PORTLAND, ORE. – Combining transcranial direct current stimulation and cognitive training resulted in an improvement in a greater number of cognitive outcomes than either intervention alone in a small, randomized, controlled trial of patients with Parkinson’s disease and mild cognitive impairment.

Researchers at Curtin University in Perth, Western Australia, conducted the trial comparing the effects of standard (not individualized) cognitive training (SCT), tailored (individualized) cognitive training (TCT), transcranial direct current stimulation (tDCS), and a combination of tDCS with either form of cognitive training on cognitive outcomes, activities of daily living, and quality of life in such Parkinson’s patients with mild cognitive impairment. Previously, it was not known whether either form of cognitive training or tDCS or a combination of the two would be most efficacious in improving cognition in such patients.

PORTLAND, ORE. – Combining transcranial direct current stimulation and cognitive training resulted in an improvement in a greater number of cognitive outcomes than either intervention alone in a small, randomized, controlled trial of patients with Parkinson’s disease and mild cognitive impairment.

Researchers at Curtin University in Perth, Western Australia, conducted the trial comparing the effects of standard (not individualized) cognitive training (SCT), tailored (individualized) cognitive training (TCT), transcranial direct current stimulation (tDCS), and a combination of tDCS with either form of cognitive training on cognitive outcomes, activities of daily living, and quality of life in such Parkinson’s patients with mild cognitive impairment. Previously, it was not known whether either form of cognitive training or tDCS or a combination of the two would be most efficacious in improving cognition in such patients.

PORTLAND, ORE. – Combining transcranial direct current stimulation and cognitive training resulted in an improvement in a greater number of cognitive outcomes than either intervention alone in a small, randomized, controlled trial of patients with Parkinson’s disease and mild cognitive impairment.

Researchers at Curtin University in Perth, Western Australia, conducted the trial comparing the effects of standard (not individualized) cognitive training (SCT), tailored (individualized) cognitive training (TCT), transcranial direct current stimulation (tDCS), and a combination of tDCS with either form of cognitive training on cognitive outcomes, activities of daily living, and quality of life in such Parkinson’s patients with mild cognitive impairment. Previously, it was not known whether either form of cognitive training or tDCS or a combination of the two would be most efficacious in improving cognition in such patients.

An increasingly number of patients with symptomatic isolated medial unicompartmental knee osteoarthritis (OA) are too young and too functionally active to be ideal candidates for total knee arthroplasty (TKA). Isolated medial compartment OA occurs in 10% to 29.5% of all cases, whereas the isolated lateral variant is less common, with a reported incidence of 1% to 7%.^1,2 In 1961, Jackson and Waugh³ introduced the high tibial osteotomy (HTO) as a surgical treatment for single-compartment OA. This procedure is designed to increase the life span of articular cartilage by unloading and redistributing the mechanical forces over the nonaffected compartment. Unicompartmental knee arthroplasty (UKA) was introduced in the 1970s as an alternative to TKA or HTO for single-compartment OA.

Since the introduction of these methods, there has been debate about which patients are appropriate candidates for each procedure. Improved surgical techniques and implant designs have led surgeons to reexamine the selection criteria and contraindications for these procedures. Furthermore, given the increasing popularity and use of UKA, the question arises as to whether HTO still has a role in clinical practice in the surgical treatment of medial OA of the knee.

To clarify current ambiguities, we review the modern indications, subjective outcome scores, and survivorship results of UKA and HTO in the treatment of isolated medial compartment degeneration of the knee. In addition, in a thorough review of the literature, we evaluate global trends in the use of both methods.

High Tibial Osteotomy for Medial Compartment OA

Indications

Before the introduction of TKA and UKA for single-compartment OA, surgical management consisted of HTO. When the mechanical axis is slightly overcorrected, the medial compartment is decompressed, ensuring tissue viability and delaying progressive compartment degeneration.

Traditionally, HTO is indicated for young (age <60 years), normal-weight, active patients with radiographic single-compartment OA.⁶ The knee should be stable and have good range of motion (ROM; flexion >120°), and pain should be localized to the tibiofemoral joint line.

Over the past few decades, numerous authors have reported similar inclusion criteria, clarifying their definition. This definition should be further refined in order to optimize survivorship and clinical outcomes.

Confirming age as an inclusion criterion for HTO, Trieb and colleagues⁷ found that the risk of failure was significantly (P = .046) higher for HTO patients older than 65 years than for those younger than 65 years (relative risk, 1.5). This finding agrees with findings of other studies, which suggests that, in particular, young patients benefit from HTO.^8-11

Moreover, there is a clear relation between HTO survival and obesity. In a study of 159 CWHTOs, Akizuki and colleagues¹² reported that preoperative body mass index (BMI) higher than 27.5 kg/m² was a significant risk factor for early failure. Using BMI higher than 30 kg/m² as a threshold, Howells and colleagues⁹ found significantly inferior Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) results for the obese group 5 years after HTO.

