 plate failure and they conclude that dual plating is not associated with an increased risk of complications, and can also be used as a salvage procedure.

While the evidence for dual plating is limited, it may provide needed additional stability in certain cases without the added cost and exposure required for allograft.

Minimally Invasive Plate Osteosynthesis

Contrary to the extensive exposure required to place allograft, minimally invasive plate osteosynthesis (MIPO) of periprosthetic femur fractures is advocated by some authors.^18,20 Ricci and colleagues¹⁸ reported no nonunions in 50 patients treated with indirect reduction techniques and laterally based plating alone without use of allograft. A combination of cables, locking, and nonlocking screws were used. Critical to their technique was preservation of the soft tissue envelope at the level of the fracture.

In further support of MIPO techniques, a systematic review of 1571 periprosthetic hip fractures reported significantly increased risk of nonunion with open approaches when compared to minimally invasive osteosynthesis,¹⁶ emphasizing the role of preservation of vascularity in treating these fractures.

Length of Fixation

For some time it was recommended that fixation of Vancouver B1 fractures end 2 cortical diameters below the level of the fracture.^37,38 More recently there has been interest in the potential benefits of increased length of fixation.

A biomechanical study comparing long (20-hole) and short (12-hole) plates for periprosthetic fracture with regard to failure found no difference in failure rates between groups.³⁹ While plate length did not appear to affect construct stiffness, the issue of subsequent fracture distal to the construct remains.

Moloney and colleagues⁴⁰ proposed fixation of Vancouver B1 fractures using plates that span the length of the femur to the level of the femoral condyles to minimize peri-implant failures in osteoporotic patients. In 36 patients treated with standard-length plates, there were 2 fractures distal to the previous fixation compared to no subsequent fractures in 21 patients treated with spanning fixation.

Similarly, in Vancouver C fractures there is some evidence that fixation should span the femoral stem, regardless of available bone for fixation proximal to the fracture. Kubiak and colleagues⁴¹ found increasing load to failure and decreased cortical strain in a biomechanical model comparing plates that stop short of the femoral stem with those that span the stem.

Clinically, this concept is supported by Froberg and colleagues.¹² In their series of 60 Vancouver B1 and C fractures treated with laterally based locked plating, 3 patients went on to refracture. All of these fractures occurred in patients with Vancouver C fractures treated with plates overlapping the preexisting stem by <50%. The fractures all occurred at the high stress area between the tip of the stem and the end of the plate.

Further support of extended plate length comes from Drew and colleagues,⁸ who demonstrated a significantly decreased risk of reoperation following ORIF of periprosthetic femur fracture when >75% of the length of the femur was spanned compared to <50%. Although in some settings short fixation may produce satisfactory results, consideration should be given to extending the length of fixation, especially in the osteoporotic population.

Interprosthetic Fractures

With a rising number of patients with ipsilateral hip and knee arthroplasty, the rate of interprosthetic fractures is rising. These fractures present additional challenges given preexisting implants above and below the level of the fracture. The use of a single precontoured laterally based locked plate has been reported with good union rates approaching 90%.^42,43 In one series, all nonunions occurred in Vancouver B1 fractures,⁴³ again bringing to light the challenging nature of the B1 fracture.

Nonunion

Success in treating periprosthetic femur fractures has improved with improved fixation methods and understanding of technique. However, current rates of nonunion are still reported up to 27% for B1 and C fractures.⁴⁴

There is limited evidence on the treatment of periprosthetic femur fracture nonunion. However, treatment is difficult and complication rates are high. Crockarell and colleagues⁴⁵ reported a 52% overall complication rate in their series of 23 periprosthetic femur fracture nonunions.

Nonunions of the femur near a prosthesis can be treated by revision of the fracture fixation using compression and grafting to achieve bone healing vs revision of the joint prosthesis to span the area of the nonunited bone. Case-by-case decision-making is based on the remaining bone stock and the type of revision prosthesis necessary to span the problem area. Given the challenges associated with their treatment, a focus on prevention of nonunion is of paramount importance.

Authors’ Preferred Treatment

Our treatment of periprosthetic femur fractures with a well-fixed hip arthroplasty stem adheres to the principles supported in the literature (Figures 1A-1D and Figures 2A, 2B).

• Soft tissue friendly dissection with limited exposure at the fracture site is preferred as the fracture allows, particularly in cases with comminution where a direct assessment of the reduction is not available.
• Plate fixation strategy is dictated by the characteristics of the fracture. Fracture patterns amenable to anatomic reduction receive interfragmentary compression and absolute stability constructs. Highly comminuted fractures receive relatively stable bridging constructs to encourage callous.
• Locking screws are used rarely in diaphyseal fracture patterns, and when employed, are applied to only one side of the fracture to limit “over stiffening” the construct.
• Liberal use of dual plating, both as a method of maintaining fracture reduction while a structural plate is applied and increasing construct rigidity.
• Proximal fixation relies heavily on bicortical screws placed through the holes of the lateral plate. Cerclage wires and unicortical screws are rarely used in our practice. In the case of larger stems, a bicortical 3.5-mm screw can be placed through a 4.5-mm plate using a reduction washer.

Summary

Techniques for treatment of periprosthetic femur fractures around a well-fixed hip arthroplasty stem are constantly evolving. Several principles have emerged to decrease rates of treatment failure and subsequent reoperation. While there are several methods to do so, it is critical to achieve stable proximal fixation. Long spanning fixation constructs are linked to lower failure and reoperation rates in both B1 and C type fractures. Additionally, the importance of soft tissue management and maintenance of local vascularity should not be underestimated.

The rate of total hip arthroplasty (THA) is rising and demand is expected to increase by 174% to 572,000 by 2030.¹ The rate of periprosthetic fracture around primary THA is frequently reported at around 1%,^2-4 though a recent study of over 32,000 THAs quotes the 20-year probability of periprosthetic fracture at 3.5%.⁵ Revision THA is also increasing in frequency and associated rates of periprosthetic fracture range from 1.5% to 7.8% following revision THA,^3,4,6 with the probability of fracture at 20 years of 11%.⁷ Projection models predict that the number of periprosthetic fractures will rise by 4.6% per decade over the next 30 years.⁸

Broadly, treatment options include open reduction internal fixation (ORIF), revision THA, and combined approaches. The Vancouver classification, based on fracture location, stem stability, and bone loss, is often used to guide fracture treatment, with stable implants treated with ORIF and unstable implants requiring revision arthroplasty.

Fixation strategies for treatment of periprosthetic fracture around a well-fixed arthroplasty stem have evolved over time, and there continue to be a variety of available internal fixation options with no clear consensus on the optimal strategy.⁹ Rates of reoperation following ORIF of periprosthetic femur fracture are reported from 13% to 23%,^8,10-12 confirming that there remains room for improvement in management of these injuries.

Locking Plate Fixation

Early fixation strategies included allograft and cables alone as well as nonlocked plate and cerclage constructs. In response to the complication and reoperation rate for nonlocked plate constructs, reported at 33%,¹³ locking plates were introduced as a treatment option, allowing for both improved osseous vascularity and added screw options.¹⁴ When compared to the traditional nonlocked Ogden construct, locking plate constructs are more resistant to axial and torsional load.¹⁵ Clinically, the relative risk of nonunion after nonlocking plate fixation is reported at 11.9 times that of fixation with locking plate technology.¹⁶

Successful use of lateral locking plate fixation for treatment of this injury has been reported on in several clinical series.^17-20 Froberg and colleagues¹² evaluated 60 Vancouver B1 and C fractures treated by locking plate osteosynthesis and reported no nonunions, an improvement from previous constructs. However, 8 out of 60 patients with 2-year follow-up required reoperation—4 for infection, 3 for refracture, and 1 for stem loosening—making it clear that the locking plate alone was not a panacea.

With locking plate fixation a mainstay of modern treatment of periprosthetic femur fractures, many questions still remain.

Proximal Fixation

Even with the introduction of locked plates, treatment success after ORIF of Vancouver B1 fractures relies on adequate proximal fixation. Options for proximal fixation around the stem include cerclage wires or cables, unicortical locked screws, obliquely directed bicortical screws, and use of the locking attachment plate to insert bicortical locked screws. These strategies can be used in the presence of cemented or uncemented stems, with biomechanical evidence that screw fixation through the cement mantle does not cause failure.²¹

Several biomechanical studies address the stiffness and strength of varying proximal fixation strategies. While early fixation relied heavily on cables, the use of cables alone as proximal fixation has been linked to significantly higher rates of failure when compared to other constructs in a large clinical series.¹¹ Multiple biomechanical studies have shown that newer methods of proximal fixation provide more rigid constructs.^22,23

Unicortical locked screws appear to outperform cables biomechanically. The use of unicortical screws in lieu of or in addition to cables provides added resistance to lateral bending as well as torsion when compared to cables alone.²⁴ A second group found that unicortical locked screws alone were superior to combined fixation with cerclage wires and unicortical locked screws.²⁵

Added stability can be demonstrated by bicortical fixation strategies, which offer increased rigidity when compared to cables or unicortical screws.²² In vitro work has shown enhanced fixation stability with bicortical screw fixation using the locking attachment plate when compared to cerclage wires alone.^23,26 Clinically, some authors have demonstrated success with the use of reversed distal femoral locking plates in order to enhance proximal locking options and allow for bicortical fixation around the stem.¹⁹ As noted above, the data favor the opinion that clinical failure rates with cerclage wires alone are high, and biomechanically, bicortical fixation around the femoral stem appears to be superior to unicortical locked screw fixation or cerclage wires. If rigid proximal fixation is desired, an effort should be made to obtain bicortical fixation around the femoral stem.

Allograft

Allograft strut, either alone or in addition to plate osteosynthesis, has long been used in treatment of periprosthetic fractures. Proponents of this technique cite improved biomechanical stability¹⁷ and allograft incorporation resulting in restoration of bone stock.

Early treatment of periprosthetic femur fractures consisted solely of allograft and cable fixation, but data on the technique is limited. A small series reported reasonable success, with only 2 out of 19 patients developing nonunion.²⁷ More recently Haddad and colleagues²⁸ reported malunions in 3 out of 19 patients treated with allograft and cables alone. Allograft alone has been largely abandoned in favor of plate fixation, and biomechanical evidence shows that plate and screw or cerclage constructs are more resistant to torsion and lateral bending than allograft with cables alone.²⁹

However, the role of allograft in treatment of periprosthetic femur fractures is not clearly defined. Some authors advocate routinely supplementing plate fixation with allograft^28,30 and others go as far as to suggest superior union rates of strut allograft augmented plate fixation when compared to plate fixation alone for periprosthetic fractures around a stable femoral stem.³¹ However, in that series, the failure rate of 5/11 patients treated with plate alone is higher than current series,¹² and others have demonstrated good success without allograft, even with nonlocked plates.³²

As recently as 2016, a lateral locking plate supplemented with allograft has been described as a successful technique, with no nonunions reported in a small series.³⁰ However, without a comparison group, it is unclear what role the allograft plays in success in that construct.

Despite some proposed benefits, the additional soft tissue stripping required to place allograft has raised the question of delayed healing and increased infection rate as a result of this technique. A systematic review by Moore and colleagues³³ looking at the use of allograft strut in Vancouver B1 fractures found increased time to union (4.4 vs 6.6 months) and deep infection rate (3.8% vs 8.3%) with the use of allograft strut, leading them to recommend cautious use of allograft when treating Vancouver B1 fractures.

With improved fixation strategies available, the role of allograft may be best reserved for patients with inadequate bone stock.

Dual Plate Fixation

Dual plate fixation has been proposed as one mechanism to increase construct strength. A periprosthetic fracture model has shown that, biomechanically, orthogonal plates have higher bending stiffness, torsional stiffness, cycles to failure, and load to failure when compared to a single lateral plate with use of a locking attachment plate proximally.³⁴ Choi and colleagues³⁵ compared lateral locking plates alone, lateral locking plates with allograft, and lateral locking plates with an orthogonal anterior plate and found the addition of an anterior plate resulted in the strongest construct.

Clinically, Müller and colleagues³⁶ reported on a series of 10 patients treated with orthogonal (anterior and lateral) plating for periprosthetic femur fractures, including 3 nonunions. In their series, there was 1 plate failure and they conclude that dual plating is not associated with an increased risk of complications, and can also be used as a salvage procedure.

While the evidence for dual plating is limited, it may provide needed additional stability in certain cases without the added cost and exposure required for allograft.

Minimally Invasive Plate Osteosynthesis

Contrary to the extensive exposure required to place allograft, minimally invasive plate osteosynthesis (MIPO) of periprosthetic femur fractures is advocated by some authors.^18,20 Ricci and colleagues¹⁸ reported no nonunions in 50 patients treated with indirect reduction techniques and laterally based plating alone without use of allograft. A combination of cables, locking, and nonlocking screws were used. Critical to their technique was preservation of the soft tissue envelope at the level of the fracture.

In further support of MIPO techniques, a systematic review of 1571 periprosthetic hip fractures reported significantly increased risk of nonunion with open approaches when compared to minimally invasive osteosynthesis,¹⁶ emphasizing the role of preservation of vascularity in treating these fractures.

Length of Fixation

For some time it was recommended that fixation of Vancouver B1 fractures end 2 cortical diameters below the level of the fracture.^37,38 More recently there has been interest in the potential benefits of increased length of fixation.

A biomechanical study comparing long (20-hole) and short (12-hole) plates for periprosthetic fracture with regard to failure found no difference in failure rates between groups.³⁹ While plate length did not appear to affect construct stiffness, the issue of subsequent fracture distal to the construct remains.

Moloney and colleagues⁴⁰ proposed fixation of Vancouver B1 fractures using plates that span the length of the femur to the level of the femoral condyles to minimize peri-implant failures in osteoporotic patients. In 36 patients treated with standard-length plates, there were 2 fractures distal to the previous fixation compared to no subsequent fractures in 21 patients treated with spanning fixation.

Similarly, in Vancouver C fractures there is some evidence that fixation should span the femoral stem, regardless of available bone for fixation proximal to the fracture. Kubiak and colleagues⁴¹ found increasing load to failure and decreased cortical strain in a biomechanical model comparing plates that stop short of the femoral stem with those that span the stem.

Clinically, this concept is supported by Froberg and colleagues.¹² In their series of 60 Vancouver B1 and C fractures treated with laterally based locked plating, 3 patients went on to refracture. All of these fractures occurred in patients with Vancouver C fractures treated with plates overlapping the preexisting stem by <50%. The fractures all occurred at the high stress area between the tip of the stem and the end of the plate.

Further support of extended plate length comes from Drew and colleagues,⁸ who demonstrated a significantly decreased risk of reoperation following ORIF of periprosthetic femur fracture when >75% of the length of the femur was spanned compared to <50%. Although in some settings short fixation may produce satisfactory results, consideration should be given to extending the length of fixation, especially in the osteoporotic population.

Interprosthetic Fractures

With a rising number of patients with ipsilateral hip and knee arthroplasty, the rate of interprosthetic fractures is rising. These fractures present additional challenges given preexisting implants above and below the level of the fracture. The use of a single precontoured laterally based locked plate has been reported with good union rates approaching 90%.^42,43 In one series, all nonunions occurred in Vancouver B1 fractures,⁴³ again bringing to light the challenging nature of the B1 fracture.

Nonunion

Success in treating periprosthetic femur fractures has improved with improved fixation methods and understanding of technique. However, current rates of nonunion are still reported up to 27% for B1 and C fractures.⁴⁴

There is limited evidence on the treatment of periprosthetic femur fracture nonunion. However, treatment is difficult and complication rates are high. Crockarell and colleagues⁴⁵ reported a 52% overall complication rate in their series of 23 periprosthetic femur fracture nonunions.

Nonunions of the femur near a prosthesis can be treated by revision of the fracture fixation using compression and grafting to achieve bone healing vs revision of the joint prosthesis to span the area of the nonunited bone. Case-by-case decision-making is based on the remaining bone stock and the type of revision prosthesis necessary to span the problem area. Given the challenges associated with their treatment, a focus on prevention of nonunion is of paramount importance.

Authors’ Preferred Treatment

Our treatment of periprosthetic femur fractures with a well-fixed hip arthroplasty stem adheres to the principles supported in the literature (Figures 1A-1D and Figures 2A, 2B).

• Soft tissue friendly dissection with limited exposure at the fracture site is preferred as the fracture allows, particularly in cases with comminution where a direct assessment of the reduction is not available.
• Plate fixation strategy is dictated by the characteristics of the fracture. Fracture patterns amenable to anatomic reduction receive interfragmentary compression and absolute stability constructs. Highly comminuted fractures receive relatively stable bridging constructs to encourage callous.
• Locking screws are used rarely in diaphyseal fracture patterns, and when employed, are applied to only one side of the fracture to limit “over stiffening” the construct.
• Liberal use of dual plating, both as a method of maintaining fracture reduction while a structural plate is applied and increasing construct rigidity.
• Proximal fixation relies heavily on bicortical screws placed through the holes of the lateral plate. Cerclage wires and unicortical screws are rarely used in our practice. In the case of larger stems, a bicortical 3.5-mm screw can be placed through a 4.5-mm plate using a reduction washer.

Summary

Techniques for treatment of periprosthetic femur fractures around a well-fixed hip arthroplasty stem are constantly evolving. Several principles have emerged to decrease rates of treatment failure and subsequent reoperation. While there are several methods to do so, it is critical to achieve stable proximal fixation. Long spanning fixation constructs are linked to lower failure and reoperation rates in both B1 and C type fractures. Additionally, the importance of soft tissue management and maintenance of local vascularity should not be underestimated.

The rate of total hip arthroplasty (THA) is rising and demand is expected to increase by 174% to 572,000 by 2030.¹ The rate of periprosthetic fracture around primary THA is frequently reported at around 1%,^2-4 though a recent study of over 32,000 THAs quotes the 20-year probability of periprosthetic fracture at 3.5%.⁵ Revision THA is also increasing in frequency and associated rates of periprosthetic fracture range from 1.5% to 7.8% following revision THA,^3,4,6 with the probability of fracture at 20 years of 11%.⁷ Projection models predict that the number of periprosthetic fractures will rise by 4.6% per decade over the next 30 years.⁸

Broadly, treatment options include open reduction internal fixation (ORIF), revision THA, and combined approaches. The Vancouver classification, based on fracture location, stem stability, and bone loss, is often used to guide fracture treatment, with stable implants treated with ORIF and unstable implants requiring revision arthroplasty.

Fixation strategies for treatment of periprosthetic fracture around a well-fixed arthroplasty stem have evolved over time, and there continue to be a variety of available internal fixation options with no clear consensus on the optimal strategy.⁹ Rates of reoperation following ORIF of periprosthetic femur fracture are reported from 13% to 23%,^8,10-12 confirming that there remains room for improvement in management of these injuries.

Locking Plate Fixation

Early fixation strategies included allograft and cables alone as well as nonlocked plate and cerclage constructs. In response to the complication and reoperation rate for nonlocked plate constructs, reported at 33%,¹³ locking plates were introduced as a treatment option, allowing for both improved osseous vascularity and added screw options.¹⁴ When compared to the traditional nonlocked Ogden construct, locking plate constructs are more resistant to axial and torsional load.¹⁵ Clinically, the relative risk of nonunion after nonlocking plate fixation is reported at 11.9 times that of fixation with locking plate technology.¹⁶

Successful use of lateral locking plate fixation for treatment of this injury has been reported on in several clinical series.^17-20 Froberg and colleagues¹² evaluated 60 Vancouver B1 and C fractures treated by locking plate osteosynthesis and reported no nonunions, an improvement from previous constructs. However, 8 out of 60 patients with 2-year follow-up required reoperation—4 for infection, 3 for refracture, and 1 for stem loosening—making it clear that the locking plate alone was not a panacea.

With locking plate fixation a mainstay of modern treatment of periprosthetic femur fractures, many questions still remain.