Radiographic evidence of severe preoperative compartment degeneration has been associated with early conversion to TKA. Flecher and colleagues¹¹ and van Raaij and colleagues¹³ both concluded the best long-term survival grades are achieved in HTO patients with mild compartment OA (Ahlbäck^14 grade I). The question then becomes whether these patients should be treated nonoperatively instead.^15,16The literature supports strict adherence to inclusion criteria in the selection of a potential HTO candidate. Age, BMI, and the preoperative state of OA should be taken into account in order to optimize clinical outcome and survivorship results in patients about to undergo HTO.

Outcomes

Multiple authors have described or compared the midterm or long-term results of the various surgical HTO techniques. Howells and colleagues⁹ noted overall survival rates of 87% (5 years after CWHTO) and 79% (10 years after CWHTO). Over the 10-year postoperative period, there was significant deterioration in clinical outcome scores and survivorship. Others authors have had similar findings.^17-19 van Raaij and colleagues¹³ found that the 10-year probability of survival after CWHTO was 75%. In 455 patients who underwent lateral CWHTO, Hui and colleagues⁸ found that 5-year probability of survival was 95%, 10-year probability was 79%, and 15-year probability was 56%. Niinimäki and colleagues¹⁰ used the Finnish Arthroplasty Register to report HTO survivorship at a national level. Using conversion to TKA as a cutoff, they noted 5-year survivorship of 89% and 10-year survivorship of 73%. To our knowledge, 2 groups, both in Japan, have reported substantially higher 15-year survival rates: 90%¹² and 93%.²⁰ The authors acknowledged that their results were significantly better than in other countries and that Japanese lifestyle, culture, and body habitus therefore require further investigation. At this time, it is not possible to compare their results with Western results.

In an attempt to compare the different survival rates of the various HTO techniques, Schallberger and colleagues²¹ conducted a retrospective study of OWHTOs and CWHTOs. At median follow-up of 16.5 years, comparative survival rates showed a trend of deterioration. Although data were limited, there were no significant differences in survival or functional outcome between the 2 techniques. In a recent randomized clinical trial, Duivenvoorden and colleagues⁵ compared these techniques’ midterm results (mean follow-up, 6 years). Clinical outcomes were not significantly different. There were more complications in the OWHTO group and more conversions to TKA in the CWHTO group. Considering these results, the authors suggested OWHTO without autologous bone graft is the best HTO treatment strategy for medial gonarthritis with varus malalignment of <12°.

The HTO results noted in these studies show a similar deteriorating trend; expected 10-year survivorship is 75%. Although modern implants and surgical techniques are being used, evidence supporting use of one surgical HTO method over another is lacking.

UKA for Medial Compartment OA

Indications

Since it was first introduced in the 1970s, use of UKA for single-compartment OA has been a subject of debate. The high failure rates reported at the time raised skepticism about the new treatment.²² Kozinn and Scott²³ defined classic indications and contraindications. Indications included isolated medial or lateral compartment OA or osteonecrosis of the knee, age over 60 years, and weight under 82 kg. In addition, the angular deformity of the affected lower extremity had to be <15° and passively correctable to neutral at time of surgery. Last, the flexion contracture had to be <5°, and ideal ROM was 90°. Contraindications included high activity, age under 60 years, and inflammatory arthritis. Strict adherence led to improved implant survival and lower revision rates. Because of improved surgical techniques, modern implant designs, and accumulating experience with the procedure, the surgical indications for UKA have expanded. Exact thresholds for UKA inclusion, however, remain unclear.

The modern literature is overturning the traditional idea that UKA is not indicated for patients under age 60 years.²³ Using KSS, Thompson and colleagues²⁴ found that younger patients did better than older patients 2 years after UKA using various types of implants. Analyzing survivorship results, Heyse and colleagues²⁵ concluded that UKA can be successful in patients under age 60 years and reported a 15-year survivorship rate of 85.6% and excellent outcome scores. Other authors have had similar findings.^26-28

Evaluating the influence of weight, Thompson and colleagues²⁴ found obese patients did not have a higher revision rate but did have slower progression of improvement 2 years after UKA. Cavaignac and colleagues²⁹ concluded that, at minimum follow-up of 7 years (range, 7-22 years), weight did not influence UKA survivorship. Other authors^30-33 have found no significant influence of BMI on survival.

Reports on preoperative radiographic parameters that can potentially influence UKA results are limited. In 113 medial UKAs studied by Niinimäki and colleagues,³⁴ mild medial compartment degeneration, seen on preoperative radiographs, was associated with significantly higher failure rates. The authors concluded that other treatment options should be favored in the absence of severe isolated compartment OA.