Proximal Fixation

Even with the introduction of locked plates, treatment success after ORIF of Vancouver B1 fractures relies on adequate proximal fixation. Options for proximal fixation around the stem include cerclage wires or cables, unicortical locked screws, obliquely directed bicortical screws, and use of the locking attachment plate to insert bicortical locked screws. These strategies can be used in the presence of cemented or uncemented stems, with biomechanical evidence that screw fixation through the cement mantle does not cause failure.²¹

Several biomechanical studies address the stiffness and strength of varying proximal fixation strategies. While early fixation relied heavily on cables, the use of cables alone as proximal fixation has been linked to significantly higher rates of failure when compared to other constructs in a large clinical series.¹¹ Multiple biomechanical studies have shown that newer methods of proximal fixation provide more rigid constructs.^22,23

Unicortical locked screws appear to outperform cables biomechanically. The use of unicortical screws in lieu of or in addition to cables provides added resistance to lateral bending as well as torsion when compared to cables alone.²⁴ A second group found that unicortical locked screws alone were superior to combined fixation with cerclage wires and unicortical locked screws.²⁵

Added stability can be demonstrated by bicortical fixation strategies, which offer increased rigidity when compared to cables or unicortical screws.²² In vitro work has shown enhanced fixation stability with bicortical screw fixation using the locking attachment plate when compared to cerclage wires alone.^23,26 Clinically, some authors have demonstrated success with the use of reversed distal femoral locking plates in order to enhance proximal locking options and allow for bicortical fixation around the stem.¹⁹ As noted above, the data favor the opinion that clinical failure rates with cerclage wires alone are high, and biomechanically, bicortical fixation around the femoral stem appears to be superior to unicortical locked screw fixation or cerclage wires. If rigid proximal fixation is desired, an effort should be made to obtain bicortical fixation around the femoral stem.

Allograft

Allograft strut, either alone or in addition to plate osteosynthesis, has long been used in treatment of periprosthetic fractures. Proponents of this technique cite improved biomechanical stability¹⁷ and allograft incorporation resulting in restoration of bone stock.

Early treatment of periprosthetic femur fractures consisted solely of allograft and cable fixation, but data on the technique is limited. A small series reported reasonable success, with only 2 out of 19 patients developing nonunion.²⁷ More recently Haddad and colleagues²⁸ reported malunions in 3 out of 19 patients treated with allograft and cables alone. Allograft alone has been largely abandoned in favor of plate fixation, and biomechanical evidence shows that plate and screw or cerclage constructs are more resistant to torsion and lateral bending than allograft with cables alone.²⁹

However, the role of allograft in treatment of periprosthetic femur fractures is not clearly defined. Some authors advocate routinely supplementing plate fixation with allograft^28,30 and others go as far as to suggest superior union rates of strut allograft augmented plate fixation when compared to plate fixation alone for periprosthetic fractures around a stable femoral stem.³¹ However, in that series, the failure rate of 5/11 patients treated with plate alone is higher than current series,¹² and others have demonstrated good success without allograft, even with nonlocked plates.³²

As recently as 2016, a lateral locking plate supplemented with allograft has been described as a successful technique, with no nonunions reported in a small series.³⁰ However, without a comparison group, it is unclear what role the allograft plays in success in that construct.

Despite some proposed benefits, the additional soft tissue stripping required to place allograft has raised the question of delayed healing and increased infection rate as a result of this technique. A systematic review by Moore and colleagues³³ looking at the use of allograft strut in Vancouver B1 fractures found increased time to union (4.4 vs 6.6 months) and deep infection rate (3.8% vs 8.3%) with the use of allograft strut, leading them to recommend cautious use of allograft when treating Vancouver B1 fractures.

With improved fixation strategies available, the role of allograft may be best reserved for patients with inadequate bone stock.

Dual Plate Fixation

Dual plate fixation has been proposed as one mechanism to increase construct strength. A periprosthetic fracture model has shown that, biomechanically, orthogonal plates have higher bending stiffness, torsional stiffness, cycles to failure, and load to failure when compared to a single lateral plate with use of a locking attachment plate proximally.³⁴ Choi and colleagues³⁵ compared lateral locking plates alone, lateral locking plates with allograft, and lateral locking plates with an orthogonal anterior plate and found the addition of an anterior plate resulted in the strongest construct.

Clinically, Müller and colleagues³⁶ reported on a series of 10 patients treated with orthogonal (anterior and lateral) plating for periprosthetic femur fractures, including 3 nonunions. In their series, there was 1 plate failure and they conclude that dual plating is not associated with an increased risk of complications, and can also be used as a salvage procedure.

While the evidence for dual plating is limited, it may provide needed additional stability in certain cases without the added cost and exposure required for allograft.

Minimally Invasive Plate Osteosynthesis

Contrary to the extensive exposure required to place allograft, minimally invasive plate osteosynthesis (MIPO) of periprosthetic femur fractures is advocated by some authors.^18,20 Ricci and colleagues¹⁸ reported no nonunions in 50 patients treated with indirect reduction techniques and laterally based plating alone without use of allograft. A combination of cables, locking, and nonlocking screws were used. Critical to their technique was preservation of the soft tissue envelope at the level of the fracture.

In further support of MIPO techniques, a systematic review of 1571 periprosthetic hip fractures reported significantly increased risk of nonunion with open approaches when compared to minimally invasive osteosynthesis,¹⁶ emphasizing the role of preservation of vascularity in treating these fractures.

Length of Fixation

For some time it was recommended that fixation of Vancouver B1 fractures end 2 cortical diameters below the level of the fracture.^37,38 More recently there has been interest in the potential benefits of increased length of fixation.

A biomechanical study comparing long (20-hole) and short (12-hole) plates for periprosthetic fracture with regard to failure found no difference in failure rates between groups.³⁹ While plate length did not appear to affect construct stiffness, the issue of subsequent fracture distal to the construct remains.

Moloney and colleagues⁴⁰ proposed fixation of Vancouver B1 fractures using plates that span the length of the femur to the level of the femoral condyles to minimize peri-implant failures in osteoporotic patients. In 36 patients treated with standard-length plates, there were 2 fractures distal to the previous fixation compared to no subsequent fractures in 21 patients treated with spanning fixation.

Similarly, in Vancouver C fractures there is some evidence that fixation should span the femoral stem, regardless of available bone for fixation proximal to the fracture. Kubiak and colleagues⁴¹ found increasing load to failure and decreased cortical strain in a biomechanical model comparing plates that stop short of the femoral stem with those that span the stem.

Clinically, this concept is supported by Froberg and colleagues.¹² In their series of 60 Vancouver B1 and C fractures treated with laterally based locked plating, 3 patients went on to refracture. All of these fractures occurred in patients with Vancouver C fractures treated with plates overlapping the preexisting stem by <50%. The fractures all occurred at the high stress area between the tip of the stem and the end of the plate.

Further support of extended plate length comes from Drew and colleagues,⁸ who demonstrated a significantly decreased risk of reoperation following ORIF of periprosthetic femur fracture when >75% of the length of the femur was spanned compared to <50%. Although in some settings short fixation may produce satisfactory results, consideration should be given to extending the length of fixation, especially in the osteoporotic population.

Interprosthetic Fractures

With a rising number of patients with ipsilateral hip and knee arthroplasty, the rate of interprosthetic fractures is rising. These fractures present additional challenges given preexisting implants above and below the level of the fracture. The use of a single precontoured laterally based locked plate has been reported with good union rates approaching 90%.^42,43 In one series, all nonunions occurred in Vancouver B1 fractures,⁴³ again bringing to light the challenging nature of the B1 fracture.

Nonunion

Success in treating periprosthetic femur fractures has improved with improved fixation methods and understanding of technique. However, current rates of nonunion are still reported up to 27% for B1 and C fractures.⁴⁴

There is limited evidence on the treatment of periprosthetic femur fracture nonunion. However, treatment is difficult and complication rates are high. Crockarell and colleagues⁴⁵ reported a 52% overall complication rate in their series of 23 periprosthetic femur fracture nonunions.

Nonunions of the femur near a prosthesis can be treated by revision of the fracture fixation using compression and grafting to achieve bone healing vs revision of the joint prosthesis to span the area of the nonunited bone. Case-by-case decision-making is based on the remaining bone stock and the type of revision prosthesis necessary to span the problem area. Given the challenges associated with their treatment, a focus on prevention of nonunion is of paramount importance.

Authors’ Preferred Treatment

Our treatment of periprosthetic femur fractures with a well-fixed hip arthroplasty stem adheres to the principles supported in the literature (Figures 1A-1D and Figures 2A, 2B).

• Soft tissue friendly dissection with limited exposure at the fracture site is preferred as the fracture allows, particularly in cases with comminution where a direct assessment of the reduction is not available.
• Plate fixation strategy is dictated by the characteristics of the fracture. Fracture patterns amenable to anatomic reduction receive interfragmentary compression and absolute stability constructs. Highly comminuted fractures receive relatively stable bridging constructs to encourage callous.
• Locking screws are used rarely in diaphyseal fracture patterns, and when employed, are applied to only one side of the fracture to limit “over stiffening” the construct.
• Liberal use of dual plating, both as a method of maintaining fracture reduction while a structural plate is applied and increasing construct rigidity.
• Proximal fixation relies heavily on bicortical screws placed through the holes of the lateral plate. Cerclage wires and unicortical screws are rarely used in our practice. In the case of larger stems, a bicortical 3.5-mm screw can be placed through a 4.5-mm plate using a reduction washer.

Summary

Techniques for treatment of periprosthetic femur fractures around a well-fixed hip arthroplasty stem are constantly evolving. Several principles have emerged to decrease rates of treatment failure and subsequent reoperation. While there are several methods to do so, it is critical to achieve stable proximal fixation. Long spanning fixation constructs are linked to lower failure and reoperation rates in both B1 and C type fractures. Additionally, the importance of soft tissue management and maintenance of local vascularity should not be underestimated.

The Food and Drug Administration is reviewing the results of a Danish study that concludes there is a possible increased risk of miscarriage with the use of oral fluconazole (Diflucan) in pregnancy, according to a safety alert issued April 26.

The current drug label for oral fluconazole states that data from studies in women does not suggest an increased risk of problems during pregnancy or abnormalities in developing babies when women used a single 150-mg dose to treat vaginal yeast infections. However, reports of abnormalities at birth have resulted from high doses (400-800 mg/day) taken during pregnancy for much longer than a single dose. The Danish study had most pregnant women use one or two doses of 150 mg.

Oral fluconazole is used to treat yeast infections of the vaginal area, mouth, and esophagus. It can also be used to treat a fungal infection of the brain and spinal cord.

The FDA is also evaluating additional data and will make recommendations when the review is complete.

“Until FDA’s review is complete and more is understood about this study and other available data, FDA advises cautious prescribing of oral fluconazole in pregnancy,” the safety alert states.

The FDA also noted that the Centers for Disease Control and Prevention recommends using topical antifungal products only when treating pregnant women with vulvovaginal yeast infections.

Read more about the investigation on the FDA website.

[email protected]

The Food and Drug Administration is reviewing the results of a Danish study that concludes there is a possible increased risk of miscarriage with the use of oral fluconazole (Diflucan) in pregnancy, according to a safety alert issued April 26.

The current drug label for oral fluconazole states that data from studies in women does not suggest an increased risk of problems during pregnancy or abnormalities in developing babies when women used a single 150-mg dose to treat vaginal yeast infections. However, reports of abnormalities at birth have resulted from high doses (400-800 mg/day) taken during pregnancy for much longer than a single dose. The Danish study had most pregnant women use one or two doses of 150 mg.

Oral fluconazole is used to treat yeast infections of the vaginal area, mouth, and esophagus. It can also be used to treat a fungal infection of the brain and spinal cord.

The FDA is also evaluating additional data and will make recommendations when the review is complete.

“Until FDA’s review is complete and more is understood about this study and other available data, FDA advises cautious prescribing of oral fluconazole in pregnancy,” the safety alert states.

The FDA also noted that the Centers for Disease Control and Prevention recommends using topical antifungal products only when treating pregnant women with vulvovaginal yeast infections.

Read more about the investigation on the FDA website.

[email protected]

The Food and Drug Administration is reviewing the results of a Danish study that concludes there is a possible increased risk of miscarriage with the use of oral fluconazole (Diflucan) in pregnancy, according to a safety alert issued April 26.

The current drug label for oral fluconazole states that data from studies in women does not suggest an increased risk of problems during pregnancy or abnormalities in developing babies when women used a single 150-mg dose to treat vaginal yeast infections. However, reports of abnormalities at birth have resulted from high doses (400-800 mg/day) taken during pregnancy for much longer than a single dose. The Danish study had most pregnant women use one or two doses of 150 mg.

Oral fluconazole is used to treat yeast infections of the vaginal area, mouth, and esophagus. It can also be used to treat a fungal infection of the brain and spinal cord.

The FDA is also evaluating additional data and will make recommendations when the review is complete.

“Until FDA’s review is complete and more is understood about this study and other available data, FDA advises cautious prescribing of oral fluconazole in pregnancy,” the safety alert states.

The FDA also noted that the Centers for Disease Control and Prevention recommends using topical antifungal products only when treating pregnant women with vulvovaginal yeast infections.

Read more about the investigation on the FDA website.

[email protected]

Total hip arthroplasty (THA) is a successful surgery with positive clinical outcomes and over 95% survivorship at 10-year follow-up and 80% survivorship at 25-year follow-up.^1,2 A hip replacement requires strong osteointegration^3,4 to prevent femoral osteolysis, and correct implant alignment has been shown to correlate with prolonged implant survivorship and reduced dislocation.^5,6 Robotics and computer-assisted navigation have been developed to increase the accuracy of implant placement and reduce outliers with the overall goal of improving long-term results. These technologies have shown significant improvements in implant positioning when compared to conventional techniques.⁷

The first active robotic system for use in orthopedic procedures, Robodoc (Think Surgical, Inc.), was based on a traditional computer-aided design/computer-aided manufacturing system. Currently, only 3 robotic systems for THA have clearance in the US: The Mako System (Stryker), Robodoc, and TSolution One (Think Surgical, Inc.). The TSolution One system is based on the legacy technology developed as Robodoc and currently provides assistance during preparation of the femoral canal as well as guidance and positioning assistance during acetabular cup reaming and implanting. The following is a summary of the author’s (DSD) preferred technique for robotic-assisted THA using TSolution One.

How It Works

The process begins with preoperative planning (Figure 1). A computed tomography (CT) scan is used to create a detailed 3-dimensional (3D) reconstruction of the patient’s pathologic hip anatomy. The CT scan images are uploaded to TPLAN, a preoperative planning station.

In TPLAN, the user creates a 3D template of the surgical plan for both the femoral and acetabular portions of the procedure. The system has an open platform, meaning that the user is not limited to a single implant design or manufacturer. The surgeon can control every aspect of implant positioning: rotation, anteversion, fit and fill on the femoral side and anteversion, inclination/lateral opening, and depth on the acetabular side. Additional features available to the surgeon include accurately defining bony deficits, identifying outlier implant sizes, and checking for excess native version. The system allows the surgeon to determine the native center of hip rotation, which can then be used during templating to give the patient a hip that feels natural because the native muscle tension is restored. Once the desired plan has been achieved, it is uploaded to the robot.The TCAT robot is an active system similar to those used in manufacturing assembly plants (eg, automobiles) in that it follows a predetermined path and can do so in an efficient manner. More specifically, once the user has defined the patient’s anatomy within its workspace, it will proceed with actively milling the femur as planned with sub-millimeter accuracy without the use of navigation. This is in contrast to a haptic system, where the user manually guides the robotic arm within a predefined boundary.

The acetabular portion of the procedure currently uses a standard reamer system and power tools, but the TCAT guides the surgeon to the planned cup orientation, which is maintained during reaming and impaction.

In the Operating Suite

Once in the operating suite, the plan is uploaded into TCAT. Confirmation of the plan and the patient are incorporated into the surgical “time out.” Currently, the system supports patient positioning in standard lateral decubitus using a posterior approach with a standard operating room table. A posterior approach is undertaken to expose and dislocate the hip, with retractors placed to protect the soft tissues and allow the robot its working space.

One procedural difference from the standard THA technique is that the femoral head is initially retained to fixate the femur relative to the robot. A 5-mm Schanz pin is placed in the femoral head and then rigidly attached to the base of the robot. During a process called registration, a series of points on the surface of the exposed bone are collected by the surgeon via a digitizer probe attached to the robot. The TCAT monitor will guide the surgeon through point collection using a map showing the patient’s 3D bone model generated from the CT scan. The software then “finds” the patient’s femur in space and matches it to the 3D CT plan. Milling begins with a burr spinning at 80,000 rpm and saline to irrigate and remove bone debris (Figure 2). The actual milling process takes 5 to 15 minutes, depending on the choice and size of the implant.

A bone motion monitor (BMM) is also attached to the femur, along with recovery markers (RM). The BMM immediately pauses the robot during any active bone milling if it senses femoral motion from the original position. The surgeon then touches the RM with the digitizer to re-register the bone’s position and resume the milling process.

Attention is then turned to the acetabular portion of the procedure. Again, the robot must be rigidly fixed to the patient’s pelvis, along with the RM. Once the surgeon has registered the acetabular position using the digitizer, the robotic arm moves into the preoperatively planned orientation. A universal quick-release allows the surgeon to attach a standard reamer to the robot arm and ream while the robot holds the reamer in place. Once the acetabular preparation is complete, the cup impactor is placed onto the robotic arm and the implant is impacted into the patient. Thereafter, the digitizer can be used to collect points on the surface of the cup and confirm the exact cup placement (Figure 3).

Outcomes

The legacy system, Robodoc, has been used in thousands of clinical cases for both THA and total knee arthroplasty. The Table represents a summary of the THA clinical studies during a time frame in which only the femoral portion of the procedure was available to surgeons.

Bargar and colleagues⁸ describe the first Robodoc clinical trial in the US, along with the first 900 THA procedures performed in Germany. In the US, researchers conducted a prospective, randomized control study with 65 robotic cases and 62 conventional control cases. In terms of functional outcomes, there were no differences between the 2 groups. The robot group had improved radiographic fit and component positioning but significantly increased surgical time and blood loss. There were no femoral fractures in the robot group but 3 cases in the control group. In Germany, they reported on 870 primary THAs and 30 revision THA cases. For the primary cases, Harris hip scores rose from 43.7 preoperatively to 91.5 postoperatively. Complication rates were similar to conventional techniques, except the robot cases had no intraoperative femoral fractures.

Several prospective randomized clinical studies compared use of the Robodoc system with a conventional technique. The group studied by Honl and colleagues⁹ included 61 robotic cases and 80 conventional cases. The robot group had significant improvements in limb-length equality and varus-valgus orientation of the stem. When the revision cases were excluded, the authors found the Harris hip scores, prosthetic alignment, and limb length differentials were better for the robotic group at both 6 and 12 months.

Nakamura and colleagues¹⁰ looked at 75 robotic cases and 71 conventional cases. The results showed that at 2 and 3 years postoperatively, the robotic group had better Japanese Orthopaedic Association (JOA) scores, but by 5 years postoperatively, the differences were no longer significant. The robotic group had a smaller range for leg length inequality (0-12 mm) compared to the conventional group (0-29 mm). The results also showed that at both 2 and 5 years postoperatively, there was more significant stress shielding of the proximal femur, suggesting greater bone loss in the conventional group.

Nishihara and colleagues¹¹ had 78 subjects in each of the robotic and conventional groups and found significantly better Merle d’Aubigné hip scores at 2 years postoperatively in the robotic group. The conventional group suffered 5 intraoperative fractures compared with none in the robotic group, along with greater estimated blood loss, an increased use of undersized stems, higher-than-expected vertical seating, and unexpected femoral anteversion. The robotic cases did, however, take 19 minutes longer than the conventional cases.

Hananouchi and colleagues¹² looked at periprosthetic bone remodeling in 31 robotic hips and 27 conventional hips to determine whether load was effectively transferred from implant to bone after using the Robodoc system to prepare the femoral canal. Using dual energy X-ray absorptiometry (DEXA) to measure bone density, they found significantly less bone loss in the proximal periprosthetic areas in the robotic group compared to the conventional group; however, there were no differences in the Merle d’Aubigné hip scores.

Lim and colleagues¹³ looked specifically at alignment accuracy and clinical outcomes specifically for short femoral stem implants. In a group of 24 robotic cases and 25 conventional cases, they found significantly improved stem alignment and leg length inequality and no differences in Harris Hip score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, or complications at 24 months.

In 2004, Nishihara and colleagues¹⁴ evaluated the accuracy of femoral canal preparation using postoperative CT images for 75 cases of THA performed with the original pin-based version of Robodoc. The results showed that the differences between the preoperative plan and the postoperative CT were <5% in terms of canal fill, <1 mm in gap, and <1° in mediolateral and anteroposterior alignment with no reported fractures or complications. They concluded that the Robodoc system resulted in a high degree of accuracy.