Although the classic indications defined by Kozinn and Scott²³ have yielded good to excellent UKA results, improvements in implants and surgical techniques^35-38 have extended the criteria. The modern literature demonstrates that age and BMI should not be used as criteria for excluding UKA candidates. Radiographically, there should be significant isolated compartment degeneration in order to optimize patient-reported outcome and survivorship.

Outcomes

Improved implant designs and modern minimally invasive techniques have effected a change in outcome results and a renewed interest in implants. Over the past decade, multiple authors have described the various modern UKA implants and their survivorship. Reports published since UKA was introduced in the 1970s show a continual increase in implant survival. Koskinen and colleagues,³⁹ using Finnish Arthroplasty Register data on 1819 UKAs performed between 1985 and 2003, found 10-year survival rates of 81% for Oxford implants (Zimmer Biomet), 79% for Miller-Galante II (Zimmer Biomet), 78% for Duracon (Howmedica), and 53% for PCA unicompartmental knee (Howmedica). Heyse and colleagues²⁵ reported 10- and 15-year survivorship data (93.5% and 86.3%, respectively) for 223 patients under age 60 years at the time of their index surgery (Genesis Unicondylar implant, Smith & Nephew), performed between 1993 and 2005. KSS was good to excellent. Similar numbers in cohorts under age 60 years were reported by Schai and colleagues²⁶ using the PFC system (Johnson & Johnson) and by Price and colleagues²⁷ using the medial Oxford UKA. Both groups reported excellent survivorship rates: 93% at 2- to 6-year follow-up and 91% at 10-year follow-up. The outcome in older patients seems satisfactory as well. In another multicenter report, by Price and colleagues,⁴⁰ medial Oxford UKAs had a 15-year survival rate of 93%. Berger and colleagues⁴¹ reported similar numbers for the Miller-Galante prosthesis. Survival rates were 98% (10 years) and 95.7% (13 years), and 92% of patients had good to excellent Hospital for Special Surgery knee scores.

Although various modern implants have had good to excellent results, the historical question of what type of UKA to use (mobile or fixed-bearing) remains unanswered. To try to address it, Peersman and colleagues⁴² performed a systematic review of 44 papers (9463 knees). The 2 implant types had comparable revision rates. Another recent retrospective study tried to determine what is crucial for implant survival: implant design or surgeon experience.⁴³ The authors concluded that prosthetic component positioning is key. Other authors have reported high-volume centers are crucial for satisfactory UKA results and lower revision rates.^44-46

Results of these studies indicate that, where UKAs are being performed in volume, 10-year survivorship rates higher than 90% and good to excellent outcomes can be expected.

UKA vs HTO

Cohort studies that have directly compared the 2 treatment modalities are scarce, and most have been retrospective. In a prospective study, Stukenborg-Colsman and colleagues⁴⁷ randomized patients with medial compartment OA to undergo either CWHTO (32 patients) with a technique reported by Coventry⁴⁸ or UKA (28 patients) with the unicondylar knee sliding prosthesis, Tübingen pattern (Aesculap), between 1988 and 1991. Patients were assessed 2.5, 4.5, and 7.5 years after surgery. More postoperative complications were noted in the HTO group. At 7- to 10-year follow-up, 71% of the HTO group and 65% of the UKA group had excellent KSS. Mean ROM was 103° after UKA (range, 35°-140°) and 117° after HTO (range, 85°-135°) during the same assessment. Although differences were not significant, Kaplan-Meier survival analysis was 60% for HTO and 77% for UKA at 10 years. Results were not promising for the implants used, compared with other implants, but the authors concluded that, because of improvements in implant designs and image-guided techniques, better long-term success can be expected with UKA than with HTO.

In another prospective study, Börjesson and colleagues⁴⁹ evaluated pain during walking, ROM, British Orthopaedic Association (BOA) scores, and gait variables at 1- and 5-year follow-up. Patients with moderate medial OA (Ahlbäck¹⁴ grade I-III) were randomly selected to undergo CWHTO or UKA (Brigham, DePuy). There were no significant differences in BOA scores, ROM, or pain during walking between the 2 groups at 3 months, 1 year, and 5 years after surgery. Gait analysis showed a significant difference in favor of UKA only at 3 months after surgery. At 1- and 5-year follow-up, no significant differences were noted.

To clarify current ambiguities, Fu and colleagues⁵⁰ performed a systematic review of all (11) comparative studies. These studies had a total of 5840 (5081 UKA, 759 HTO) patients. Although ROM was significantly better for the HTO group than the UKA group, the UKA group had significantly better functional results. Walking after surgery was significantly faster for the UKA group. The authors suggested the difference might be attributed to the different postoperative regimens—HTO patients wore a whole-leg plaster cast for 6 weeks, and UKA patients were allowed immediate postoperative weight-bearing. Regarding rates of survival and complications, pooled data showed no significant differences. Despite these results, the authors acknowledged the limitation of available randomized clinical trials and the multiple techniques and implants used. We share their assertion that larger prospective controlled trials are needed. These are crucial to getting a definitive answer regarding which of the 2 treatment strategies should be used for isolated compartment OA.

Current Trends in Use of UKA and HTO

Evaluation of national registries and recent reports showed a global shift in use of both HTO and UKA. Despite the lack of national HTO registries, a few reports have described use of TKA, UKA, and HTO in Western populations over the past 2 decades. Using 1998-2007 data from the Swedish Knee Arthroplasty Register, W-Dahl and colleagues⁵¹ found a 3-fold increase in UKA use, whereas HTO use was halved over the same period. Niinimäki and colleagues⁵² reported similar findings with the Finnish National Hospital Discharge Register. They noted a steady 6.8% annual decrease in osteotomies, whereas UKA use increased sharply after the Oxford UKA was introduced (Phase 3; Biomet). These findings are consistent with several reports from North America. In their epidemiologic analysis covering the period 1985-1990, Wright and colleagues⁵³ found an 11% to 14% annual decrease in osteotomies among the elderly, compared with an annual decrease of only 3% to 4% among patients younger than 65 years. Nwachukwu and colleagues⁵⁴ recently compared UKA and HTO practice patterns between 2007 and 2011, using data from a large US private payer insurance database. They noted an annual growth rate of 4.7% in UKA use, compared with an annual 3.9% decrease in HTO use. Furthermore, based on their subgroup analysis, they speculated there was a demographic shift toward UKA, as opposed to TKA, particularly in older women. Bolognesi and colleagues⁵⁵ investigated further. Evaluating all Medicare beneficiaries who underwent knee arthroplasty in the United States between 2000 and 2009, they noted a 1.7-fold increase in TKA use and a 6.2-fold increase in UKA use. As there were no substantial changes in patient characteristics over that period, the authors hypothesized that a possible broadening of inclusion criteria may have led to the increased use of UKA.

There is a possible multifactorial explanation for the current global shift in favor of UKA. First, UKA was once a technically demanding procedure, but improved surgical techniques, image guidance, and robot assistance⁵⁶ have made it relatively less difficult. Second, UKA surgery is associated with lower reported perioperative morbidities.⁵⁷ We think these factors have contributed to the global trend of less HTO use and more UKA use in the treatment of unicompartmental OA.

Conclusion

The modern literature suggests the inclusion criteria for HTO have been well investigated and defined; the UKA criteria remain a matter of debate but seem to be expanding. Long-term survival results seem to favor UKA, though patient satisfaction with both procedures is good to excellent. The broadening range of inclusion criteria and consistent reports of durable outcomes, coupled with excellent patient satisfaction, likely explain the shift toward UKA in the treatment of isolated compartment degeneration.

Am J Orthop. 2016;45(6):E355-E361. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

An increasingly number of patients with symptomatic isolated medial unicompartmental knee osteoarthritis (OA) are too young and too functionally active to be ideal candidates for total knee arthroplasty (TKA). Isolated medial compartment OA occurs in 10% to 29.5% of all cases, whereas the isolated lateral variant is less common, with a reported incidence of 1% to 7%.^1,2 In 1961, Jackson and Waugh³ introduced the high tibial osteotomy (HTO) as a surgical treatment for single-compartment OA. This procedure is designed to increase the life span of articular cartilage by unloading and redistributing the mechanical forces over the nonaffected compartment. Unicompartmental knee arthroplasty (UKA) was introduced in the 1970s as an alternative to TKA or HTO for single-compartment OA.

Since the introduction of these methods, there has been debate about which patients are appropriate candidates for each procedure. Improved surgical techniques and implant designs have led surgeons to reexamine the selection criteria and contraindications for these procedures. Furthermore, given the increasing popularity and use of UKA, the question arises as to whether HTO still has a role in clinical practice in the surgical treatment of medial OA of the knee.

To clarify current ambiguities, we review the modern indications, subjective outcome scores, and survivorship results of UKA and HTO in the treatment of isolated medial compartment degeneration of the knee. In addition, in a thorough review of the literature, we evaluate global trends in the use of both methods.

High Tibial Osteotomy for Medial Compartment OA

Indications

Before the introduction of TKA and UKA for single-compartment OA, surgical management consisted of HTO. When the mechanical axis is slightly overcorrected, the medial compartment is decompressed, ensuring tissue viability and delaying progressive compartment degeneration.

Traditionally, HTO is indicated for young (age <60 years), normal-weight, active patients with radiographic single-compartment OA.⁶ The knee should be stable and have good range of motion (ROM; flexion >120°), and pain should be localized to the tibiofemoral joint line.

Over the past few decades, numerous authors have reported similar inclusion criteria, clarifying their definition. This definition should be further refined in order to optimize survivorship and clinical outcomes.