Schulz and colleagues¹⁵ reported on 97 of 143 consecutive cases performed from 1997 to 2002. Technical complications were described in 9 cases. Five of the reported complications included the BMM pausing cutting as designed for patient safety, which led to re-registration, and slightly prolonged surgery. The remaining 4 complications included 2 femoral shaft fissures requiring wire cerclage, 1 case of damage to the acetabular rim from the milling device, and 1 defect of the greater trochanter that was milled. In terms of clinical results, they found that the complications, functional outcomes, and radiographic outcomes were comparable to conventional techniques. The rate of femoral shaft fissures, which had been zero in all other studies with Robodoc, was comparable to conventional technique.

Conclusion

The most significant change in hip arthroplasty until now has been the transition from a cemented technique to a press-fit or ingrowth prosthesis.¹⁶ The first robotic surgery was performed in the US in 1992 using the legacy system upon which the current TSolution One was based. Since then, the use of surgical robots has seen a 30% increase annually over the last decade in a variety of surgical fields.¹⁷ In orthopedics, specifically THA, the results have shown that robotics clearly offers benefits in terms of accuracy, precision, and reproducibility. These benefits will likely translate into improved long-term outcomes and increased survivorship in future studies.

Total hip arthroplasty (THA) is a successful surgery with positive clinical outcomes and over 95% survivorship at 10-year follow-up and 80% survivorship at 25-year follow-up.^1,2 A hip replacement requires strong osteointegration^3,4 to prevent femoral osteolysis, and correct implant alignment has been shown to correlate with prolonged implant survivorship and reduced dislocation.^5,6 Robotics and computer-assisted navigation have been developed to increase the accuracy of implant placement and reduce outliers with the overall goal of improving long-term results. These technologies have shown significant improvements in implant positioning when compared to conventional techniques.⁷

The first active robotic system for use in orthopedic procedures, Robodoc (Think Surgical, Inc.), was based on a traditional computer-aided design/computer-aided manufacturing system. Currently, only 3 robotic systems for THA have clearance in the US: The Mako System (Stryker), Robodoc, and TSolution One (Think Surgical, Inc.). The TSolution One system is based on the legacy technology developed as Robodoc and currently provides assistance during preparation of the femoral canal as well as guidance and positioning assistance during acetabular cup reaming and implanting. The following is a summary of the author’s (DSD) preferred technique for robotic-assisted THA using TSolution One.

How It Works

The process begins with preoperative planning (Figure 1). A computed tomography (CT) scan is used to create a detailed 3-dimensional (3D) reconstruction of the patient’s pathologic hip anatomy. The CT scan images are uploaded to TPLAN, a preoperative planning station.

In TPLAN, the user creates a 3D template of the surgical plan for both the femoral and acetabular portions of the procedure. The system has an open platform, meaning that the user is not limited to a single implant design or manufacturer. The surgeon can control every aspect of implant positioning: rotation, anteversion, fit and fill on the femoral side and anteversion, inclination/lateral opening, and depth on the acetabular side. Additional features available to the surgeon include accurately defining bony deficits, identifying outlier implant sizes, and checking for excess native version. The system allows the surgeon to determine the native center of hip rotation, which can then be used during templating to give the patient a hip that feels natural because the native muscle tension is restored. Once the desired plan has been achieved, it is uploaded to the robot.The TCAT robot is an active system similar to those used in manufacturing assembly plants (eg, automobiles) in that it follows a predetermined path and can do so in an efficient manner. More specifically, once the user has defined the patient’s anatomy within its workspace, it will proceed with actively milling the femur as planned with sub-millimeter accuracy without the use of navigation. This is in contrast to a haptic system, where the user manually guides the robotic arm within a predefined boundary.

The acetabular portion of the procedure currently uses a standard reamer system and power tools, but the TCAT guides the surgeon to the planned cup orientation, which is maintained during reaming and impaction.

In the Operating Suite

Once in the operating suite, the plan is uploaded into TCAT. Confirmation of the plan and the patient are incorporated into the surgical “time out.” Currently, the system supports patient positioning in standard lateral decubitus using a posterior approach with a standard operating room table. A posterior approach is undertaken to expose and dislocate the hip, with retractors placed to protect the soft tissues and allow the robot its working space.

One procedural difference from the standard THA technique is that the femoral head is initially retained to fixate the femur relative to the robot. A 5-mm Schanz pin is placed in the femoral head and then rigidly attached to the base of the robot. During a process called registration, a series of points on the surface of the exposed bone are collected by the surgeon via a digitizer probe attached to the robot. The TCAT monitor will guide the surgeon through point collection using a map showing the patient’s 3D bone model generated from the CT scan. The software then “finds” the patient’s femur in space and matches it to the 3D CT plan. Milling begins with a burr spinning at 80,000 rpm and saline to irrigate and remove bone debris (Figure 2). The actual milling process takes 5 to 15 minutes, depending on the choice and size of the implant.

A bone motion monitor (BMM) is also attached to the femur, along with recovery markers (RM). The BMM immediately pauses the robot during any active bone milling if it senses femoral motion from the original position. The surgeon then touches the RM with the digitizer to re-register the bone’s position and resume the milling process.

Attention is then turned to the acetabular portion of the procedure. Again, the robot must be rigidly fixed to the patient’s pelvis, along with the RM. Once the surgeon has registered the acetabular position using the digitizer, the robotic arm moves into the preoperatively planned orientation. A universal quick-release allows the surgeon to attach a standard reamer to the robot arm and ream while the robot holds the reamer in place. Once the acetabular preparation is complete, the cup impactor is placed onto the robotic arm and the implant is impacted into the patient. Thereafter, the digitizer can be used to collect points on the surface of the cup and confirm the exact cup placement (Figure 3).

Outcomes

The legacy system, Robodoc, has been used in thousands of clinical cases for both THA and total knee arthroplasty. The Table represents a summary of the THA clinical studies during a time frame in which only the femoral portion of the procedure was available to surgeons.

Bargar and colleagues⁸ describe the first Robodoc clinical trial in the US, along with the first 900 THA procedures performed in Germany. In the US, researchers conducted a prospective, randomized control study with 65 robotic cases and 62 conventional control cases. In terms of functional outcomes, there were no differences between the 2 groups. The robot group had improved radiographic fit and component positioning but significantly increased surgical time and blood loss. There were no femoral fractures in the robot group but 3 cases in the control group. In Germany, they reported on 870 primary THAs and 30 revision THA cases. For the primary cases, Harris hip scores rose from 43.7 preoperatively to 91.5 postoperatively. Complication rates were similar to conventional techniques, except the robot cases had no intraoperative femoral fractures.

Several prospective randomized clinical studies compared use of the Robodoc system with a conventional technique. The group studied by Honl and colleagues⁹ included 61 robotic cases and 80 conventional cases. The robot group had significant improvements in limb-length equality and varus-valgus orientation of the stem. When the revision cases were excluded, the authors found the Harris hip scores, prosthetic alignment, and limb length differentials were better for the robotic group at both 6 and 12 months.

Nakamura and colleagues¹⁰ looked at 75 robotic cases and 71 conventional cases. The results showed that at 2 and 3 years postoperatively, the robotic group had better Japanese Orthopaedic Association (JOA) scores, but by 5 years postoperatively, the differences were no longer significant. The robotic group had a smaller range for leg length inequality (0-12 mm) compared to the conventional group (0-29 mm). The results also showed that at both 2 and 5 years postoperatively, there was more significant stress shielding of the proximal femur, suggesting greater bone loss in the conventional group.

Nishihara and colleagues¹¹ had 78 subjects in each of the robotic and conventional groups and found significantly better Merle d’Aubigné hip scores at 2 years postoperatively in the robotic group. The conventional group suffered 5 intraoperative fractures compared with none in the robotic group, along with greater estimated blood loss, an increased use of undersized stems, higher-than-expected vertical seating, and unexpected femoral anteversion. The robotic cases did, however, take 19 minutes longer than the conventional cases.

Hananouchi and colleagues¹² looked at periprosthetic bone remodeling in 31 robotic hips and 27 conventional hips to determine whether load was effectively transferred from implant to bone after using the Robodoc system to prepare the femoral canal. Using dual energy X-ray absorptiometry (DEXA) to measure bone density, they found significantly less bone loss in the proximal periprosthetic areas in the robotic group compared to the conventional group; however, there were no differences in the Merle d’Aubigné hip scores.

Lim and colleagues¹³ looked specifically at alignment accuracy and clinical outcomes specifically for short femoral stem implants. In a group of 24 robotic cases and 25 conventional cases, they found significantly improved stem alignment and leg length inequality and no differences in Harris Hip score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, or complications at 24 months.

In 2004, Nishihara and colleagues¹⁴ evaluated the accuracy of femoral canal preparation using postoperative CT images for 75 cases of THA performed with the original pin-based version of Robodoc. The results showed that the differences between the preoperative plan and the postoperative CT were <5% in terms of canal fill, <1 mm in gap, and <1° in mediolateral and anteroposterior alignment with no reported fractures or complications. They concluded that the Robodoc system resulted in a high degree of accuracy.

Schulz and colleagues¹⁵ reported on 97 of 143 consecutive cases performed from 1997 to 2002. Technical complications were described in 9 cases. Five of the reported complications included the BMM pausing cutting as designed for patient safety, which led to re-registration, and slightly prolonged surgery. The remaining 4 complications included 2 femoral shaft fissures requiring wire cerclage, 1 case of damage to the acetabular rim from the milling device, and 1 defect of the greater trochanter that was milled. In terms of clinical results, they found that the complications, functional outcomes, and radiographic outcomes were comparable to conventional techniques. The rate of femoral shaft fissures, which had been zero in all other studies with Robodoc, was comparable to conventional technique.

Conclusion

The most significant change in hip arthroplasty until now has been the transition from a cemented technique to a press-fit or ingrowth prosthesis.¹⁶ The first robotic surgery was performed in the US in 1992 using the legacy system upon which the current TSolution One was based. Since then, the use of surgical robots has seen a 30% increase annually over the last decade in a variety of surgical fields.¹⁷ In orthopedics, specifically THA, the results have shown that robotics clearly offers benefits in terms of accuracy, precision, and reproducibility. These benefits will likely translate into improved long-term outcomes and increased survivorship in future studies.

Total hip arthroplasty (THA) is a successful surgery with positive clinical outcomes and over 95% survivorship at 10-year follow-up and 80% survivorship at 25-year follow-up.^1,2 A hip replacement requires strong osteointegration^3,4 to prevent femoral osteolysis, and correct implant alignment has been shown to correlate with prolonged implant survivorship and reduced dislocation.^5,6 Robotics and computer-assisted navigation have been developed to increase the accuracy of implant placement and reduce outliers with the overall goal of improving long-term results. These technologies have shown significant improvements in implant positioning when compared to conventional techniques.⁷

The first active robotic system for use in orthopedic procedures, Robodoc (Think Surgical, Inc.), was based on a traditional computer-aided design/computer-aided manufacturing system. Currently, only 3 robotic systems for THA have clearance in the US: The Mako System (Stryker), Robodoc, and TSolution One (Think Surgical, Inc.). The TSolution One system is based on the legacy technology developed as Robodoc and currently provides assistance during preparation of the femoral canal as well as guidance and positioning assistance during acetabular cup reaming and implanting. The following is a summary of the author’s (DSD) preferred technique for robotic-assisted THA using TSolution One.

How It Works

The process begins with preoperative planning (Figure 1). A computed tomography (CT) scan is used to create a detailed 3-dimensional (3D) reconstruction of the patient’s pathologic hip anatomy. The CT scan images are uploaded to TPLAN, a preoperative planning station.

In TPLAN, the user creates a 3D template of the surgical plan for both the femoral and acetabular portions of the procedure. The system has an open platform, meaning that the user is not limited to a single implant design or manufacturer. The surgeon can control every aspect of implant positioning: rotation, anteversion, fit and fill on the femoral side and anteversion, inclination/lateral opening, and depth on the acetabular side. Additional features available to the surgeon include accurately defining bony deficits, identifying outlier implant sizes, and checking for excess native version. The system allows the surgeon to determine the native center of hip rotation, which can then be used during templating to give the patient a hip that feels natural because the native muscle tension is restored. Once the desired plan has been achieved, it is uploaded to the robot.The TCAT robot is an active system similar to those used in manufacturing assembly plants (eg, automobiles) in that it follows a predetermined path and can do so in an efficient manner. More specifically, once the user has defined the patient’s anatomy within its workspace, it will proceed with actively milling the femur as planned with sub-millimeter accuracy without the use of navigation. This is in contrast to a haptic system, where the user manually guides the robotic arm within a predefined boundary.

The acetabular portion of the procedure currently uses a standard reamer system and power tools, but the TCAT guides the surgeon to the planned cup orientation, which is maintained during reaming and impaction.

In the Operating Suite

Once in the operating suite, the plan is uploaded into TCAT. Confirmation of the plan and the patient are incorporated into the surgical “time out.” Currently, the system supports patient positioning in standard lateral decubitus using a posterior approach with a standard operating room table. A posterior approach is undertaken to expose and dislocate the hip, with retractors placed to protect the soft tissues and allow the robot its working space.

One procedural difference from the standard THA technique is that the femoral head is initially retained to fixate the femur relative to the robot. A 5-mm Schanz pin is placed in the femoral head and then rigidly attached to the base of the robot. During a process called registration, a series of points on the surface of the exposed bone are collected by the surgeon via a digitizer probe attached to the robot. The TCAT monitor will guide the surgeon through point collection using a map showing the patient’s 3D bone model generated from the CT scan. The software then “finds” the patient’s femur in space and matches it to the 3D CT plan. Milling begins with a burr spinning at 80,000 rpm and saline to irrigate and remove bone debris (Figure 2). The actual milling process takes 5 to 15 minutes, depending on the choice and size of the implant.

A bone motion monitor (BMM) is also attached to the femur, along with recovery markers (RM). The BMM immediately pauses the robot during any active bone milling if it senses femoral motion from the original position. The surgeon then touches the RM with the digitizer to re-register the bone’s position and resume the milling process.

Attention is then turned to the acetabular portion of the procedure. Again, the robot must be rigidly fixed to the patient’s pelvis, along with the RM. Once the surgeon has registered the acetabular position using the digitizer, the robotic arm moves into the preoperatively planned orientation. A universal quick-release allows the surgeon to attach a standard reamer to the robot arm and ream while the robot holds the reamer in place. Once the acetabular preparation is complete, the cup impactor is placed onto the robotic arm and the implant is impacted into the patient. Thereafter, the digitizer can be used to collect points on the surface of the cup and confirm the exact cup placement (Figure 3).

Outcomes

The legacy system, Robodoc, has been used in thousands of clinical cases for both THA and total knee arthroplasty. The Table represents a summary of the THA clinical studies during a time frame in which only the femoral portion of the procedure was available to surgeons.

Bargar and colleagues⁸ describe the first Robodoc clinical trial in the US, along with the first 900 THA procedures performed in Germany. In the US, researchers conducted a prospective, randomized control study with 65 robotic cases and 62 conventional control cases. In terms of functional outcomes, there were no differences between the 2 groups. The robot group had improved radiographic fit and component positioning but significantly increased surgical time and blood loss. There were no femoral fractures in the robot group but 3 cases in the control group. In Germany, they reported on 870 primary THAs and 30 revision THA cases. For the primary cases, Harris hip scores rose from 43.7 preoperatively to 91.5 postoperatively. Complication rates were similar to conventional techniques, except the robot cases had no intraoperative femoral fractures.

Several prospective randomized clinical studies compared use of the Robodoc system with a conventional technique. The group studied by Honl and colleagues⁹ included 61 robotic cases and 80 conventional cases. The robot group had significant improvements in limb-length equality and varus-valgus orientation of the stem. When the revision cases were excluded, the authors found the Harris hip scores, prosthetic alignment, and limb length differentials were better for the robotic group at both 6 and 12 months.

Nakamura and colleagues¹⁰ looked at 75 robotic cases and 71 conventional cases. The results showed that at 2 and 3 years postoperatively, the robotic group had better Japanese Orthopaedic Association (JOA) scores, but by 5 years postoperatively, the differences were no longer significant. The robotic group had a smaller range for leg length inequality (0-12 mm) compared to the conventional group (0-29 mm). The results also showed that at both 2 and 5 years postoperatively, there was more significant stress shielding of the proximal femur, suggesting greater bone loss in the conventional group.

Nishihara and colleagues¹¹ had 78 subjects in each of the robotic and conventional groups and found significantly better Merle d’Aubigné hip scores at 2 years postoperatively in the robotic group. The conventional group suffered 5 intraoperative fractures compared with none in the robotic group, along with greater estimated blood loss, an increased use of undersized stems, higher-than-expected vertical seating, and unexpected femoral anteversion. The robotic cases did, however, take 19 minutes longer than the conventional cases.

Hananouchi and colleagues¹² looked at periprosthetic bone remodeling in 31 robotic hips and 27 conventional hips to determine whether load was effectively transferred from implant to bone after using the Robodoc system to prepare the femoral canal. Using dual energy X-ray absorptiometry (DEXA) to measure bone density, they found significantly less bone loss in the proximal periprosthetic areas in the robotic group compared to the conventional group; however, there were no differences in the Merle d’Aubigné hip scores.

Lim and colleagues¹³ looked specifically at alignment accuracy and clinical outcomes specifically for short femoral stem implants. In a group of 24 robotic cases and 25 conventional cases, they found significantly improved stem alignment and leg length inequality and no differences in Harris Hip score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, or complications at 24 months.

In 2004, Nishihara and colleagues¹⁴ evaluated the accuracy of femoral canal preparation using postoperative CT images for 75 cases of THA performed with the original pin-based version of Robodoc. The results showed that the differences between the preoperative plan and the postoperative CT were <5% in terms of canal fill, <1 mm in gap, and <1° in mediolateral and anteroposterior alignment with no reported fractures or complications. They concluded that the Robodoc system resulted in a high degree of accuracy.

Schulz and colleagues¹⁵ reported on 97 of 143 consecutive cases performed from 1997 to 2002. Technical complications were described in 9 cases. Five of the reported complications included the BMM pausing cutting as designed for patient safety, which led to re-registration, and slightly prolonged surgery. The remaining 4 complications included 2 femoral shaft fissures requiring wire cerclage, 1 case of damage to the acetabular rim from the milling device, and 1 defect of the greater trochanter that was milled. In terms of clinical results, they found that the complications, functional outcomes, and radiographic outcomes were comparable to conventional techniques. The rate of femoral shaft fissures, which had been zero in all other studies with Robodoc, was comparable to conventional technique.

Conclusion

The most significant change in hip arthroplasty until now has been the transition from a cemented technique to a press-fit or ingrowth prosthesis.¹⁶ The first robotic surgery was performed in the US in 1992 using the legacy system upon which the current TSolution One was based. Since then, the use of surgical robots has seen a 30% increase annually over the last decade in a variety of surgical fields.¹⁷ In orthopedics, specifically THA, the results have shown that robotics clearly offers benefits in terms of accuracy, precision, and reproducibility. These benefits will likely translate into improved long-term outcomes and increased survivorship in future studies.