Confirming age as an inclusion criterion for HTO, Trieb and colleagues⁷ found that the risk of failure was significantly (P = .046) higher for HTO patients older than 65 years than for those younger than 65 years (relative risk, 1.5). This finding agrees with findings of other studies, which suggests that, in particular, young patients benefit from HTO.^8-11

Moreover, there is a clear relation between HTO survival and obesity. In a study of 159 CWHTOs, Akizuki and colleagues¹² reported that preoperative body mass index (BMI) higher than 27.5 kg/m² was a significant risk factor for early failure. Using BMI higher than 30 kg/m² as a threshold, Howells and colleagues⁹ found significantly inferior Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) results for the obese group 5 years after HTO.

Radiographic evidence of severe preoperative compartment degeneration has been associated with early conversion to TKA. Flecher and colleagues¹¹ and van Raaij and colleagues¹³ both concluded the best long-term survival grades are achieved in HTO patients with mild compartment OA (Ahlbäck^14 grade I). The question then becomes whether these patients should be treated nonoperatively instead.^15,16The literature supports strict adherence to inclusion criteria in the selection of a potential HTO candidate. Age, BMI, and the preoperative state of OA should be taken into account in order to optimize clinical outcome and survivorship results in patients about to undergo HTO.

Outcomes

Multiple authors have described or compared the midterm or long-term results of the various surgical HTO techniques. Howells and colleagues⁹ noted overall survival rates of 87% (5 years after CWHTO) and 79% (10 years after CWHTO). Over the 10-year postoperative period, there was significant deterioration in clinical outcome scores and survivorship. Others authors have had similar findings.^17-19 van Raaij and colleagues¹³ found that the 10-year probability of survival after CWHTO was 75%. In 455 patients who underwent lateral CWHTO, Hui and colleagues⁸ found that 5-year probability of survival was 95%, 10-year probability was 79%, and 15-year probability was 56%. Niinimäki and colleagues¹⁰ used the Finnish Arthroplasty Register to report HTO survivorship at a national level. Using conversion to TKA as a cutoff, they noted 5-year survivorship of 89% and 10-year survivorship of 73%. To our knowledge, 2 groups, both in Japan, have reported substantially higher 15-year survival rates: 90%¹² and 93%.²⁰ The authors acknowledged that their results were significantly better than in other countries and that Japanese lifestyle, culture, and body habitus therefore require further investigation. At this time, it is not possible to compare their results with Western results.

In an attempt to compare the different survival rates of the various HTO techniques, Schallberger and colleagues²¹ conducted a retrospective study of OWHTOs and CWHTOs. At median follow-up of 16.5 years, comparative survival rates showed a trend of deterioration. Although data were limited, there were no significant differences in survival or functional outcome between the 2 techniques. In a recent randomized clinical trial, Duivenvoorden and colleagues⁵ compared these techniques’ midterm results (mean follow-up, 6 years). Clinical outcomes were not significantly different. There were more complications in the OWHTO group and more conversions to TKA in the CWHTO group. Considering these results, the authors suggested OWHTO without autologous bone graft is the best HTO treatment strategy for medial gonarthritis with varus malalignment of <12°.

The HTO results noted in these studies show a similar deteriorating trend; expected 10-year survivorship is 75%. Although modern implants and surgical techniques are being used, evidence supporting use of one surgical HTO method over another is lacking.

UKA for Medial Compartment OA

Indications

Since it was first introduced in the 1970s, use of UKA for single-compartment OA has been a subject of debate. The high failure rates reported at the time raised skepticism about the new treatment.²² Kozinn and Scott²³ defined classic indications and contraindications. Indications included isolated medial or lateral compartment OA or osteonecrosis of the knee, age over 60 years, and weight under 82 kg. In addition, the angular deformity of the affected lower extremity had to be <15° and passively correctable to neutral at time of surgery. Last, the flexion contracture had to be <5°, and ideal ROM was 90°. Contraindications included high activity, age under 60 years, and inflammatory arthritis. Strict adherence led to improved implant survival and lower revision rates. Because of improved surgical techniques, modern implant designs, and accumulating experience with the procedure, the surgical indications for UKA have expanded. Exact thresholds for UKA inclusion, however, remain unclear.

The modern literature is overturning the traditional idea that UKA is not indicated for patients under age 60 years.²³ Using KSS, Thompson and colleagues²⁴ found that younger patients did better than older patients 2 years after UKA using various types of implants. Analyzing survivorship results, Heyse and colleagues²⁵ concluded that UKA can be successful in patients under age 60 years and reported a 15-year survivorship rate of 85.6% and excellent outcome scores. Other authors have had similar findings.^26-28

Evaluating the influence of weight, Thompson and colleagues²⁴ found obese patients did not have a higher revision rate but did have slower progression of improvement 2 years after UKA. Cavaignac and colleagues²⁹ concluded that, at minimum follow-up of 7 years (range, 7-22 years), weight did not influence UKA survivorship. Other authors^30-33 have found no significant influence of BMI on survival.

Reports on preoperative radiographic parameters that can potentially influence UKA results are limited. In 113 medial UKAs studied by Niinimäki and colleagues,³⁴ mild medial compartment degeneration, seen on preoperative radiographs, was associated with significantly higher failure rates. The authors concluded that other treatment options should be favored in the absence of severe isolated compartment OA.

Although the classic indications defined by Kozinn and Scott²³ have yielded good to excellent UKA results, improvements in implants and surgical techniques^35-38 have extended the criteria. The modern literature demonstrates that age and BMI should not be used as criteria for excluding UKA candidates. Radiographically, there should be significant isolated compartment degeneration in order to optimize patient-reported outcome and survivorship.

Outcomes

Improved implant designs and modern minimally invasive techniques have effected a change in outcome results and a renewed interest in implants. Over the past decade, multiple authors have described the various modern UKA implants and their survivorship. Reports published since UKA was introduced in the 1970s show a continual increase in implant survival. Koskinen and colleagues,³⁹ using Finnish Arthroplasty Register data on 1819 UKAs performed between 1985 and 2003, found 10-year survival rates of 81% for Oxford implants (Zimmer Biomet), 79% for Miller-Galante II (Zimmer Biomet), 78% for Duracon (Howmedica), and 53% for PCA unicompartmental knee (Howmedica). Heyse and colleagues²⁵ reported 10- and 15-year survivorship data (93.5% and 86.3%, respectively) for 223 patients under age 60 years at the time of their index surgery (Genesis Unicondylar implant, Smith & Nephew), performed between 1993 and 2005. KSS was good to excellent. Similar numbers in cohorts under age 60 years were reported by Schai and colleagues²⁶ using the PFC system (Johnson & Johnson) and by Price and colleagues²⁷ using the medial Oxford UKA. Both groups reported excellent survivorship rates: 93% at 2- to 6-year follow-up and 91% at 10-year follow-up. The outcome in older patients seems satisfactory as well. In another multicenter report, by Price and colleagues,⁴⁰ medial Oxford UKAs had a 15-year survival rate of 93%. Berger and colleagues⁴¹ reported similar numbers for the Miller-Galante prosthesis. Survival rates were 98% (10 years) and 95.7% (13 years), and 92% of patients had good to excellent Hospital for Special Surgery knee scores.

Although various modern implants have had good to excellent results, the historical question of what type of UKA to use (mobile or fixed-bearing) remains unanswered. To try to address it, Peersman and colleagues⁴² performed a systematic review of 44 papers (9463 knees). The 2 implant types had comparable revision rates. Another recent retrospective study tried to determine what is crucial for implant survival: implant design or surgeon experience.⁴³ The authors concluded that prosthetic component positioning is key. Other authors have reported high-volume centers are crucial for satisfactory UKA results and lower revision rates.^44-46

Results of these studies indicate that, where UKAs are being performed in volume, 10-year survivorship rates higher than 90% and good to excellent outcomes can be expected.

UKA vs HTO

Cohort studies that have directly compared the 2 treatment modalities are scarce, and most have been retrospective. In a prospective study, Stukenborg-Colsman and colleagues⁴⁷ randomized patients with medial compartment OA to undergo either CWHTO (32 patients) with a technique reported by Coventry⁴⁸ or UKA (28 patients) with the unicondylar knee sliding prosthesis, Tübingen pattern (Aesculap), between 1988 and 1991. Patients were assessed 2.5, 4.5, and 7.5 years after surgery. More postoperative complications were noted in the HTO group. At 7- to 10-year follow-up, 71% of the HTO group and 65% of the UKA group had excellent KSS. Mean ROM was 103° after UKA (range, 35°-140°) and 117° after HTO (range, 85°-135°) during the same assessment. Although differences were not significant, Kaplan-Meier survival analysis was 60% for HTO and 77% for UKA at 10 years. Results were not promising for the implants used, compared with other implants, but the authors concluded that, because of improvements in implant designs and image-guided techniques, better long-term success can be expected with UKA than with HTO.

In another prospective study, Börjesson and colleagues⁴⁹ evaluated pain during walking, ROM, British Orthopaedic Association (BOA) scores, and gait variables at 1- and 5-year follow-up. Patients with moderate medial OA (Ahlbäck¹⁴ grade I-III) were randomly selected to undergo CWHTO or UKA (Brigham, DePuy). There were no significant differences in BOA scores, ROM, or pain during walking between the 2 groups at 3 months, 1 year, and 5 years after surgery. Gait analysis showed a significant difference in favor of UKA only at 3 months after surgery. At 1- and 5-year follow-up, no significant differences were noted.