The concept of robotics is relatively new in medical practice. The term “robot” itself is less than 100 years old, having been first introduced to popular culture in 1917 by Joseph Capek in the science fiction story Opilec.^1,2 Robots eventually transitioned from this initial fictional literary setting to reality in 1958, when General Motors began adding automated machines to its assembly lines.¹ However, it was not until the 1980s that robotics and their exacting efficiencies would be introduced in the medical field, and it would take another decade before they would enter the specialty of orthopedics.^1-4

The first robotic-assisted orthopedic surgery was reportedly performed in 1992, when the Robodoc autonomous system was utilized for total hip arthroplasty.^2-4 A robotic system for total knee arthroplasty (TKA) was first described in 1993, but it would take several more years until a system for unicompartmental knee arthroplasty (UKA) would be commercialized and used clinically.^5,6 The rationale for advancement of robotic technology for isolated medial or lateral knee arthritis stems from the recognition that while UKA is effective and durable when components and limb are well aligned and soft tissues appropriately balanced, they are less forgiving of even slight component malalignment of as little as 2° to 3° and prone to premature loosening or wear in those circumstances.^7-13,14 In the mid 2000s, Cobb and colleagues⁶ reported using a semiautonomous robot for UKA. Since then, emergence of other semiautonomous robotic systems has led to greater market penetration and technology utilization.¹⁵

Currently, an estimated 15% to 20% of UKA surgeries are being performed with robotic assistance.¹⁶ Further, patent activity and peer-reviewed publications related to robotic technology in UKA (which can be considered surrogate measures of interest and evolving development and experience with robotic technologies) have increased dramatically over the past few years.^{2,6,14,17,18-34} To date, while the most dramatic growth of robotic utilization and case volumes has occurred in the subspecialty of UKA, semiautonomous robotic systems have been used with increasing frequency for patellofemoral and bicompartmental knee arthroplasty.^35,36 Robotics have been used sparingly for TKA, and limited to autonomous systems;^37,38 however, it is anticipated that emergence of semiautonomous platforms for TKA will further expand the role of robotics over the next decade, particularly as our focus shifts beyond component and limb alignment in TKA and more towards the role of robotics in soft tissue balancing, reduction in instrumentation and inventory and its attendant cost savings, and surgical efficiencies. One semiautonomous robotic technology first used in 2006 (Mako, Stryker) reported a 130% increase in robotic volume from 2011 to 2012; another, first used in 2013, reported growth of 480% between 2013 and 2014, due to its improved cost structure, ease of use, smaller footprint, image-free platform and applicability in ambulatory surgery centers (Navio, Smith & Nephew; data supplied by manufacturer), demonstrating the growing popularity of robotic technology.^17,39 Further, a recent analysis of potential market penetration over the next decade published by Medical Device and Diagnostic Industry (http://www.mddionline.com) projected that nearly 37% of UKAs and 23% of TKAs will be performed with robotics in 10 years.

Distinction Between Robotic-Assisted Technologies

Autonomous systems involve pre-programming the system with parameters that define the amount and orientation of bone to be removed, after which the system prepares the surfaces independent of surgeon control, other than having access to a “shutdown” switch. There are currently no autonomous robotic tools approved by the US Food and Drug Administration (FDA) for knee arthroplasty.

Semiautonomous systems involve the mapping of condylar landmarks and determination of alignment indices, which also defines the volume and orientation of bone to be removed. While the systems remove bone and cartilage within the pre-established parameters, the robotic tools are controlled and manipulated by the surgeon (Figure 1). The predetermined safe zones modulate and safeguard the surgical actions. These systems also provide real-time quantification of soft tissue balancing, which may contribute to the reported successful clinical and functional outcomes with semiautonomous systems (Figure 2).^2,4,19,22 There are several semiautonomous robotic systems that are approved for use by the FDA.

Each robotic-assisted surgery (RAS) system utilizes some sort of 3-dimensional digital map of the surgical surfaces after a process of surface mapping and landmark registration.² In the case of Mako, this planning process also requires a preoperative computed tomography (CT) scan. Over the past few years, the requirement of a CT scan has proven problematic and costly, as increasingly third-party payers and insurers are denying coverage for additional studies used for preoperative planning, leaving the burden of cost on the patients and/or hospitals. Additionally, in an era in which bundled payment arrangements are commonplace or in which providers are held accountable for costly care, the use of costly preoperative imaging is untenable. Furthermore, there is a growing concern regarding the risk of radiation exposure from CT scans that makes image-free technologies, such as Navio, an alternative for stakeholders.⁴⁰

At this time, the 2 semiautonomous systems in use for UKA employ different methods to safeguard against inadvertent bone preparation: one by providing haptic constraint beyond which movement of the bur is limited (Mako); the other by modulating the exposure or speed of the handheld robotic bur (Navio) (Figure 3).

Outcomes of RAS in UKA

Compared to conventional UKA, robotic assistance has consistently demonstrated improved surgical accuracy, even through minimally invasive incisions (Figures 4, 5).^6,20-28 Several studies have found substantial reduction in variability and error of component positioning with use of semiautonomous robotic tools.^6,21,25 In fact, precision appears to be comparable regardless of whether an image-free system or one requiring a preoperative CT scan is used (Table). Further, in addition to improving component and limb alignment, Plate and colleagues²² demonstrated that RAS-based UKA systems can help the surgeon precisely reproduce plans for soft-tissue balancing. The authors reported ligament balancing to be accurate up to .53 mm compared to the preoperative plan, with approximately 83% of cases balanced within 1 mm of the plan through a full range of flexion.²²

When evaluating advanced and novel technologies, there is undoubtedly concern that there will be increased operative time and a substantial learning curve with those technologies. Karia and colleagues³⁰ found that when inexperienced surgeons performed UKA on synthetic bone models using robotics, the mean compound rotational and translational errors were lower than when conventional techniques were used. Among those using conventional techniques, although surgical times improved during the learning period, positional inaccuracies persisted. On the other hand, robotic assistance enabled surgeons to achieve precision and accuracy when positioning UKA components irrespective of their learning experience.³⁰ Another study, by Coon,³¹ similarly suggested a shorter learning curve and greater accuracy with RAS using the Mako system compared to conventional techniques. A prospective, multicenter, observational study evaluated the operative times of 11 surgeons during their initial clinical cases using Navio robotic technology for medial UKA after a period of training using cadaver knees and sawbones.⁴¹ The learning curve for total surgical time (tracker placement to implant trial phase) indicates that it takes 8 cases to achieve 95% of total learning and maintain a steady state surgical time.

Potential Disadvantages of RAS in UKA

RAS for UKA has several potential disadvantages that must be weighed against their potential benefits. One major barrier to broader use of RAS is the increased cost associated with the technologies.^17,19,27,32 Capital and maintenance costs for these systems can be high, and those that require additional advanced imaging, such as CT scans, further challenge the return on investment.^17,19,32 In a Markov analysis of one robotic system (Mako), Moschetti and colleagues¹⁷ found that if one assumes a system cost of $1.362 million, value can be attained due to slightly better outcomes despite being more expensive than traditional methods. Nonetheless, their analysis of the Mako system estimated that each robot-assisted UKA case cost $19,219, compared to $16,476 with traditional UKA, and was associated with an incremental cost of $47,180 per quality-adjusted life-year. Their analysis further demonstrated that the cost-effectiveness was very sensitive to case volume, with lower costs realized once volumes surpassed 94 cases per year. On the other hand, costs (and thus value) will also obviously vary depending on the capital costs, annual service charges, and avoidance of unnecessary preoperative scans.¹⁹ For instance, assuming a cost of $500,000 for the image-free Navio robotic system, return on investment is achievable within 25 cases annually, roughly one-quarter of the cases necessary with the image-based system.

Another disadvantage of RAS systems in UKA is the unique complications associated with their use. Both RAS and conventional UKA can be complicated by similar problems such as component loosening, polyethylene wear, progressive arthritis, infection, stiffness, instability, and thromboembolism. RAS systems, however, carry the additional risk of specific robot-related issues.^19,27 Perhaps most notably, the pin tracts for the required optical tracking arrays can create a stress riser in the cortical bone,^19,27,33,42 highlighting the importance of inserting these pins in metaphyseal, and not diaphyseal, bone. Soft tissue complications have been reported during bone preparation with autonomous systems in total knee and hip arthroplasty;^37,38 however, the senior author (JHL) has not observed that in 1000 consecutive cases with either semiautonomous surgeon-driven robotic tool.¹⁹

Finally, systems that require a preoperative CT scan pose an increased radiation risk.⁴⁰ Ponzio and Lonner⁴⁰ recently reported that each preoperative CT scan for robotic-assisted knee arthroplasty (using a Mako protocol) is associated with a mean effective dose of radiation of 4.8 mSv, which is approximately equivalent to 48 chest radiographs.³⁴ Further, in that study, at least 25% of patients had been subjected to multiple scans, with some being exposed to cumulative effective doses of up to 103 mSv. This risk should not be considered completely negligible given that 10 mSv may be associated with an increase in the possibility of fatal cancer, and an estimated 29,000 excess cancer cases in the United States annually are reportedly caused by CT scans.^40,43,44 However, this increased radiation risk is not inherent to all RAS systems. Image-free systems, such as Navio, do not require CT scans and are thus not associated with this potential disadvantage.

Conclusion

Robotics has come a long way from its humble conceptual beginnings nearly a century ago. Rapid advances in medical technology over the past 10 years have led to the development and growing popularity of RAS in orthopedic surgery, particularly during UKA. Component placement, quantified soft tissue balance, and radiographic alignment appear to be improved and the incidence of outliers reduced with the use of RAS during UKA. Further assessment is needed to determine whether the improved alignment and balance will impact clinical function and/or durability. Early results are very promising, though, creating optimism that the full benefits of RAS in UKA will be further confirmed with additional time and research.

The concept of robotics is relatively new in medical practice. The term “robot” itself is less than 100 years old, having been first introduced to popular culture in 1917 by Joseph Capek in the science fiction story Opilec.^1,2 Robots eventually transitioned from this initial fictional literary setting to reality in 1958, when General Motors began adding automated machines to its assembly lines.¹ However, it was not until the 1980s that robotics and their exacting efficiencies would be introduced in the medical field, and it would take another decade before they would enter the specialty of orthopedics.^1-4

The first robotic-assisted orthopedic surgery was reportedly performed in 1992, when the Robodoc autonomous system was utilized for total hip arthroplasty.^2-4 A robotic system for total knee arthroplasty (TKA) was first described in 1993, but it would take several more years until a system for unicompartmental knee arthroplasty (UKA) would be commercialized and used clinically.^5,6 The rationale for advancement of robotic technology for isolated medial or lateral knee arthritis stems from the recognition that while UKA is effective and durable when components and limb are well aligned and soft tissues appropriately balanced, they are less forgiving of even slight component malalignment of as little as 2° to 3° and prone to premature loosening or wear in those circumstances.^7-13,14 In the mid 2000s, Cobb and colleagues⁶ reported using a semiautonomous robot for UKA. Since then, emergence of other semiautonomous robotic systems has led to greater market penetration and technology utilization.¹⁵

Currently, an estimated 15% to 20% of UKA surgeries are being performed with robotic assistance.¹⁶ Further, patent activity and peer-reviewed publications related to robotic technology in UKA (which can be considered surrogate measures of interest and evolving development and experience with robotic technologies) have increased dramatically over the past few years.^{2,6,14,17,18-34} To date, while the most dramatic growth of robotic utilization and case volumes has occurred in the subspecialty of UKA, semiautonomous robotic systems have been used with increasing frequency for patellofemoral and bicompartmental knee arthroplasty.^35,36 Robotics have been used sparingly for TKA, and limited to autonomous systems;^37,38 however, it is anticipated that emergence of semiautonomous platforms for TKA will further expand the role of robotics over the next decade, particularly as our focus shifts beyond component and limb alignment in TKA and more towards the role of robotics in soft tissue balancing, reduction in instrumentation and inventory and its attendant cost savings, and surgical efficiencies. One semiautonomous robotic technology first used in 2006 (Mako, Stryker) reported a 130% increase in robotic volume from 2011 to 2012; another, first used in 2013, reported growth of 480% between 2013 and 2014, due to its improved cost structure, ease of use, smaller footprint, image-free platform and applicability in ambulatory surgery centers (Navio, Smith & Nephew; data supplied by manufacturer), demonstrating the growing popularity of robotic technology.^17,39 Further, a recent analysis of potential market penetration over the next decade published by Medical Device and Diagnostic Industry (http://www.mddionline.com) projected that nearly 37% of UKAs and 23% of TKAs will be performed with robotics in 10 years.

Distinction Between Robotic-Assisted Technologies

Autonomous systems involve pre-programming the system with parameters that define the amount and orientation of bone to be removed, after which the system prepares the surfaces independent of surgeon control, other than having access to a “shutdown” switch. There are currently no autonomous robotic tools approved by the US Food and Drug Administration (FDA) for knee arthroplasty.

Semiautonomous systems involve the mapping of condylar landmarks and determination of alignment indices, which also defines the volume and orientation of bone to be removed. While the systems remove bone and cartilage within the pre-established parameters, the robotic tools are controlled and manipulated by the surgeon (Figure 1). The predetermined safe zones modulate and safeguard the surgical actions. These systems also provide real-time quantification of soft tissue balancing, which may contribute to the reported successful clinical and functional outcomes with semiautonomous systems (Figure 2).^2,4,19,22 There are several semiautonomous robotic systems that are approved for use by the FDA.

Each robotic-assisted surgery (RAS) system utilizes some sort of 3-dimensional digital map of the surgical surfaces after a process of surface mapping and landmark registration.² In the case of Mako, this planning process also requires a preoperative computed tomography (CT) scan. Over the past few years, the requirement of a CT scan has proven problematic and costly, as increasingly third-party payers and insurers are denying coverage for additional studies used for preoperative planning, leaving the burden of cost on the patients and/or hospitals. Additionally, in an era in which bundled payment arrangements are commonplace or in which providers are held accountable for costly care, the use of costly preoperative imaging is untenable. Furthermore, there is a growing concern regarding the risk of radiation exposure from CT scans that makes image-free technologies, such as Navio, an alternative for stakeholders.⁴⁰

At this time, the 2 semiautonomous systems in use for UKA employ different methods to safeguard against inadvertent bone preparation: one by providing haptic constraint beyond which movement of the bur is limited (Mako); the other by modulating the exposure or speed of the handheld robotic bur (Navio) (Figure 3).

Outcomes of RAS in UKA

Compared to conventional UKA, robotic assistance has consistently demonstrated improved surgical accuracy, even through minimally invasive incisions (Figures 4, 5).^6,20-28 Several studies have found substantial reduction in variability and error of component positioning with use of semiautonomous robotic tools.^6,21,25 In fact, precision appears to be comparable regardless of whether an image-free system or one requiring a preoperative CT scan is used (Table). Further, in addition to improving component and limb alignment, Plate and colleagues²² demonstrated that RAS-based UKA systems can help the surgeon precisely reproduce plans for soft-tissue balancing. The authors reported ligament balancing to be accurate up to .53 mm compared to the preoperative plan, with approximately 83% of cases balanced within 1 mm of the plan through a full range of flexion.²²

When evaluating advanced and novel technologies, there is undoubtedly concern that there will be increased operative time and a substantial learning curve with those technologies. Karia and colleagues³⁰ found that when inexperienced surgeons performed UKA on synthetic bone models using robotics, the mean compound rotational and translational errors were lower than when conventional techniques were used. Among those using conventional techniques, although surgical times improved during the learning period, positional inaccuracies persisted. On the other hand, robotic assistance enabled surgeons to achieve precision and accuracy when positioning UKA components irrespective of their learning experience.³⁰ Another study, by Coon,³¹ similarly suggested a shorter learning curve and greater accuracy with RAS using the Mako system compared to conventional techniques. A prospective, multicenter, observational study evaluated the operative times of 11 surgeons during their initial clinical cases using Navio robotic technology for medial UKA after a period of training using cadaver knees and sawbones.⁴¹ The learning curve for total surgical time (tracker placement to implant trial phase) indicates that it takes 8 cases to achieve 95% of total learning and maintain a steady state surgical time.

Potential Disadvantages of RAS in UKA

RAS for UKA has several potential disadvantages that must be weighed against their potential benefits. One major barrier to broader use of RAS is the increased cost associated with the technologies.^17,19,27,32 Capital and maintenance costs for these systems can be high, and those that require additional advanced imaging, such as CT scans, further challenge the return on investment.^17,19,32 In a Markov analysis of one robotic system (Mako), Moschetti and colleagues¹⁷ found that if one assumes a system cost of $1.362 million, value can be attained due to slightly better outcomes despite being more expensive than traditional methods. Nonetheless, their analysis of the Mako system estimated that each robot-assisted UKA case cost $19,219, compared to $16,476 with traditional UKA, and was associated with an incremental cost of $47,180 per quality-adjusted life-year. Their analysis further demonstrated that the cost-effectiveness was very sensitive to case volume, with lower costs realized once volumes surpassed 94 cases per year. On the other hand, costs (and thus value) will also obviously vary depending on the capital costs, annual service charges, and avoidance of unnecessary preoperative scans.¹⁹ For instance, assuming a cost of $500,000 for the image-free Navio robotic system, return on investment is achievable within 25 cases annually, roughly one-quarter of the cases necessary with the image-based system.

Another disadvantage of RAS systems in UKA is the unique complications associated with their use. Both RAS and conventional UKA can be complicated by similar problems such as component loosening, polyethylene wear, progressive arthritis, infection, stiffness, instability, and thromboembolism. RAS systems, however, carry the additional risk of specific robot-related issues.^19,27 Perhaps most notably, the pin tracts for the required optical tracking arrays can create a stress riser in the cortical bone,^19,27,33,42 highlighting the importance of inserting these pins in metaphyseal, and not diaphyseal, bone. Soft tissue complications have been reported during bone preparation with autonomous systems in total knee and hip arthroplasty;^37,38 however, the senior author (JHL) has not observed that in 1000 consecutive cases with either semiautonomous surgeon-driven robotic tool.¹⁹

Finally, systems that require a preoperative CT scan pose an increased radiation risk.⁴⁰ Ponzio and Lonner⁴⁰ recently reported that each preoperative CT scan for robotic-assisted knee arthroplasty (using a Mako protocol) is associated with a mean effective dose of radiation of 4.8 mSv, which is approximately equivalent to 48 chest radiographs.³⁴ Further, in that study, at least 25% of patients had been subjected to multiple scans, with some being exposed to cumulative effective doses of up to 103 mSv. This risk should not be considered completely negligible given that 10 mSv may be associated with an increase in the possibility of fatal cancer, and an estimated 29,000 excess cancer cases in the United States annually are reportedly caused by CT scans.^40,43,44 However, this increased radiation risk is not inherent to all RAS systems. Image-free systems, such as Navio, do not require CT scans and are thus not associated with this potential disadvantage.

Conclusion

Robotics has come a long way from its humble conceptual beginnings nearly a century ago. Rapid advances in medical technology over the past 10 years have led to the development and growing popularity of RAS in orthopedic surgery, particularly during UKA. Component placement, quantified soft tissue balance, and radiographic alignment appear to be improved and the incidence of outliers reduced with the use of RAS during UKA. Further assessment is needed to determine whether the improved alignment and balance will impact clinical function and/or durability. Early results are very promising, though, creating optimism that the full benefits of RAS in UKA will be further confirmed with additional time and research.

The concept of robotics is relatively new in medical practice. The term “robot” itself is less than 100 years old, having been first introduced to popular culture in 1917 by Joseph Capek in the science fiction story Opilec.^1,2 Robots eventually transitioned from this initial fictional literary setting to reality in 1958, when General Motors began adding automated machines to its assembly lines.¹ However, it was not until the 1980s that robotics and their exacting efficiencies would be introduced in the medical field, and it would take another decade before they would enter the specialty of orthopedics.^1-4

The first robotic-assisted orthopedic surgery was reportedly performed in 1992, when the Robodoc autonomous system was utilized for total hip arthroplasty.^2-4 A robotic system for total knee arthroplasty (TKA) was first described in 1993, but it would take several more years until a system for unicompartmental knee arthroplasty (UKA) would be commercialized and used clinically.^5,6 The rationale for advancement of robotic technology for isolated medial or lateral knee arthritis stems from the recognition that while UKA is effective and durable when components and limb are well aligned and soft tissues appropriately balanced, they are less forgiving of even slight component malalignment of as little as 2° to 3° and prone to premature loosening or wear in those circumstances.^7-13,14 In the mid 2000s, Cobb and colleagues⁶ reported using a semiautonomous robot for UKA. Since then, emergence of other semiautonomous robotic systems has led to greater market penetration and technology utilization.¹⁵

Currently, an estimated 15% to 20% of UKA surgeries are being performed with robotic assistance.¹⁶ Further, patent activity and peer-reviewed publications related to robotic technology in UKA (which can be considered surrogate measures of interest and evolving development and experience with robotic technologies) have increased dramatically over the past few years.^{2,6,14,17,18-34} To date, while the most dramatic growth of robotic utilization and case volumes has occurred in the subspecialty of UKA, semiautonomous robotic systems have been used with increasing frequency for patellofemoral and bicompartmental knee arthroplasty.^35,36 Robotics have been used sparingly for TKA, and limited to autonomous systems;^37,38 however, it is anticipated that emergence of semiautonomous platforms for TKA will further expand the role of robotics over the next decade, particularly as our focus shifts beyond component and limb alignment in TKA and more towards the role of robotics in soft tissue balancing, reduction in instrumentation and inventory and its attendant cost savings, and surgical efficiencies. One semiautonomous robotic technology first used in 2006 (Mako, Stryker) reported a 130% increase in robotic volume from 2011 to 2012; another, first used in 2013, reported growth of 480% between 2013 and 2014, due to its improved cost structure, ease of use, smaller footprint, image-free platform and applicability in ambulatory surgery centers (Navio, Smith & Nephew; data supplied by manufacturer), demonstrating the growing popularity of robotic technology.^17,39 Further, a recent analysis of potential market penetration over the next decade published by Medical Device and Diagnostic Industry (http://www.mddionline.com) projected that nearly 37% of UKAs and 23% of TKAs will be performed with robotics in 10 years.