To clarify current ambiguities, Fu and colleagues⁵⁰ performed a systematic review of all (11) comparative studies. These studies had a total of 5840 (5081 UKA, 759 HTO) patients. Although ROM was significantly better for the HTO group than the UKA group, the UKA group had significantly better functional results. Walking after surgery was significantly faster for the UKA group. The authors suggested the difference might be attributed to the different postoperative regimens—HTO patients wore a whole-leg plaster cast for 6 weeks, and UKA patients were allowed immediate postoperative weight-bearing. Regarding rates of survival and complications, pooled data showed no significant differences. Despite these results, the authors acknowledged the limitation of available randomized clinical trials and the multiple techniques and implants used. We share their assertion that larger prospective controlled trials are needed. These are crucial to getting a definitive answer regarding which of the 2 treatment strategies should be used for isolated compartment OA.

Current Trends in Use of UKA and HTO

Evaluation of national registries and recent reports showed a global shift in use of both HTO and UKA. Despite the lack of national HTO registries, a few reports have described use of TKA, UKA, and HTO in Western populations over the past 2 decades. Using 1998-2007 data from the Swedish Knee Arthroplasty Register, W-Dahl and colleagues⁵¹ found a 3-fold increase in UKA use, whereas HTO use was halved over the same period. Niinimäki and colleagues⁵² reported similar findings with the Finnish National Hospital Discharge Register. They noted a steady 6.8% annual decrease in osteotomies, whereas UKA use increased sharply after the Oxford UKA was introduced (Phase 3; Biomet). These findings are consistent with several reports from North America. In their epidemiologic analysis covering the period 1985-1990, Wright and colleagues⁵³ found an 11% to 14% annual decrease in osteotomies among the elderly, compared with an annual decrease of only 3% to 4% among patients younger than 65 years. Nwachukwu and colleagues⁵⁴ recently compared UKA and HTO practice patterns between 2007 and 2011, using data from a large US private payer insurance database. They noted an annual growth rate of 4.7% in UKA use, compared with an annual 3.9% decrease in HTO use. Furthermore, based on their subgroup analysis, they speculated there was a demographic shift toward UKA, as opposed to TKA, particularly in older women. Bolognesi and colleagues⁵⁵ investigated further. Evaluating all Medicare beneficiaries who underwent knee arthroplasty in the United States between 2000 and 2009, they noted a 1.7-fold increase in TKA use and a 6.2-fold increase in UKA use. As there were no substantial changes in patient characteristics over that period, the authors hypothesized that a possible broadening of inclusion criteria may have led to the increased use of UKA.

There is a possible multifactorial explanation for the current global shift in favor of UKA. First, UKA was once a technically demanding procedure, but improved surgical techniques, image guidance, and robot assistance⁵⁶ have made it relatively less difficult. Second, UKA surgery is associated with lower reported perioperative morbidities.⁵⁷ We think these factors have contributed to the global trend of less HTO use and more UKA use in the treatment of unicompartmental OA.

Conclusion

The modern literature suggests the inclusion criteria for HTO have been well investigated and defined; the UKA criteria remain a matter of debate but seem to be expanding. Long-term survival results seem to favor UKA, though patient satisfaction with both procedures is good to excellent. The broadening range of inclusion criteria and consistent reports of durable outcomes, coupled with excellent patient satisfaction, likely explain the shift toward UKA in the treatment of isolated compartment degeneration.

Am J Orthop. 2016;45(6):E355-E361. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

An increasingly number of patients with symptomatic isolated medial unicompartmental knee osteoarthritis (OA) are too young and too functionally active to be ideal candidates for total knee arthroplasty (TKA). Isolated medial compartment OA occurs in 10% to 29.5% of all cases, whereas the isolated lateral variant is less common, with a reported incidence of 1% to 7%.^1,2 In 1961, Jackson and Waugh³ introduced the high tibial osteotomy (HTO) as a surgical treatment for single-compartment OA. This procedure is designed to increase the life span of articular cartilage by unloading and redistributing the mechanical forces over the nonaffected compartment. Unicompartmental knee arthroplasty (UKA) was introduced in the 1970s as an alternative to TKA or HTO for single-compartment OA.

Since the introduction of these methods, there has been debate about which patients are appropriate candidates for each procedure. Improved surgical techniques and implant designs have led surgeons to reexamine the selection criteria and contraindications for these procedures. Furthermore, given the increasing popularity and use of UKA, the question arises as to whether HTO still has a role in clinical practice in the surgical treatment of medial OA of the knee.

To clarify current ambiguities, we review the modern indications, subjective outcome scores, and survivorship results of UKA and HTO in the treatment of isolated medial compartment degeneration of the knee. In addition, in a thorough review of the literature, we evaluate global trends in the use of both methods.