Distinction Between Robotic-Assisted Technologies

Autonomous systems involve pre-programming the system with parameters that define the amount and orientation of bone to be removed, after which the system prepares the surfaces independent of surgeon control, other than having access to a “shutdown” switch. There are currently no autonomous robotic tools approved by the US Food and Drug Administration (FDA) for knee arthroplasty.

Semiautonomous systems involve the mapping of condylar landmarks and determination of alignment indices, which also defines the volume and orientation of bone to be removed. While the systems remove bone and cartilage within the pre-established parameters, the robotic tools are controlled and manipulated by the surgeon (Figure 1). The predetermined safe zones modulate and safeguard the surgical actions. These systems also provide real-time quantification of soft tissue balancing, which may contribute to the reported successful clinical and functional outcomes with semiautonomous systems (Figure 2).^2,4,19,22 There are several semiautonomous robotic systems that are approved for use by the FDA.

Each robotic-assisted surgery (RAS) system utilizes some sort of 3-dimensional digital map of the surgical surfaces after a process of surface mapping and landmark registration.² In the case of Mako, this planning process also requires a preoperative computed tomography (CT) scan. Over the past few years, the requirement of a CT scan has proven problematic and costly, as increasingly third-party payers and insurers are denying coverage for additional studies used for preoperative planning, leaving the burden of cost on the patients and/or hospitals. Additionally, in an era in which bundled payment arrangements are commonplace or in which providers are held accountable for costly care, the use of costly preoperative imaging is untenable. Furthermore, there is a growing concern regarding the risk of radiation exposure from CT scans that makes image-free technologies, such as Navio, an alternative for stakeholders.⁴⁰

At this time, the 2 semiautonomous systems in use for UKA employ different methods to safeguard against inadvertent bone preparation: one by providing haptic constraint beyond which movement of the bur is limited (Mako); the other by modulating the exposure or speed of the handheld robotic bur (Navio) (Figure 3).

Outcomes of RAS in UKA

Compared to conventional UKA, robotic assistance has consistently demonstrated improved surgical accuracy, even through minimally invasive incisions (Figures 4, 5).^6,20-28 Several studies have found substantial reduction in variability and error of component positioning with use of semiautonomous robotic tools.^6,21,25 In fact, precision appears to be comparable regardless of whether an image-free system or one requiring a preoperative CT scan is used (Table). Further, in addition to improving component and limb alignment, Plate and colleagues²² demonstrated that RAS-based UKA systems can help the surgeon precisely reproduce plans for soft-tissue balancing. The authors reported ligament balancing to be accurate up to .53 mm compared to the preoperative plan, with approximately 83% of cases balanced within 1 mm of the plan through a full range of flexion.²²

When evaluating advanced and novel technologies, there is undoubtedly concern that there will be increased operative time and a substantial learning curve with those technologies. Karia and colleagues³⁰ found that when inexperienced surgeons performed UKA on synthetic bone models using robotics, the mean compound rotational and translational errors were lower than when conventional techniques were used. Among those using conventional techniques, although surgical times improved during the learning period, positional inaccuracies persisted. On the other hand, robotic assistance enabled surgeons to achieve precision and accuracy when positioning UKA components irrespective of their learning experience.³⁰ Another study, by Coon,³¹ similarly suggested a shorter learning curve and greater accuracy with RAS using the Mako system compared to conventional techniques. A prospective, multicenter, observational study evaluated the operative times of 11 surgeons during their initial clinical cases using Navio robotic technology for medial UKA after a period of training using cadaver knees and sawbones.⁴¹ The learning curve for total surgical time (tracker placement to implant trial phase) indicates that it takes 8 cases to achieve 95% of total learning and maintain a steady state surgical time.

Potential Disadvantages of RAS in UKA

RAS for UKA has several potential disadvantages that must be weighed against their potential benefits. One major barrier to broader use of RAS is the increased cost associated with the technologies.^17,19,27,32 Capital and maintenance costs for these systems can be high, and those that require additional advanced imaging, such as CT scans, further challenge the return on investment.^17,19,32 In a Markov analysis of one robotic system (Mako), Moschetti and colleagues¹⁷ found that if one assumes a system cost of $1.362 million, value can be attained due to slightly better outcomes despite being more expensive than traditional methods. Nonetheless, their analysis of the Mako system estimated that each robot-assisted UKA case cost $19,219, compared to $16,476 with traditional UKA, and was associated with an incremental cost of $47,180 per quality-adjusted life-year. Their analysis further demonstrated that the cost-effectiveness was very sensitive to case volume, with lower costs realized once volumes surpassed 94 cases per year. On the other hand, costs (and thus value) will also obviously vary depending on the capital costs, annual service charges, and avoidance of unnecessary preoperative scans.¹⁹ For instance, assuming a cost of $500,000 for the image-free Navio robotic system, return on investment is achievable within 25 cases annually, roughly one-quarter of the cases necessary with the image-based system.

Another disadvantage of RAS systems in UKA is the unique complications associated with their use. Both RAS and conventional UKA can be complicated by similar problems such as component loosening, polyethylene wear, progressive arthritis, infection, stiffness, instability, and thromboembolism. RAS systems, however, carry the additional risk of specific robot-related issues.^19,27 Perhaps most notably, the pin tracts for the required optical tracking arrays can create a stress riser in the cortical bone,^19,27,33,42 highlighting the importance of inserting these pins in metaphyseal, and not diaphyseal, bone. Soft tissue complications have been reported during bone preparation with autonomous systems in total knee and hip arthroplasty;^37,38 however, the senior author (JHL) has not observed that in 1000 consecutive cases with either semiautonomous surgeon-driven robotic tool.¹⁹

Finally, systems that require a preoperative CT scan pose an increased radiation risk.⁴⁰ Ponzio and Lonner⁴⁰ recently reported that each preoperative CT scan for robotic-assisted knee arthroplasty (using a Mako protocol) is associated with a mean effective dose of radiation of 4.8 mSv, which is approximately equivalent to 48 chest radiographs.³⁴ Further, in that study, at least 25% of patients had been subjected to multiple scans, with some being exposed to cumulative effective doses of up to 103 mSv. This risk should not be considered completely negligible given that 10 mSv may be associated with an increase in the possibility of fatal cancer, and an estimated 29,000 excess cancer cases in the United States annually are reportedly caused by CT scans.^40,43,44 However, this increased radiation risk is not inherent to all RAS systems. Image-free systems, such as Navio, do not require CT scans and are thus not associated with this potential disadvantage.

Conclusion

Robotics has come a long way from its humble conceptual beginnings nearly a century ago. Rapid advances in medical technology over the past 10 years have led to the development and growing popularity of RAS in orthopedic surgery, particularly during UKA. Component placement, quantified soft tissue balance, and radiographic alignment appear to be improved and the incidence of outliers reduced with the use of RAS during UKA. Further assessment is needed to determine whether the improved alignment and balance will impact clinical function and/or durability. Early results are very promising, though, creating optimism that the full benefits of RAS in UKA will be further confirmed with additional time and research.

BARCELONA – An investigational drug that targets the hepatitis B virus (HBV) core protein is a “totally new approach” to treating chronic HBV infection according to the results of an early-phase clinical study.

In an ongoing, international, phase I study presented during the late-breaker session at the International Liver Congress, 4 weeks of treatment with NVR 3-778 was well tolerated and did not result in any drug discontinuations in chronically infected patients. There were dose-related reductions in HBV DNA and early reductions in HBeAg were observed.

“NVR 3-778 is a first-in-class HBV core inhibitor,” study investigator Dr. Man-Fung Yuen, Queen Mary Hospital, Hong Kong, said at a press briefing held at the meeting, which is sponsored by the European Association for the Study of the Liver (EASL). “The HBV core protein has many functions and is responsible for the most important pathway of the virus’ replication – nucleocapsid formation,” he explained.

The rationale behind its development is that although there are effective treatments such as nucleoside and nucleotide analogs (NAs) and pegylated interferon (peg-IFN) that can suppress the activity of HBV for many years and thus slow down damage to the liver, it is unusual to clear the virus permanently. Furthermore, as most patients require potentially life-long treatment, issues such as long-term safety, patients’ adherence, resistance, and cost of therapy come into play.

Dr. Yuen observed that achieving durable responses in patients with chronic HBV is likely to require combinations of potential agents, probably with complementary modes of action.

Preclinical data have shown that NVR 3-778 induces the rapid assembly of nonfunctional capsids and that it inhibits viral replication in a humanized mouse hepatocyte cell model. It has also been shown to reduce HBV DNA to a comparable extent as entecavir when used alone in a mouse model, with undetectable levels reached when used in combination with peg-IFN alpha-2a.

Dr. Yuen reported the preliminary results from the second part of the phase I study in 64 adults with chronic HBV, noting that the first part of the study in healthy volunteers had been completed successfully.

The aim was to examine the safety and efficacy of NVR 3-778 alone and in combination with peg-IFN alpha-2a in previously untreated patients aged between 18 and 65 years who were HBsAg- and HbeAg-positive, had HBV DNA of 20,000 or more copies per IU/mL, with no cirrhosis of the liver, as determined by liver biopsy or imaging.

Patients were randomly assigned to six groups, with four groups receiving the investigational therapy alone at four increasing doses (100, 200, 400, once daily and 600 mg twice daily). There was a staged initiation of each escalating dose of NVR 3-778 used in these groups, with the 100 mg initiated first and if, after 2 weeks, there were no interim safety concerns, the next dose groups, 200 mg, then 400 mg, then 600 mg were started. The other two groups of patients received NVR 3-788 (600 mg) with peg-IFN alpha-2a (180 microg/week) or peg-IFN alpha-2a plus placebo. Treatment for all groups was for 28 days with 28 days of follow-up.

The mean age of patients in each group ranged from 32 to 48 years, with the older patients more likely to be treated with peg-IFN alpha-2a alone or with NVR 3-788. Most of the patients studied were Chinese and the mean baseline HBV DNA was 7.5-8.3 log₁₀ IU/mL.

A total of 98 adverse events were seen in 40 of 64 patients treated, although there was not any trend for more effects with the investigational treatment versus placebo as doses escalated. There were 21 adverse events seen in 20 of 46 patients that were possibly or probably related to the study drug, of which most were grade 1 nausea. Grade 2 nausea occurred only once in a patient given the 100-mg dose. There was one serious adverse event, a grade 3 papulovesicular rash on the hands and feet that occurred in a patient in the 100-mg group, but this responded to therapy. This side effect started about 20 days after treatment and resolved over a period of 7 months.

Although generally mild, more adverse effects were seen in the patients treated with a combination of NVR 3-788 and peg-IFN alpha-2a, which Dr. Yuen noted was thought to be more likely a result of the IFN therapy.

There was not much difference in the mean change in HBV DNA from baseline for the 100-400-mg groups, but there was a 1.72-log₁₀ IU/mL decrease achieved with the 600-mg twice-daily dose. The greatest reduction, however, was seen when NVR 3-788 was combined with peg-IFN alpha-2a, with a 1.97-log₁₀ IU/mL change.

“Encouraging early reductions in HBV RNA and quantitative serum HBeAg were observed,” Dr. Yuen said. He noted that the longer-term safety and efficacy of the novel agent in combination with peg-IFN alpha-2a and first-line HBV NAs will now be further assessed in phase II studies.

“At the moment we do not have a cure for hepatitis B, only treatment,” said Dr. Frank Tacke of the University Hospital Aachen (Germany), who chaired the press briefing where Dr. Yuen first aired the findings. NVR 3-788 represents “a totally new approach to this disease that we hope will lead to a cure,” Dr. Tacke said.

In an EASL-issued press release, Dr. Tacke also noted: “The results from this study are certainly interesting and promising for the treatment of patients with hepatitis B. The medical community is always on the lookout for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm.”

Novira Therapeutics financed the study. Dr. Yuen has been a consultant, speaker, or both for Arrowhead, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, and Roche. Dr. Tacke did not have any relevant disclosures.

BARCELONA – An investigational drug that targets the hepatitis B virus (HBV) core protein is a “totally new approach” to treating chronic HBV infection according to the results of an early-phase clinical study.

In an ongoing, international, phase I study presented during the late-breaker session at the International Liver Congress, 4 weeks of treatment with NVR 3-778 was well tolerated and did not result in any drug discontinuations in chronically infected patients. There were dose-related reductions in HBV DNA and early reductions in HBeAg were observed.

“NVR 3-778 is a first-in-class HBV core inhibitor,” study investigator Dr. Man-Fung Yuen, Queen Mary Hospital, Hong Kong, said at a press briefing held at the meeting, which is sponsored by the European Association for the Study of the Liver (EASL). “The HBV core protein has many functions and is responsible for the most important pathway of the virus’ replication – nucleocapsid formation,” he explained.

The rationale behind its development is that although there are effective treatments such as nucleoside and nucleotide analogs (NAs) and pegylated interferon (peg-IFN) that can suppress the activity of HBV for many years and thus slow down damage to the liver, it is unusual to clear the virus permanently. Furthermore, as most patients require potentially life-long treatment, issues such as long-term safety, patients’ adherence, resistance, and cost of therapy come into play.

Dr. Yuen observed that achieving durable responses in patients with chronic HBV is likely to require combinations of potential agents, probably with complementary modes of action.

Preclinical data have shown that NVR 3-778 induces the rapid assembly of nonfunctional capsids and that it inhibits viral replication in a humanized mouse hepatocyte cell model. It has also been shown to reduce HBV DNA to a comparable extent as entecavir when used alone in a mouse model, with undetectable levels reached when used in combination with peg-IFN alpha-2a.

Dr. Yuen reported the preliminary results from the second part of the phase I study in 64 adults with chronic HBV, noting that the first part of the study in healthy volunteers had been completed successfully.

The aim was to examine the safety and efficacy of NVR 3-778 alone and in combination with peg-IFN alpha-2a in previously untreated patients aged between 18 and 65 years who were HBsAg- and HbeAg-positive, had HBV DNA of 20,000 or more copies per IU/mL, with no cirrhosis of the liver, as determined by liver biopsy or imaging.

Patients were randomly assigned to six groups, with four groups receiving the investigational therapy alone at four increasing doses (100, 200, 400, once daily and 600 mg twice daily). There was a staged initiation of each escalating dose of NVR 3-778 used in these groups, with the 100 mg initiated first and if, after 2 weeks, there were no interim safety concerns, the next dose groups, 200 mg, then 400 mg, then 600 mg were started. The other two groups of patients received NVR 3-788 (600 mg) with peg-IFN alpha-2a (180 microg/week) or peg-IFN alpha-2a plus placebo. Treatment for all groups was for 28 days with 28 days of follow-up.

The mean age of patients in each group ranged from 32 to 48 years, with the older patients more likely to be treated with peg-IFN alpha-2a alone or with NVR 3-788. Most of the patients studied were Chinese and the mean baseline HBV DNA was 7.5-8.3 log₁₀ IU/mL.

A total of 98 adverse events were seen in 40 of 64 patients treated, although there was not any trend for more effects with the investigational treatment versus placebo as doses escalated. There were 21 adverse events seen in 20 of 46 patients that were possibly or probably related to the study drug, of which most were grade 1 nausea. Grade 2 nausea occurred only once in a patient given the 100-mg dose. There was one serious adverse event, a grade 3 papulovesicular rash on the hands and feet that occurred in a patient in the 100-mg group, but this responded to therapy. This side effect started about 20 days after treatment and resolved over a period of 7 months.

Although generally mild, more adverse effects were seen in the patients treated with a combination of NVR 3-788 and peg-IFN alpha-2a, which Dr. Yuen noted was thought to be more likely a result of the IFN therapy.

There was not much difference in the mean change in HBV DNA from baseline for the 100-400-mg groups, but there was a 1.72-log₁₀ IU/mL decrease achieved with the 600-mg twice-daily dose. The greatest reduction, however, was seen when NVR 3-788 was combined with peg-IFN alpha-2a, with a 1.97-log₁₀ IU/mL change.

“Encouraging early reductions in HBV RNA and quantitative serum HBeAg were observed,” Dr. Yuen said. He noted that the longer-term safety and efficacy of the novel agent in combination with peg-IFN alpha-2a and first-line HBV NAs will now be further assessed in phase II studies.

“At the moment we do not have a cure for hepatitis B, only treatment,” said Dr. Frank Tacke of the University Hospital Aachen (Germany), who chaired the press briefing where Dr. Yuen first aired the findings. NVR 3-788 represents “a totally new approach to this disease that we hope will lead to a cure,” Dr. Tacke said.

In an EASL-issued press release, Dr. Tacke also noted: “The results from this study are certainly interesting and promising for the treatment of patients with hepatitis B. The medical community is always on the lookout for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm.”

Novira Therapeutics financed the study. Dr. Yuen has been a consultant, speaker, or both for Arrowhead, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, and Roche. Dr. Tacke did not have any relevant disclosures.

BARCELONA – An investigational drug that targets the hepatitis B virus (HBV) core protein is a “totally new approach” to treating chronic HBV infection according to the results of an early-phase clinical study.

In an ongoing, international, phase I study presented during the late-breaker session at the International Liver Congress, 4 weeks of treatment with NVR 3-778 was well tolerated and did not result in any drug discontinuations in chronically infected patients. There were dose-related reductions in HBV DNA and early reductions in HBeAg were observed.

“NVR 3-778 is a first-in-class HBV core inhibitor,” study investigator Dr. Man-Fung Yuen, Queen Mary Hospital, Hong Kong, said at a press briefing held at the meeting, which is sponsored by the European Association for the Study of the Liver (EASL). “The HBV core protein has many functions and is responsible for the most important pathway of the virus’ replication – nucleocapsid formation,” he explained.

The rationale behind its development is that although there are effective treatments such as nucleoside and nucleotide analogs (NAs) and pegylated interferon (peg-IFN) that can suppress the activity of HBV for many years and thus slow down damage to the liver, it is unusual to clear the virus permanently. Furthermore, as most patients require potentially life-long treatment, issues such as long-term safety, patients’ adherence, resistance, and cost of therapy come into play.

Dr. Yuen observed that achieving durable responses in patients with chronic HBV is likely to require combinations of potential agents, probably with complementary modes of action.

Preclinical data have shown that NVR 3-778 induces the rapid assembly of nonfunctional capsids and that it inhibits viral replication in a humanized mouse hepatocyte cell model. It has also been shown to reduce HBV DNA to a comparable extent as entecavir when used alone in a mouse model, with undetectable levels reached when used in combination with peg-IFN alpha-2a.

Dr. Yuen reported the preliminary results from the second part of the phase I study in 64 adults with chronic HBV, noting that the first part of the study in healthy volunteers had been completed successfully.

The aim was to examine the safety and efficacy of NVR 3-778 alone and in combination with peg-IFN alpha-2a in previously untreated patients aged between 18 and 65 years who were HBsAg- and HbeAg-positive, had HBV DNA of 20,000 or more copies per IU/mL, with no cirrhosis of the liver, as determined by liver biopsy or imaging.

Patients were randomly assigned to six groups, with four groups receiving the investigational therapy alone at four increasing doses (100, 200, 400, once daily and 600 mg twice daily). There was a staged initiation of each escalating dose of NVR 3-778 used in these groups, with the 100 mg initiated first and if, after 2 weeks, there were no interim safety concerns, the next dose groups, 200 mg, then 400 mg, then 600 mg were started. The other two groups of patients received NVR 3-788 (600 mg) with peg-IFN alpha-2a (180 microg/week) or peg-IFN alpha-2a plus placebo. Treatment for all groups was for 28 days with 28 days of follow-up.

The mean age of patients in each group ranged from 32 to 48 years, with the older patients more likely to be treated with peg-IFN alpha-2a alone or with NVR 3-788. Most of the patients studied were Chinese and the mean baseline HBV DNA was 7.5-8.3 log₁₀ IU/mL.

A total of 98 adverse events were seen in 40 of 64 patients treated, although there was not any trend for more effects with the investigational treatment versus placebo as doses escalated. There were 21 adverse events seen in 20 of 46 patients that were possibly or probably related to the study drug, of which most were grade 1 nausea. Grade 2 nausea occurred only once in a patient given the 100-mg dose. There was one serious adverse event, a grade 3 papulovesicular rash on the hands and feet that occurred in a patient in the 100-mg group, but this responded to therapy. This side effect started about 20 days after treatment and resolved over a period of 7 months.

Although generally mild, more adverse effects were seen in the patients treated with a combination of NVR 3-788 and peg-IFN alpha-2a, which Dr. Yuen noted was thought to be more likely a result of the IFN therapy.

There was not much difference in the mean change in HBV DNA from baseline for the 100-400-mg groups, but there was a 1.72-log₁₀ IU/mL decrease achieved with the 600-mg twice-daily dose. The greatest reduction, however, was seen when NVR 3-788 was combined with peg-IFN alpha-2a, with a 1.97-log₁₀ IU/mL change.

“Encouraging early reductions in HBV RNA and quantitative serum HBeAg were observed,” Dr. Yuen said. He noted that the longer-term safety and efficacy of the novel agent in combination with peg-IFN alpha-2a and first-line HBV NAs will now be further assessed in phase II studies.

“At the moment we do not have a cure for hepatitis B, only treatment,” said Dr. Frank Tacke of the University Hospital Aachen (Germany), who chaired the press briefing where Dr. Yuen first aired the findings. NVR 3-788 represents “a totally new approach to this disease that we hope will lead to a cure,” Dr. Tacke said.

In an EASL-issued press release, Dr. Tacke also noted: “The results from this study are certainly interesting and promising for the treatment of patients with hepatitis B. The medical community is always on the lookout for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm.”

Novira Therapeutics financed the study. Dr. Yuen has been a consultant, speaker, or both for Arrowhead, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, and Roche. Dr. Tacke did not have any relevant disclosures.

Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Joseph Riccio/Adirondack Health

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.

[email protected]

Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Joseph Riccio/Adirondack Health

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.

[email protected]

Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.

Joseph Riccio/Adirondack Health

Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.

It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.

Labeling questions

It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).

While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.

“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.

Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.

In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”

Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.

Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”

Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.

“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”

“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”

Substitution concerns

Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.

The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.

Patient costs uncertain

Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.

“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”

The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.

“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.

Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.

“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.

It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”

Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”

Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.

It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”

Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.

[email protected]

Hospital air is a potential route of transmission of beta-lactam–resistant bacteria (BLRB), which are important causative agents of nosocomial infections, according to research published in the American Journal of Infection Control.

Dr. Mahnaz Nikaeen of the department of environmental health engineering at Isfahan (Iran) University of Medical Sciences, and his coauthors collected and tested 64 air samples from four hospital wards to determine the prevalence of airborne BLRB in different teaching hospitals, to evaluate the frequency of five common beta-lactamase–encoding genes in isolated resistant bacteria, and to identify the most predominant BLRB by 16s rRNA gene sequencing. The sampling locations in each hospital included operating rooms, ICUs, surgery wards, and internal medicine wards.

©Andrei Malov/ThinkStock.com

The investigators detected airborne bacteria by using culture plates with and without beta-lactams.

The prevalence of BLRB in the air samples ranged between 3% and 34%, Dr. Nikaeen said. Oxacillin-resistant bacteria had the highest prevalence, followed by ceftazidime- and cefazolin-resistant bacteria. Acinetobacter spp, Acinetobacter baumannii, and Staphylococcus spp were the most predominant BLRB.

Gene sequencing revealed that the frequency of beta-lactamase–encoding genes in isolated BLRB ranged between 0% and 47%, with the highest and lowest detection for OXA-23, commonly found in Acinetobacter spp, and CTX-m-32, a gene prevalent in extended-spectrum beta-lactamase–producing Enterobacteriaceae, respectively. MecA, a genetic element found in methicillin-resistant Staphylococcus spp, had a relatively high frequency in surgery wards and operating rooms, whereas the frequency of blaTEM, another common extended-spectrum beta-lactamase produced by Enterobacteriaceae, was higher in intensive care units and internal medicine wards. OXA-51, a chromosomally located intrinsic gene in A. baumannii, was detected in four wards.

“Isolation of beta-lactam–resistant Staphylococcus spp and A. baumannii as the most predominant BLRB indicated the potential role of airborne bacteria in dissemination of nosocomial infections,” Dr. Nikaeen and his coauthors said. “The results confirm the necessity for application of effective control measures that significantly decrease the exposure of high-risk patients to potentially airborne nosocomial infections.”

The authors reported having no conflicts.

Read the complete study in the American Journal of Infection Control (doi:10.1016/j.ajic.2016.01.041).

[email protected]

On Twitter @richpizzi

Hospital air is a potential route of transmission of beta-lactam–resistant bacteria (BLRB), which are important causative agents of nosocomial infections, according to research published in the American Journal of Infection Control.

Dr. Mahnaz Nikaeen of the department of environmental health engineering at Isfahan (Iran) University of Medical Sciences, and his coauthors collected and tested 64 air samples from four hospital wards to determine the prevalence of airborne BLRB in different teaching hospitals, to evaluate the frequency of five common beta-lactamase–encoding genes in isolated resistant bacteria, and to identify the most predominant BLRB by 16s rRNA gene sequencing. The sampling locations in each hospital included operating rooms, ICUs, surgery wards, and internal medicine wards.

©Andrei Malov/ThinkStock.com

The investigators detected airborne bacteria by using culture plates with and without beta-lactams.

The prevalence of BLRB in the air samples ranged between 3% and 34%, Dr. Nikaeen said. Oxacillin-resistant bacteria had the highest prevalence, followed by ceftazidime- and cefazolin-resistant bacteria. Acinetobacter spp, Acinetobacter baumannii, and Staphylococcus spp were the most predominant BLRB.

Gene sequencing revealed that the frequency of beta-lactamase–encoding genes in isolated BLRB ranged between 0% and 47%, with the highest and lowest detection for OXA-23, commonly found in Acinetobacter spp, and CTX-m-32, a gene prevalent in extended-spectrum beta-lactamase–producing Enterobacteriaceae, respectively. MecA, a genetic element found in methicillin-resistant Staphylococcus spp, had a relatively high frequency in surgery wards and operating rooms, whereas the frequency of blaTEM, another common extended-spectrum beta-lactamase produced by Enterobacteriaceae, was higher in intensive care units and internal medicine wards. OXA-51, a chromosomally located intrinsic gene in A. baumannii, was detected in four wards.

“Isolation of beta-lactam–resistant Staphylococcus spp and A. baumannii as the most predominant BLRB indicated the potential role of airborne bacteria in dissemination of nosocomial infections,” Dr. Nikaeen and his coauthors said. “The results confirm the necessity for application of effective control measures that significantly decrease the exposure of high-risk patients to potentially airborne nosocomial infections.”

The authors reported having no conflicts.

Read the complete study in the American Journal of Infection Control (doi:10.1016/j.ajic.2016.01.041).

[email protected]

On Twitter @richpizzi

Hospital air is a potential route of transmission of beta-lactam–resistant bacteria (BLRB), which are important causative agents of nosocomial infections, according to research published in the American Journal of Infection Control.

Dr. Mahnaz Nikaeen of the department of environmental health engineering at Isfahan (Iran) University of Medical Sciences, and his coauthors collected and tested 64 air samples from four hospital wards to determine the prevalence of airborne BLRB in different teaching hospitals, to evaluate the frequency of five common beta-lactamase–encoding genes in isolated resistant bacteria, and to identify the most predominant BLRB by 16s rRNA gene sequencing. The sampling locations in each hospital included operating rooms, ICUs, surgery wards, and internal medicine wards.

©Andrei Malov/ThinkStock.com

The investigators detected airborne bacteria by using culture plates with and without beta-lactams.

The prevalence of BLRB in the air samples ranged between 3% and 34%, Dr. Nikaeen said. Oxacillin-resistant bacteria had the highest prevalence, followed by ceftazidime- and cefazolin-resistant bacteria. Acinetobacter spp, Acinetobacter baumannii, and Staphylococcus spp were the most predominant BLRB.

Gene sequencing revealed that the frequency of beta-lactamase–encoding genes in isolated BLRB ranged between 0% and 47%, with the highest and lowest detection for OXA-23, commonly found in Acinetobacter spp, and CTX-m-32, a gene prevalent in extended-spectrum beta-lactamase–producing Enterobacteriaceae, respectively. MecA, a genetic element found in methicillin-resistant Staphylococcus spp, had a relatively high frequency in surgery wards and operating rooms, whereas the frequency of blaTEM, another common extended-spectrum beta-lactamase produced by Enterobacteriaceae, was higher in intensive care units and internal medicine wards. OXA-51, a chromosomally located intrinsic gene in A. baumannii, was detected in four wards.

“Isolation of beta-lactam–resistant Staphylococcus spp and A. baumannii as the most predominant BLRB indicated the potential role of airborne bacteria in dissemination of nosocomial infections,” Dr. Nikaeen and his coauthors said. “The results confirm the necessity for application of effective control measures that significantly decrease the exposure of high-risk patients to potentially airborne nosocomial infections.”

The authors reported having no conflicts.

Read the complete study in the American Journal of Infection Control (doi:10.1016/j.ajic.2016.01.041).

[email protected]

On Twitter @richpizzi

Screening asymptomatic patients admitted through the emergency department for occult Clostridium difficile infection, then isolating those found to be carriers throughout their hospital stay, substantially reduced the incidence of hospital-acquired C. difficile infection in a tertiary acute-care hospital, according to a report published online April 25 in JAMA Internal Medicine.

In what investigators described as the first study to assess the benefit of such an intervention, the Quebec Heart and Lung Institute (QHLI) in Quebec City went from being endemic for C. difficile infection to having the lowest incidence among 22 academic hospitals across the province of Quebec. “If confirmed in subsequent studies, isolating asymptomatic carriers could potentially prevent thousands of cases of hospital-acquired C. difficile infection every year in North America,” said Dr. Yves Longtin of the infection prevention and control unit at Jewish General Hospital, Montreal, and his associates.

CDC/D. Holdeman

The QHLI implemented the screen-and-isolate program because, despite robust infection-control efforts, it continued to exceed the government-imposed target level of 9.0 C. difficile infections per 10,000 patient-days. The program, which involved 7,599 patients admitted to the facility through its ED during a 17-month period, called for rectal sampling with a sterile swab, using a polymerase chain reaction (PCR) assay to detect the tcdB gene, obtaining the results within 24 hours, and isolating any carriers for the remainder of their stay. A total of 368 asymptomatic patients (4.8%) were found to be carriers.

Before the intervention, the hospital’s monthly incidence averaged 8.2 cases per 10,000 patient-days, with a high of 28.6 cases per 10,000 patient-days during an epidemic. After the intervention was implemented, the monthly incidence dropped to 3.0 per 10,000 patient-days. The hospital exceeded target levels of cases in 24.4% of the months preceding the intervention, compared with none of the months afterward. The investigators calculated that only 121 patients needed to be screened and 6 asymptomatic carriers needed to be isolated to prevent 1 case of hospital-acquired C. difficile infection.

During the same time period, rates of C. difficile infection remained stable at other hospitals across the province, Dr. Longtin and his associates said (JAMA Intern Med. 2016 Apr 25. doi: 10.1001/jamainternmed.2016.0177).

“The intervention may be effective not only by preventing direct patient-to-patient transmission but also by limiting contamination of the hospital environment,” they noted.

The study was supported by the Quebec Heart and Lung Institute, the Quebec Ministry of Health and Social Services, and the Quebec Foundation for Health Research. Dr. Longtin reported being a coapplicant on a patent for methods, reagents, and kits for the assessment of bacterial infections. His associates reported ties to Sanofi Pasteur, Merck, and Otsuka.

Screening asymptomatic patients admitted through the emergency department for occult Clostridium difficile infection, then isolating those found to be carriers throughout their hospital stay, substantially reduced the incidence of hospital-acquired C. difficile infection in a tertiary acute-care hospital, according to a report published online April 25 in JAMA Internal Medicine.

In what investigators described as the first study to assess the benefit of such an intervention, the Quebec Heart and Lung Institute (QHLI) in Quebec City went from being endemic for C. difficile infection to having the lowest incidence among 22 academic hospitals across the province of Quebec. “If confirmed in subsequent studies, isolating asymptomatic carriers could potentially prevent thousands of cases of hospital-acquired C. difficile infection every year in North America,” said Dr. Yves Longtin of the infection prevention and control unit at Jewish General Hospital, Montreal, and his associates.

CDC/D. Holdeman

The QHLI implemented the screen-and-isolate program because, despite robust infection-control efforts, it continued to exceed the government-imposed target level of 9.0 C. difficile infections per 10,000 patient-days. The program, which involved 7,599 patients admitted to the facility through its ED during a 17-month period, called for rectal sampling with a sterile swab, using a polymerase chain reaction (PCR) assay to detect the tcdB gene, obtaining the results within 24 hours, and isolating any carriers for the remainder of their stay. A total of 368 asymptomatic patients (4.8%) were found to be carriers.

Before the intervention, the hospital’s monthly incidence averaged 8.2 cases per 10,000 patient-days, with a high of 28.6 cases per 10,000 patient-days during an epidemic. After the intervention was implemented, the monthly incidence dropped to 3.0 per 10,000 patient-days. The hospital exceeded target levels of cases in 24.4% of the months preceding the intervention, compared with none of the months afterward. The investigators calculated that only 121 patients needed to be screened and 6 asymptomatic carriers needed to be isolated to prevent 1 case of hospital-acquired C. difficile infection.

During the same time period, rates of C. difficile infection remained stable at other hospitals across the province, Dr. Longtin and his associates said (JAMA Intern Med. 2016 Apr 25. doi: 10.1001/jamainternmed.2016.0177).

“The intervention may be effective not only by preventing direct patient-to-patient transmission but also by limiting contamination of the hospital environment,” they noted.

The study was supported by the Quebec Heart and Lung Institute, the Quebec Ministry of Health and Social Services, and the Quebec Foundation for Health Research. Dr. Longtin reported being a coapplicant on a patent for methods, reagents, and kits for the assessment of bacterial infections. His associates reported ties to Sanofi Pasteur, Merck, and Otsuka.

Screening asymptomatic patients admitted through the emergency department for occult Clostridium difficile infection, then isolating those found to be carriers throughout their hospital stay, substantially reduced the incidence of hospital-acquired C. difficile infection in a tertiary acute-care hospital, according to a report published online April 25 in JAMA Internal Medicine.

In what investigators described as the first study to assess the benefit of such an intervention, the Quebec Heart and Lung Institute (QHLI) in Quebec City went from being endemic for C. difficile infection to having the lowest incidence among 22 academic hospitals across the province of Quebec. “If confirmed in subsequent studies, isolating asymptomatic carriers could potentially prevent thousands of cases of hospital-acquired C. difficile infection every year in North America,” said Dr. Yves Longtin of the infection prevention and control unit at Jewish General Hospital, Montreal, and his associates.

CDC/D. Holdeman

The QHLI implemented the screen-and-isolate program because, despite robust infection-control efforts, it continued to exceed the government-imposed target level of 9.0 C. difficile infections per 10,000 patient-days. The program, which involved 7,599 patients admitted to the facility through its ED during a 17-month period, called for rectal sampling with a sterile swab, using a polymerase chain reaction (PCR) assay to detect the tcdB gene, obtaining the results within 24 hours, and isolating any carriers for the remainder of their stay. A total of 368 asymptomatic patients (4.8%) were found to be carriers.

Before the intervention, the hospital’s monthly incidence averaged 8.2 cases per 10,000 patient-days, with a high of 28.6 cases per 10,000 patient-days during an epidemic. After the intervention was implemented, the monthly incidence dropped to 3.0 per 10,000 patient-days. The hospital exceeded target levels of cases in 24.4% of the months preceding the intervention, compared with none of the months afterward. The investigators calculated that only 121 patients needed to be screened and 6 asymptomatic carriers needed to be isolated to prevent 1 case of hospital-acquired C. difficile infection.

During the same time period, rates of C. difficile infection remained stable at other hospitals across the province, Dr. Longtin and his associates said (JAMA Intern Med. 2016 Apr 25. doi: 10.1001/jamainternmed.2016.0177).

“The intervention may be effective not only by preventing direct patient-to-patient transmission but also by limiting contamination of the hospital environment,” they noted.

The study was supported by the Quebec Heart and Lung Institute, the Quebec Ministry of Health and Social Services, and the Quebec Foundation for Health Research. Dr. Longtin reported being a coapplicant on a patent for methods, reagents, and kits for the assessment of bacterial infections. His associates reported ties to Sanofi Pasteur, Merck, and Otsuka.

(Reuters Health) - Some cancer patients may turn down care that could ease their pain and improve their quality of life because they think this type of "palliative" treatment amounts

to giving up and simply waiting to die, a small Canadian study suggests.

Even though the World Health Organization recommends early palliative care for patients living with any serious illness, negative attitudes among patients and family caregivers often lead them to reject this option, researchers note in the Canadian Medical Association Journal.

"Patients and caregivers in our study saw palliative care as being equated with death, loss of hope, dependency, and going into places you never get out of again," said lead study author Dr. Camilla Zimmermann, head of the division of palliative care at the University Health Network in Toronto.

"This is in stark contrast with the actual definition of palliative care, which is interdisciplinary care that provides quality of life for patients with any serious illness and their families, and that is provided throughout the course of the illness rather than only at the end of life," Zimmermann added by email.

Zimmermann and colleagues interviewed 48 cancer patients and 23 of their family caregivers in cases when life expectancy was six to 24 months.

The researchers randomly assigned 26 patients to receive palliative care in addition to standard cancer care, while another 22 patients had only standard care.

Twenty-two patients in the palliative care group and 20 in the control group were receiving chemotherapy.

Over four months, patients in the palliative care group had at least monthly palliative care clinic visits, while those in the standard care group didn't receive any formal interventions. Caregivers could attend clinic visits for the palliative care participants, but they weren't required to do so.

Patients were typically in their early to mid 60s. Most were married and had at least some education beyond high school.

Most family caregivers were spouses, but a few were children or other relatives.

Initial perceptions of palliative care were similar in both groups - patients generally thought this was done only for the dying. While patients in both groups thought of palliative care

as providing comfort, they also associated it with giving up on treatment.

Once some patients received palliative care, however, their thinking shifted. Some patients now saw this as a way to live life to the fullest despite the terminal diagnosis, while others

suggested that doctors might have better luck renaming this as something other than "palliative care."

Calling palliative care providers "pain specialists" because they treat discomfort and focus on quality of life would make this sound more appealing and less frightening, some patients

said after getting this type of care.

But in the control group, without any experience with palliative care during the study, patients didn't see the point of renaming it because they thought it would still carry the stigma of giving up and waiting to die.

"Palliative care should not be framed as a last resort option," said Dr. Anthony Caprio, a geriatrician and hospice and palliative medicine physician at Carolinas HealthCare System in

North Carolina.

"These `nothing left to do' conversations often frame palliative care as a way to help people die comfortably, rather than an approach to care that allows them to live with the highest quality of life for as long as possible," said Caprio, who wrote an editorial that was published with the study.

Using different language in discussions with patients can make a big difference, Caprio added.

"I often describe palliative care as an extra layer of support," Caprio said. "Who wouldn't want more support, especially during a difficult illness?"

(Reuters Health) - Some cancer patients may turn down care that could ease their pain and improve their quality of life because they think this type of "palliative" treatment amounts

to giving up and simply waiting to die, a small Canadian study suggests.

Even though the World Health Organization recommends early palliative care for patients living with any serious illness, negative attitudes among patients and family caregivers often lead them to reject this option, researchers note in the Canadian Medical Association Journal.

"Patients and caregivers in our study saw palliative care as being equated with death, loss of hope, dependency, and going into places you never get out of again," said lead study author Dr. Camilla Zimmermann, head of the division of palliative care at the University Health Network in Toronto.

"This is in stark contrast with the actual definition of palliative care, which is interdisciplinary care that provides quality of life for patients with any serious illness and their families, and that is provided throughout the course of the illness rather than only at the end of life," Zimmermann added by email.

Zimmermann and colleagues interviewed 48 cancer patients and 23 of their family caregivers in cases when life expectancy was six to 24 months.

The researchers randomly assigned 26 patients to receive palliative care in addition to standard cancer care, while another 22 patients had only standard care.

Twenty-two patients in the palliative care group and 20 in the control group were receiving chemotherapy.

Over four months, patients in the palliative care group had at least monthly palliative care clinic visits, while those in the standard care group didn't receive any formal interventions. Caregivers could attend clinic visits for the palliative care participants, but they weren't required to do so.

Patients were typically in their early to mid 60s. Most were married and had at least some education beyond high school.

Most family caregivers were spouses, but a few were children or other relatives.

Initial perceptions of palliative care were similar in both groups - patients generally thought this was done only for the dying. While patients in both groups thought of palliative care

as providing comfort, they also associated it with giving up on treatment.

Once some patients received palliative care, however, their thinking shifted. Some patients now saw this as a way to live life to the fullest despite the terminal diagnosis, while others

suggested that doctors might have better luck renaming this as something other than "palliative care."

Calling palliative care providers "pain specialists" because they treat discomfort and focus on quality of life would make this sound more appealing and less frightening, some patients

said after getting this type of care.

But in the control group, without any experience with palliative care during the study, patients didn't see the point of renaming it because they thought it would still carry the stigma of giving up and waiting to die.

"Palliative care should not be framed as a last resort option," said Dr. Anthony Caprio, a geriatrician and hospice and palliative medicine physician at Carolinas HealthCare System in

North Carolina.

"These `nothing left to do' conversations often frame palliative care as a way to help people die comfortably, rather than an approach to care that allows them to live with the highest quality of life for as long as possible," said Caprio, who wrote an editorial that was published with the study.

Using different language in discussions with patients can make a big difference, Caprio added.

"I often describe palliative care as an extra layer of support," Caprio said. "Who wouldn't want more support, especially during a difficult illness?"

(Reuters Health) - Some cancer patients may turn down care that could ease their pain and improve their quality of life because they think this type of "palliative" treatment amounts

to giving up and simply waiting to die, a small Canadian study suggests.

Even though the World Health Organization recommends early palliative care for patients living with any serious illness, negative attitudes among patients and family caregivers often lead them to reject this option, researchers note in the Canadian Medical Association Journal.

"Patients and caregivers in our study saw palliative care as being equated with death, loss of hope, dependency, and going into places you never get out of again," said lead study author Dr. Camilla Zimmermann, head of the division of palliative care at the University Health Network in Toronto.

"This is in stark contrast with the actual definition of palliative care, which is interdisciplinary care that provides quality of life for patients with any serious illness and their families, and that is provided throughout the course of the illness rather than only at the end of life," Zimmermann added by email.

Zimmermann and colleagues interviewed 48 cancer patients and 23 of their family caregivers in cases when life expectancy was six to 24 months.

The researchers randomly assigned 26 patients to receive palliative care in addition to standard cancer care, while another 22 patients had only standard care.

Twenty-two patients in the palliative care group and 20 in the control group were receiving chemotherapy.

Over four months, patients in the palliative care group had at least monthly palliative care clinic visits, while those in the standard care group didn't receive any formal interventions. Caregivers could attend clinic visits for the palliative care participants, but they weren't required to do so.

Patients were typically in their early to mid 60s. Most were married and had at least some education beyond high school.

Most family caregivers were spouses, but a few were children or other relatives.

Initial perceptions of palliative care were similar in both groups - patients generally thought this was done only for the dying. While patients in both groups thought of palliative care

as providing comfort, they also associated it with giving up on treatment.

Once some patients received palliative care, however, their thinking shifted. Some patients now saw this as a way to live life to the fullest despite the terminal diagnosis, while others

suggested that doctors might have better luck renaming this as something other than "palliative care."

Calling palliative care providers "pain specialists" because they treat discomfort and focus on quality of life would make this sound more appealing and less frightening, some patients

said after getting this type of care.

But in the control group, without any experience with palliative care during the study, patients didn't see the point of renaming it because they thought it would still carry the stigma of giving up and waiting to die.

"Palliative care should not be framed as a last resort option," said Dr. Anthony Caprio, a geriatrician and hospice and palliative medicine physician at Carolinas HealthCare System in

North Carolina.

"These `nothing left to do' conversations often frame palliative care as a way to help people die comfortably, rather than an approach to care that allows them to live with the highest quality of life for as long as possible," said Caprio, who wrote an editorial that was published with the study.

Using different language in discussions with patients can make a big difference, Caprio added.

"I often describe palliative care as an extra layer of support," Caprio said. "Who wouldn't want more support, especially during a difficult illness?"

Total knee arthroplasty (TKA) continues to be a widely utilized treatment option for end-stage knee osteoarthritis, and the number of patients undergoing TKA is projected to continually increase over the next decade.¹ Although TKA is highly successful for many patients, studies continue to report that approximately 20% of patients are dissatisfied after undergoing TKA, and nearly 25% of knee revisions are performed for instability or malalignment.^2,3 Technological advances have been developed to help improve clinical outcomes and implant survivorship. Over the past decade, computer navigation and intraoperative guides have been introduced to help control surgical variables and overcome the limitations and inaccuracies of traditional mechanical instrumentation. Currently, there are a variety of technologies available to assist surgeons with component alignment, including extramedullary devices, computer-assisted navigation systems (CAS), and patient-specific instrumentation (PSI) that help achieve desired alignment goals.^4,5

Computer-assisted navigation tools were introduced in an effort to improve implant alignment and clinical outcomes compared to traditional mechanical guides. Some argue that the use of computer-assisted surgery has a steep learning curve and successful use is dependent on the user’s experience; however, studies have suggested computer-assisted surgery may allow less experienced surgeons to reliably achieve anticipated intraoperative alignment goals with a low complication rate.^6,7 Various studies have looked at computer-assisted TKA at short to mid-term follow-up, but few studies have reported long-term outcomes.^6-9 de Steiger and colleagues¹⁰ recently found that computer-assisted TKA reduced the overall revision rate for aseptic loosening following TKA in patients younger than age 65 years, which suggests benefit of CAS for younger patients. Short-term follow-up has also shown the benefit of CAS TKA in patients with severe extra-articular deformity, where traditional instrumentation cannot be utilized.¹¹ Currently, there is no consensus that computer-assisted TKA leads to improved postoperative patient reported outcomes, because many studies are limited by study design or small cohorts; however, current literature does show an improvement in component alignment as compared to mechanical instrumentation.^9,12,13 As future implant and position targets are defined to improve implant survivorship and clinical outcomes in total joint arthroplasty, computer-assisted devices will be useful to help achieve more precise and accurate component positioning.

In addition to CAS devices, some companies have sought to improve TKA surgery by introducing PSI. PSI was introduced to improve component alignment in TKA, with the purported advantages of a shorter surgical time, decrease in the number of instruments needed, and improved clinical outcomes. PSI accuracy remains variable, which may be attributed to the various systems and implant designs in each study.^14-17 In addition, advanced preoperative imaging is necessary, which further adds to the overall cost.¹⁷ While the recent advancement in technology may provide decreased costs at the time of surgery, the increased cost and time incurred by the patient preoperatively has not resulted in significantly better clinical outcomes.^18,19 Additionally, recent work has not shown PSI to have superior accuracy as compared to currently available CAS devices.¹⁴ These findings suggest that the additional cost and time incurred by patients may limit the widespread use of PSI.

Although computer navigation has been shown to be more accurate than conventional instrumentation and PSI, the lack of improvement in long-term clinical outcome data has limited its use. In a meta-analysis, Bauwens and colleagues²⁰ suggested that while navigated TKAs have improved component alignment outcomes as compared to conventional surgery, the clinical benefit remains unclear. Less than 5% of surgeons are currently using navigation systems due to the perceived learning curve, cost, additional surgical time, and imaging required to utilize these systems. Certain navigation systems can be seemingly cumbersome, with large consoles, increased number of instruments required, and optical instruments with line-of-sight issues. Recent technological advances have worked to decrease this challenge by using accelerometer- and gyroscope-based electronic components, which combine the accuracy of computer-assisted technology with the ease of use of mechanical guides.

Accelerometer and gyroscope technology systems, such as the iAssist system, are portable devices that do not require a large computer console or navigation arrays. This technology relies on accelerator-based navigation without additional preoperative imaging. A recent study demonstrated the iAssist had reproducible accuracy in component alignment that could be easily incorporated into the operating room without optical trackers.²¹ The use of portable computer-assisted devices provides a more compact and easily accessible technology that can be used to achieve accurate component alignment without additional large equipment in the operating room.²² These new handheld intraoperative tools have been introduced to place implants according to a preoperative plan in order to minimize failure due to preoperative extra-articular deformity or intraoperative technical miscues.²³ Nam and colleagues²⁴ used an accelerometer-based surgical navigation system to perform tibial resections in cadaveric models, and found that the accelerometer-based guide was accurate for tibial resection in both the coronal and sagittal planes. In a prospective randomized controlled trial evaluating 100 patients undergoing a TKA using either an accelerometer-based guide or conventional alignment methods, the authors showed that the accelerometer-based guide decreased outliers in tibial component alignment compared to conventional guides.²⁵ In the accelerometer-based guide cohort, 95.7% of tibial components were within 2° of perpendicular to the tibial mechanical axis, compared to 68.1% in the conventional group (P < .001). These results suggested that portable accelerometer-based navigation allows surgeons to achieve satisfactory tibial component alignment with a decrease in the number of potential outliers.^24,25 Similarly, Bugbee and colleagues²⁶ found that accelerometer-based handheld navigation was accurate for tibial coronal and sagittal alignment and no additional surgical time was required compared to conventional techniques.

The relationship between knee alignment and clinical outcomes for TKA remains controversial. Regardless of the surgeon’s alignment preference, it is important to reliably and accurately execute the preoperative plan in a reproducible fashion. Advances in technology that assist with intraoperative component alignment can be useful, and may help decrease the incidence of implant malalignment in clinical practice.

Preoperative Planning and Intraoperative Technique

Preoperative planning is carried out in a manner identical to the use of conventional mechanical guides. Long leg films are taken for evaluation of overall limb alignment, and calibrated lateral images are taken for templating implant sizes. Lines are drawn on the images to determine the difference between the mechanical and anatomic axis of the femur, and a line drawn perpendicular to the mechanical axis is placed to show the expected bone cut. In similar fashion a perpendicular line to the tibial mechanical axis is also drawn to show the expected tibial resection. This preoperative plan allows the surgeon to have an additional intraoperative guide to ensure accuracy of the computer-assisted device.

After standard exposure, the distal femoral or proximal tibial cut can be made based on surgeon preference. The system being demonstrated in the accompanying photos is the KneeAlign 2 system (OrthAlign).

Distal Femoral Cut

The KneeAlign 2 femoral cutting guide is attached to the distal femur with a central pin that is placed in the middle of the distal femur measured from medial to lateral, and 1 cm anterior to the intercondylar notch. It is important to note that this spot is often more medial than traditionally used for insertion of an intramedullary rod. This central point sets the distal point of the femoral mechanical axis. The device is then held in place with 2 oblique pins, and is solidly fixed to the bone. Using a rotating motion, the femur is rotated around the hip joint. The accelerometer and gyroscope in the unit are able to determine the center of the hip joint from this motion, creating the proximal point of the mechanical axis of the femur. Once the mechanical axis of the femur is determined, varus/valgus and flexion/extension can be adjusted on the guide. One adjustment screw is available for varus/valgus, and a second is available for flexion/extension. Numbers on the device screen show real-time alignment, and are easily adjusted to set the desired alignment (Figure 1). Once alignment is obtained, a mechanical stylus is used to determine depth of resection, and the distal femoral cutting block is pinned. After pinning the block, the 3 pins in the device are removed, and the device is removed from the bone. This leaves only the distal femoral cutting block in place. In experienced hands, this part of the procedure takes less than 3 minutes.

Proximal Tibial Cut

The KneeAlign 2 proximal tibial guide is similar in appearance to a standard mechanical tibial cutting guide. It is attached to the proximal tibia with a spring around the calf and 2 pins that hold the device aligned with the medial third of the tibial tubercle. A stylus is then centered on the anterior cruciate ligament (ACL) footprint, which sets the proximal mechanical axis point of the tibia (Figure 2). An offset number is read off the stylus on the ACL footprint, and this number is matched on the ankle offset portion of the guide. The device has 2 sensors. One sensor is on the chassis of the device, and the other is on a mobile arm. Movements between the 2 are monitored by the accelerometers, allowing for accurate maintenance of alignment position even with motion in the leg. A point is taken from the lateral malleolus and then a second point is taken from the medial malleolus. These points are used to determine the center of the ankle joint, which sets the distal mechanical axis point. Once mechanical axis of the tibia is determined, the tibial cutting guide is pinned in place, and can be adjusted with real-time guidance of the varus/valgus and posterior slope values seen on the device (Figure 3). Cut depth is once again determined with a mechanical stylus.

Limitations

Although these devices have proven to be very accurate, surgeons must continue to recognize that all tools can have errors. With computerized guides of any sort, these errors are usually user errors that cannot be detected by the device. Surgeons need to be able to recognize this and always double-check bone cuts for accuracy. Templating the bone cuts prior to surgery is an effective double-check. In addition, many handheld accelerometer devices do not currently assist with the rotational alignment of the femoral component. This is still performed using the surgeon’s preferred technique, and is a limitation of these systems.

Discussion

Currently, TKA provides satisfactory 10-year results with modern implant designs and survival rates as high as 90% to 95%.^27,28 Even with good survival rates, a percentage of patients fail within the first 5 years.³ At a single institution, 50% of revision TKAs were related to instability, malalignment, or failure of fixation that occurred less than 2 years after the index procedure.²⁹ In general, TKA with mechanical instrumentation provides satisfactory pain relief and postoperative knee function; however, studies have consistently shown that the use of advanced technology decreases the risk of implant malalignment, which may decrease early implant failure rates as compared to mechanical and some PSI.^13,14,22 While there is a paucity of literature that has shown better clinical outcomes with the use of advanced technology, there are studies supporting the notion that proper limb alignment and component positioning improves implant survivorship.^23,30

CAS may have additional advantages if the surgeon chooses to place the TKA in an alignment other than a neutral mechanical axis. Kinematic alignment for TKA has gained increasing popularity, where the target of a neutral mechanical axis alignment is not always the goal.^31,32 The reported benefit is a more natural ligament tension with the hope of improving patient satisfaction. One concern with this technique is that it is a departure from the long-held teaching that a TKA aligned to a neutral mechanical axis is necessary for long-term implant survivorship.^33,34 In addition, if the goal of surgery is to cut the tibia and femur at a specific varus/valgus cut, standard instrumentation may not allow for this level of accuracy. This in turn increases the risk of having a tibial or femoral cut that is outside the commonly accepted standards of alignment, which may lead to early implant failure. If further research suggests alignment is a variable that differs from patient to patient, the use of precise tools to ensure accuracy of executing the preoperatively templated alignment becomes even more important.

As the number of TKAs continues to rise each year, even a small percentage of malaligned knees that go on to revision surgery will create a large burden on the healthcare system.^1,3 Although the short-term clinical benefits of CAS have not shown substantial differences as compared to conventional TKA, the number of knees aligned outside of a desired neutral mechanical axis alignment has been shown in multiple studies to be decreased with the use of advanced technology.^7,12,34 Although CAS is an additional cost to a primary TKA, if the orthopedic community can decrease the number of TKA revisions due to malalignment from 6.6% to nearly zero, this may decrease the revision burden and overall cost to the healthcare system.^1,3

TKA technology continues to evolve, and we must continue to assess each new advance not only to understand how it works, but also to ensure it addresses a specific clinical problem, and to be aware of the costs associated before incorporating it into routine practice. Some argue that the use of advanced technology requires increased surgical time, which in turn ultimately increases costs; however, one study has documented no increase in surgical time with handheld navigation while maintaining the accuracy of the device.³⁴ In addition, no significant radiographic or clinical differences have been found between handheld navigation and larger console CAS systems, but large console systems have been associated with increased surgical times.²² The use of handheld accelerometer- and gyroscope-based guides has proven to provide reliable coronal and sagittal implant alignment that can easily be incorporated into the operating room. More widespread use of such technology will help decrease alignment outliers for TKA, and future long-term clinical outcome studies will be necessary to assess functional outcomes.

Conclusion

Advanced computer based technology offers an additional tool to the surgeon for reliably improving component positioning during TKA. The use of handheld accelerometer- and gyroscope-based guides increases the accuracy of component placement while decreasing the incidence of outliers compared to standard mechanical guides, without the need for a large computer console. Long-term radiographic and patient-reported outcomes are necessary to further validate these devices.

Total knee arthroplasty (TKA) continues to be a widely utilized treatment option for end-stage knee osteoarthritis, and the number of patients undergoing TKA is projected to continually increase over the next decade.¹ Although TKA is highly successful for many patients, studies continue to report that approximately 20% of patients are dissatisfied after undergoing TKA, and nearly 25% of knee revisions are performed for instability or malalignment.^2,3 Technological advances have been developed to help improve clinical outcomes and implant survivorship. Over the past decade, computer navigation and intraoperative guides have been introduced to help control surgical variables and overcome the limitations and inaccuracies of traditional mechanical instrumentation. Currently, there are a variety of technologies available to assist surgeons with component alignment, including extramedullary devices, computer-assisted navigation systems (CAS), and patient-specific instrumentation (PSI) that help achieve desired alignment goals.^4,5

Computer-assisted navigation tools were introduced in an effort to improve implant alignment and clinical outcomes compared to traditional mechanical guides. Some argue that the use of computer-assisted surgery has a steep learning curve and successful use is dependent on the user’s experience; however, studies have suggested computer-assisted surgery may allow less experienced surgeons to reliably achieve anticipated intraoperative alignment goals with a low complication rate.^6,7 Various studies have looked at computer-assisted TKA at short to mid-term follow-up, but few studies have reported long-term outcomes.^6-9 de Steiger and colleagues¹⁰ recently found that computer-assisted TKA reduced the overall revision rate for aseptic loosening following TKA in patients younger than age 65 years, which suggests benefit of CAS for younger patients. Short-term follow-up has also shown the benefit of CAS TKA in patients with severe extra-articular deformity, where traditional instrumentation cannot be utilized.¹¹ Currently, there is no consensus that computer-assisted TKA leads to improved postoperative patient reported outcomes, because many studies are limited by study design or small cohorts; however, current literature does show an improvement in component alignment as compared to mechanical instrumentation.^9,12,13 As future implant and position targets are defined to improve implant survivorship and clinical outcomes in total joint arthroplasty, computer-assisted devices will be useful to help achieve more precise and accurate component positioning.

In addition to CAS devices, some companies have sought to improve TKA surgery by introducing PSI. PSI was introduced to improve component alignment in TKA, with the purported advantages of a shorter surgical time, decrease in the number of instruments needed, and improved clinical outcomes. PSI accuracy remains variable, which may be attributed to the various systems and implant designs in each study.^14-17 In addition, advanced preoperative imaging is necessary, which further adds to the overall cost.¹⁷ While the recent advancement in technology may provide decreased costs at the time of surgery, the increased cost and time incurred by the patient preoperatively has not resulted in significantly better clinical outcomes.^18,19 Additionally, recent work has not shown PSI to have superior accuracy as compared to currently available CAS devices.¹⁴ These findings suggest that the additional cost and time incurred by patients may limit the widespread use of PSI.

Although computer navigation has been shown to be more accurate than conventional instrumentation and PSI, the lack of improvement in long-term clinical outcome data has limited its use. In a meta-analysis, Bauwens and colleagues²⁰ suggested that while navigated TKAs have improved component alignment outcomes as compared to conventional surgery, the clinical benefit remains unclear. Less than 5% of surgeons are currently using navigation systems due to the perceived learning curve, cost, additional surgical time, and imaging required to utilize these systems. Certain navigation systems can be seemingly cumbersome, with large consoles, increased number of instruments required, and optical instruments with line-of-sight issues. Recent technological advances have worked to decrease this challenge by using accelerometer- and gyroscope-based electronic components, which combine the accuracy of computer-assisted technology with the ease of use of mechanical guides.

Accelerometer and gyroscope technology systems, such as the iAssist system, are portable devices that do not require a large computer console or navigation arrays. This technology relies on accelerator-based navigation without additional preoperative imaging. A recent study demonstrated the iAssist had reproducible accuracy in component alignment that could be easily incorporated into the operating room without optical trackers.²¹ The use of portable computer-assisted devices provides a more compact and easily accessible technology that can be used to achieve accurate component alignment without additional large equipment in the operating room.²² These new handheld intraoperative tools have been introduced to place implants according to a preoperative plan in order to minimize failure due to preoperative extra-articular deformity or intraoperative technical miscues.²³ Nam and colleagues²⁴ used an accelerometer-based surgical navigation system to perform tibial resections in cadaveric models, and found that the accelerometer-based guide was accurate for tibial resection in both the coronal and sagittal planes. In a prospective randomized controlled trial evaluating 100 patients undergoing a TKA using either an accelerometer-based guide or conventional alignment methods, the authors showed that the accelerometer-based guide decreased outliers in tibial component alignment compared to conventional guides.²⁵ In the accelerometer-based guide cohort, 95.7% of tibial components were within 2° of perpendicular to the tibial mechanical axis, compared to 68.1% in the conventional group (P < .001). These results suggested that portable accelerometer-based navigation allows surgeons to achieve satisfactory tibial component alignment with a decrease in the number of potential outliers.^24,25 Similarly, Bugbee and colleagues²⁶ found that accelerometer-based handheld navigation was accurate for tibial coronal and sagittal alignment and no additional surgical time was required compared to conventional techniques.

The relationship between knee alignment and clinical outcomes for TKA remains controversial. Regardless of the surgeon’s alignment preference, it is important to reliably and accurately execute the preoperative plan in a reproducible fashion. Advances in technology that assist with intraoperative component alignment can be useful, and may help decrease the incidence of implant malalignment in clinical practice.

Preoperative Planning and Intraoperative Technique

Preoperative planning is carried out in a manner identical to the use of conventional mechanical guides. Long leg films are taken for evaluation of overall limb alignment, and calibrated lateral images are taken for templating implant sizes. Lines are drawn on the images to determine the difference between the mechanical and anatomic axis of the femur, and a line drawn perpendicular to the mechanical axis is placed to show the expected bone cut. In similar fashion a perpendicular line to the tibial mechanical axis is also drawn to show the expected tibial resection. This preoperative plan allows the surgeon to have an additional intraoperative guide to ensure accuracy of the computer-assisted device.

After standard exposure, the distal femoral or proximal tibial cut can be made based on surgeon preference. The system being demonstrated in the accompanying photos is the KneeAlign 2 system (OrthAlign).

Distal Femoral Cut

The KneeAlign 2 femoral cutting guide is attached to the distal femur with a central pin that is placed in the middle of the distal femur measured from medial to lateral, and 1 cm anterior to the intercondylar notch. It is important to note that this spot is often more medial than traditionally used for insertion of an intramedullary rod. This central point sets the distal point of the femoral mechanical axis. The device is then held in place with 2 oblique pins, and is solidly fixed to the bone. Using a rotating motion, the femur is rotated around the hip joint. The accelerometer and gyroscope in the unit are able to determine the center of the hip joint from this motion, creating the proximal point of the mechanical axis of the femur. Once the mechanical axis of the femur is determined, varus/valgus and flexion/extension can be adjusted on the guide. One adjustment screw is available for varus/valgus, and a second is available for flexion/extension. Numbers on the device screen show real-time alignment, and are easily adjusted to set the desired alignment (Figure 1). Once alignment is obtained, a mechanical stylus is used to determine depth of resection, and the distal femoral cutting block is pinned. After pinning the block, the 3 pins in the device are removed, and the device is removed from the bone. This leaves only the distal femoral cutting block in place. In experienced hands, this part of the procedure takes less than 3 minutes.

Proximal Tibial Cut

The KneeAlign 2 proximal tibial guide is similar in appearance to a standard mechanical tibial cutting guide. It is attached to the proximal tibia with a spring around the calf and 2 pins that hold the device aligned with the medial third of the tibial tubercle. A stylus is then centered on the anterior cruciate ligament (ACL) footprint, which sets the proximal mechanical axis point of the tibia (Figure 2). An offset number is read off the stylus on the ACL footprint, and this number is matched on the ankle offset portion of the guide. The device has 2 sensors. One sensor is on the chassis of the device, and the other is on a mobile arm. Movements between the 2 are monitored by the accelerometers, allowing for accurate maintenance of alignment position even with motion in the leg. A point is taken from the lateral malleolus and then a second point is taken from the medial malleolus. These points are used to determine the center of the ankle joint, which sets the distal mechanical axis point. Once mechanical axis of the tibia is determined, the tibial cutting guide is pinned in place, and can be adjusted with real-time guidance of the varus/valgus and posterior slope values seen on the device (Figure 3). Cut depth is once again determined with a mechanical stylus.

Limitations

Although these devices have proven to be very accurate, surgeons must continue to recognize that all tools can have errors. With computerized guides of any sort, these errors are usually user errors that cannot be detected by the device. Surgeons need to be able to recognize this and always double-check bone cuts for accuracy. Templating the bone cuts prior to surgery is an effective double-check. In addition, many handheld accelerometer devices do not currently assist with the rotational alignment of the femoral component. This is still performed using the surgeon’s preferred technique, and is a limitation of these systems.

Discussion

Currently, TKA provides satisfactory 10-year results with modern implant designs and survival rates as high as 90% to 95%.^27,28 Even with good survival rates, a percentage of patients fail within the first 5 years.³ At a single institution, 50% of revision TKAs were related to instability, malalignment, or failure of fixation that occurred less than 2 years after the index procedure.²⁹ In general, TKA with mechanical instrumentation provides satisfactory pain relief and postoperative knee function; however, studies have consistently shown that the use of advanced technology decreases the risk of implant malalignment, which may decrease early implant failure rates as compared to mechanical and some PSI.^13,14,22 While there is a paucity of literature that has shown better clinical outcomes with the use of advanced technology, there are studies supporting the notion that proper limb alignment and component positioning improves implant survivorship.^23,30

CAS may have additional advantages if the surgeon chooses to place the TKA in an alignment other than a neutral mechanical axis. Kinematic alignment for TKA has gained increasing popularity, where the target of a neutral mechanical axis alignment is not always the goal.^31,32 The reported benefit is a more natural ligament tension with the hope of improving patient satisfaction. One concern with this technique is that it is a departure from the long-held teaching that a TKA aligned to a neutral mechanical axis is necessary for long-term implant survivorship.^33,34 In addition, if the goal of surgery is to cut the tibia and femur at a specific varus/valgus cut, standard instrumentation may not allow for this level of accuracy. This in turn increases the risk of having a tibial or femoral cut that is outside the commonly accepted standards of alignment, which may lead to early implant failure. If further research suggests alignment is a variable that differs from patient to patient, the use of precise tools to ensure accuracy of executing the preoperatively templated alignment becomes even more important.

As the number of TKAs continues to rise each year, even a small percentage of malaligned knees that go on to revision surgery will create a large burden on the healthcare system.^1,3 Although the short-term clinical benefits of CAS have not shown substantial differences as compared to conventional TKA, the number of knees aligned outside of a desired neutral mechanical axis alignment has been shown in multiple studies to be decreased with the use of advanced technology.^7,12,34 Although CAS is an additional cost to a primary TKA, if the orthopedic community can decrease the number of TKA revisions due to malalignment from 6.6% to nearly zero, this may decrease the revision burden and overall cost to the healthcare system.^1,3

TKA technology continues to evolve, and we must continue to assess each new advance not only to understand how it works, but also to ensure it addresses a specific clinical problem, and to be aware of the costs associated before incorporating it into routine practice. Some argue that the use of advanced technology requires increased surgical time, which in turn ultimately increases costs; however, one study has documented no increase in surgical time with handheld navigation while maintaining the accuracy of the device.³⁴ In addition, no significant radiographic or clinical differences have been found between handheld navigation and larger console CAS systems, but large console systems have been associated with increased surgical times.²² The use of handheld accelerometer- and gyroscope-based guides has proven to provide reliable coronal and sagittal implant alignment that can easily be incorporated into the operating room. More widespread use of such technology will help decrease alignment outliers for TKA, and future long-term clinical outcome studies will be necessary to assess functional outcomes.

Conclusion

Advanced computer based technology offers an additional tool to the surgeon for reliably improving component positioning during TKA. The use of handheld accelerometer- and gyroscope-based guides increases the accuracy of component placement while decreasing the incidence of outliers compared to standard mechanical guides, without the need for a large computer console. Long-term radiographic and patient-reported outcomes are necessary to further validate these devices.

Total knee arthroplasty (TKA) continues to be a widely utilized treatment option for end-stage knee osteoarthritis, and the number of patients undergoing TKA is projected to continually increase over the next decade.¹ Although TKA is highly successful for many patients, studies continue to report that approximately 20% of patients are dissatisfied after undergoing TKA, and nearly 25% of knee revisions are performed for instability or malalignment.^2,3 Technological advances have been developed to help improve clinical outcomes and implant survivorship. Over the past decade, computer navigation and intraoperative guides have been introduced to help control surgical variables and overcome the limitations and inaccuracies of traditional mechanical instrumentation. Currently, there are a variety of technologies available to assist surgeons with component alignment, including extramedullary devices, computer-assisted navigation systems (CAS), and patient-specific instrumentation (PSI) that help achieve desired alignment goals.^4,5

Computer-assisted navigation tools were introduced in an effort to improve implant alignment and clinical outcomes compared to traditional mechanical guides. Some argue that the use of computer-assisted surgery has a steep learning curve and successful use is dependent on the user’s experience; however, studies have suggested computer-assisted surgery may allow less experienced surgeons to reliably achieve anticipated intraoperative alignment goals with a low complication rate.^6,7 Various studies have looked at computer-assisted TKA at short to mid-term follow-up, but few studies have reported long-term outcomes.^6-9 de Steiger and colleagues¹⁰ recently found that computer-assisted TKA reduced the overall revision rate for aseptic loosening following TKA in patients younger than age 65 years, which suggests benefit of CAS for younger patients. Short-term follow-up has also shown the benefit of CAS TKA in patients with severe extra-articular deformity, where traditional instrumentation cannot be utilized.¹¹ Currently, there is no consensus that computer-assisted TKA leads to improved postoperative patient reported outcomes, because many studies are limited by study design or small cohorts; however, current literature does show an improvement in component alignment as compared to mechanical instrumentation.^9,12,13 As future implant and position targets are defined to improve implant survivorship and clinical outcomes in total joint arthroplasty, computer-assisted devices will be useful to help achieve more precise and accurate component positioning.

In addition to CAS devices, some companies have sought to improve TKA surgery by introducing PSI. PSI was introduced to improve component alignment in TKA, with the purported advantages of a shorter surgical time, decrease in the number of instruments needed, and improved clinical outcomes. PSI accuracy remains variable, which may be attributed to the various systems and implant designs in each study.^14-17 In addition, advanced preoperative imaging is necessary, which further adds to the overall cost.¹⁷ While the recent advancement in technology may provide decreased costs at the time of surgery, the increased cost and time incurred by the patient preoperatively has not resulted in significantly better clinical outcomes.^18,19 Additionally, recent work has not shown PSI to have superior accuracy as compared to currently available CAS devices.¹⁴ These findings suggest that the additional cost and time incurred by patients may limit the widespread use of PSI.

Although computer navigation has been shown to be more accurate than conventional instrumentation and PSI, the lack of improvement in long-term clinical outcome data has limited its use. In a meta-analysis, Bauwens and colleagues²⁰ suggested that while navigated TKAs have improved component alignment outcomes as compared to conventional surgery, the clinical benefit remains unclear. Less than 5% of surgeons are currently using navigation systems due to the perceived learning curve, cost, additional surgical time, and imaging required to utilize these systems. Certain navigation systems can be seemingly cumbersome, with large consoles, increased number of instruments required, and optical instruments with line-of-sight issues. Recent technological advances have worked to decrease this challenge by using accelerometer- and gyroscope-based electronic components, which combine the accuracy of computer-assisted technology with the ease of use of mechanical guides.

Accelerometer and gyroscope technology systems, such as the iAssist system, are portable devices that do not require a large computer console or navigation arrays. This technology relies on accelerator-based navigation without additional preoperative imaging. A recent study demonstrated the iAssist had reproducible accuracy in component alignment that could be easily incorporated into the operating room without optical trackers.²¹ The use of portable computer-assisted devices provides a more compact and easily accessible technology that can be used to achieve accurate component alignment without additional large equipment in the operating room.²² These new handheld intraoperative tools have been introduced to place implants according to a preoperative plan in order to minimize failure due to preoperative extra-articular deformity or intraoperative technical miscues.²³ Nam and colleagues²⁴ used an accelerometer-based surgical navigation system to perform tibial resections in cadaveric models, and found that the accelerometer-based guide was accurate for tibial resection in both the coronal and sagittal planes. In a prospective randomized controlled trial evaluating 100 patients undergoing a TKA using either an accelerometer-based guide or conventional alignment methods, the authors showed that the accelerometer-based guide decreased outliers in tibial component alignment compared to conventional guides.²⁵ In the accelerometer-based guide cohort, 95.7% of tibial components were within 2° of perpendicular to the tibial mechanical axis, compared to 68.1% in the conventional group (P < .001). These results suggested that portable accelerometer-based navigation allows surgeons to achieve satisfactory tibial component alignment with a decrease in the number of potential outliers.^24,25 Similarly, Bugbee and colleagues²⁶ found that accelerometer-based handheld navigation was accurate for tibial coronal and sagittal alignment and no additional surgical time was required compared to conventional techniques.

The relationship between knee alignment and clinical outcomes for TKA remains controversial. Regardless of the surgeon’s alignment preference, it is important to reliably and accurately execute the preoperative plan in a reproducible fashion. Advances in technology that assist with intraoperative component alignment can be useful, and may help decrease the incidence of implant malalignment in clinical practice.

Preoperative Planning and Intraoperative Technique

Preoperative planning is carried out in a manner identical to the use of conventional mechanical guides. Long leg films are taken for evaluation of overall limb alignment, and calibrated lateral images are taken for templating implant sizes. Lines are drawn on the images to determine the difference between the mechanical and anatomic axis of the femur, and a line drawn perpendicular to the mechanical axis is placed to show the expected bone cut. In similar fashion a perpendicular line to the tibial mechanical axis is also drawn to show the expected tibial resection. This preoperative plan allows the surgeon to have an additional intraoperative guide to ensure accuracy of the computer-assisted device.

After standard exposure, the distal femoral or proximal tibial cut can be made based on surgeon preference. The system being demonstrated in the accompanying photos is the KneeAlign 2 system (OrthAlign).

Distal Femoral Cut

The KneeAlign 2 femoral cutting guide is attached to the distal femur with a central pin that is placed in the middle of the distal femur measured from medial to lateral, and 1 cm anterior to the intercondylar notch. It is important to note that this spot is often more medial than traditionally used for insertion of an intramedullary rod. This central point sets the distal point of the femoral mechanical axis. The device is then held in place with 2 oblique pins, and is solidly fixed to the bone. Using a rotating motion, the femur is rotated around the hip joint. The accelerometer and gyroscope in the unit are able to determine the center of the hip joint from this motion, creating the proximal point of the mechanical axis of the femur. Once the mechanical axis of the femur is determined, varus/valgus and flexion/extension can be adjusted on the guide. One adjustment screw is available for varus/valgus, and a second is available for flexion/extension. Numbers on the device screen show real-time alignment, and are easily adjusted to set the desired alignment (Figure 1). Once alignment is obtained, a mechanical stylus is used to determine depth of resection, and the distal femoral cutting block is pinned. After pinning the block, the 3 pins in the device are removed, and the device is removed from the bone. This leaves only the distal femoral cutting block in place. In experienced hands, this part of the procedure takes less than 3 minutes.

Proximal Tibial Cut

The KneeAlign 2 proximal tibial guide is similar in appearance to a standard mechanical tibial cutting guide. It is attached to the proximal tibia with a spring around the calf and 2 pins that hold the device aligned with the medial third of the tibial tubercle. A stylus is then centered on the anterior cruciate ligament (ACL) footprint, which sets the proximal mechanical axis point of the tibia (Figure 2). An offset number is read off the stylus on the ACL footprint, and this number is matched on the ankle offset portion of the guide. The device has 2 sensors. One sensor is on the chassis of the device, and the other is on a mobile arm. Movements between the 2 are monitored by the accelerometers, allowing for accurate maintenance of alignment position even with motion in the leg. A point is taken from the lateral malleolus and then a second point is taken from the medial malleolus. These points are used to determine the center of the ankle joint, which sets the distal mechanical axis point. Once mechanical axis of the tibia is determined, the tibial cutting guide is pinned in place, and can be adjusted with real-time guidance of the varus/valgus and posterior slope values seen on the device (Figure 3). Cut depth is once again determined with a mechanical stylus.

Limitations

Although these devices have proven to be very accurate, surgeons must continue to recognize that all tools can have errors. With computerized guides of any sort, these errors are usually user errors that cannot be detected by the device. Surgeons need to be able to recognize this and always double-check bone cuts for accuracy. Templating the bone cuts prior to surgery is an effective double-check. In addition, many handheld accelerometer devices do not currently assist with the rotational alignment of the femoral component. This is still performed using the surgeon’s preferred technique, and is a limitation of these systems.

Discussion

Currently, TKA provides satisfactory 10-year results with modern implant designs and survival rates as high as 90% to 95%.^27,28 Even with good survival rates, a percentage of patients fail within the first 5 years.³ At a single institution, 50% of revision TKAs were related to instability, malalignment, or failure of fixation that occurred less than 2 years after the index procedure.²⁹ In general, TKA with mechanical instrumentation provides satisfactory pain relief and postoperative knee function; however, studies have consistently shown that the use of advanced technology decreases the risk of implant malalignment, which may decrease early implant failure rates as compared to mechanical and some PSI.^13,14,22 While there is a paucity of literature that has shown better clinical outcomes with the use of advanced technology, there are studies supporting the notion that proper limb alignment and component positioning improves implant survivorship.^23,30

CAS may have additional advantages if the surgeon chooses to place the TKA in an alignment other than a neutral mechanical axis. Kinematic alignment for TKA has gained increasing popularity, where the target of a neutral mechanical axis alignment is not always the goal.^31,32 The reported benefit is a more natural ligament tension with the hope of improving patient satisfaction. One concern with this technique is that it is a departure from the long-held teaching that a TKA aligned to a neutral mechanical axis is necessary for long-term implant survivorship.^33,34 In addition, if the goal of surgery is to cut the tibia and femur at a specific varus/valgus cut, standard instrumentation may not allow for this level of accuracy. This in turn increases the risk of having a tibial or femoral cut that is outside the commonly accepted standards of alignment, which may lead to early implant failure. If further research suggests alignment is a variable that differs from patient to patient, the use of precise tools to ensure accuracy of executing the preoperatively templated alignment becomes even more important.

As the number of TKAs continues to rise each year, even a small percentage of malaligned knees that go on to revision surgery will create a large burden on the healthcare system.^1,3 Although the short-term clinical benefits of CAS have not shown substantial differences as compared to conventional TKA, the number of knees aligned outside of a desired neutral mechanical axis alignment has been shown in multiple studies to be decreased with the use of advanced technology.^7,12,34 Although CAS is an additional cost to a primary TKA, if the orthopedic community can decrease the number of TKA revisions due to malalignment from 6.6% to nearly zero, this may decrease the revision burden and overall cost to the healthcare system.^1,3

TKA technology continues to evolve, and we must continue to assess each new advance not only to understand how it works, but also to ensure it addresses a specific clinical problem, and to be aware of the costs associated before incorporating it into routine practice. Some argue that the use of advanced technology requires increased surgical time, which in turn ultimately increases costs; however, one study has documented no increase in surgical time with handheld navigation while maintaining the accuracy of the device.³⁴ In addition, no significant radiographic or clinical differences have been found between handheld navigation and larger console CAS systems, but large console systems have been associated with increased surgical times.²² The use of handheld accelerometer- and gyroscope-based guides has proven to provide reliable coronal and sagittal implant alignment that can easily be incorporated into the operating room. More widespread use of such technology will help decrease alignment outliers for TKA, and future long-term clinical outcome studies will be necessary to assess functional outcomes.

Conclusion

Advanced computer based technology offers an additional tool to the surgeon for reliably improving component positioning during TKA. The use of handheld accelerometer- and gyroscope-based guides increases the accuracy of component placement while decreasing the incidence of outliers compared to standard mechanical guides, without the need for a large computer console. Long-term radiographic and patient-reported outcomes are necessary to further validate these devices.