High Tibial Osteotomy for Medial Compartment OA

Indications

Before the introduction of TKA and UKA for single-compartment OA, surgical management consisted of HTO. When the mechanical axis is slightly overcorrected, the medial compartment is decompressed, ensuring tissue viability and delaying progressive compartment degeneration.

Traditionally, HTO is indicated for young (age <60 years), normal-weight, active patients with radiographic single-compartment OA.⁶ The knee should be stable and have good range of motion (ROM; flexion >120°), and pain should be localized to the tibiofemoral joint line.

Over the past few decades, numerous authors have reported similar inclusion criteria, clarifying their definition. This definition should be further refined in order to optimize survivorship and clinical outcomes.

Confirming age as an inclusion criterion for HTO, Trieb and colleagues⁷ found that the risk of failure was significantly (P = .046) higher for HTO patients older than 65 years than for those younger than 65 years (relative risk, 1.5). This finding agrees with findings of other studies, which suggests that, in particular, young patients benefit from HTO.^8-11

Moreover, there is a clear relation between HTO survival and obesity. In a study of 159 CWHTOs, Akizuki and colleagues¹² reported that preoperative body mass index (BMI) higher than 27.5 kg/m² was a significant risk factor for early failure. Using BMI higher than 30 kg/m² as a threshold, Howells and colleagues⁹ found significantly inferior Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) results for the obese group 5 years after HTO.

Radiographic evidence of severe preoperative compartment degeneration has been associated with early conversion to TKA. Flecher and colleagues¹¹ and van Raaij and colleagues¹³ both concluded the best long-term survival grades are achieved in HTO patients with mild compartment OA (Ahlbäck^14 grade I). The question then becomes whether these patients should be treated nonoperatively instead.^15,16The literature supports strict adherence to inclusion criteria in the selection of a potential HTO candidate. Age, BMI, and the preoperative state of OA should be taken into account in order to optimize clinical outcome and survivorship results in patients about to undergo HTO.

Outcomes

Multiple authors have described or compared the midterm or long-term results of the various surgical HTO techniques. Howells and colleagues⁹ noted overall survival rates of 87% (5 years after CWHTO) and 79% (10 years after CWHTO). Over the 10-year postoperative period, there was significant deterioration in clinical outcome scores and survivorship. Others authors have had similar findings.^17-19 van Raaij and colleagues¹³ found that the 10-year probability of survival after CWHTO was 75%. In 455 patients who underwent lateral CWHTO, Hui and colleagues⁸ found that 5-year probability of survival was 95%, 10-year probability was 79%, and 15-year probability was 56%. Niinimäki and colleagues¹⁰ used the Finnish Arthroplasty Register to report HTO survivorship at a national level. Using conversion to TKA as a cutoff, they noted 5-year survivorship of 89% and 10-year survivorship of 73%. To our knowledge, 2 groups, both in Japan, have reported substantially higher 15-year survival rates: 90%¹² and 93%.²⁰ The authors acknowledged that their results were significantly better than in other countries and that Japanese lifestyle, culture, and body habitus therefore require further investigation. At this time, it is not possible to compare their results with Western results.

In an attempt to compare the different survival rates of the various HTO techniques, Schallberger and colleagues²¹ conducted a retrospective study of OWHTOs and CWHTOs. At median follow-up of 16.5 years, comparative survival rates showed a trend of deterioration. Although data were limited, there were no significant differences in survival or functional outcome between the 2 techniques. In a recent randomized clinical trial, Duivenvoorden and colleagues⁵ compared these techniques’ midterm results (mean follow-up, 6 years). Clinical outcomes were not significantly different. There were more complications in the OWHTO group and more conversions to TKA in the CWHTO group. Considering these results, the authors suggested OWHTO without autologous bone graft is the best HTO treatment strategy for medial gonarthritis with varus malalignment of <12°.

The HTO results noted in these studies show a similar deteriorating trend; expected 10-year survivorship is 75%. Although modern implants and surgical techniques are being used, evidence supporting use of one surgical HTO method over another is lacking.

UKA for Medial Compartment OA

Indications

Since it was first introduced in the 1970s, use of UKA for single-compartment OA has been a subject of debate. The high failure rates reported at the time raised skepticism about the new treatment.²² Kozinn and Scott²³ defined classic indications and contraindications. Indications included isolated medial or lateral compartment OA or osteonecrosis of the knee, age over 60 years, and weight under 82 kg. In addition, the angular deformity of the affected lower extremity had to be <15° and passively correctable to neutral at time of surgery. Last, the flexion contracture had to be <5°, and ideal ROM was 90°. Contraindications included high activity, age under 60 years, and inflammatory arthritis. Strict adherence led to improved implant survival and lower revision rates. Because of improved surgical techniques, modern implant designs, and accumulating experience with the procedure, the surgical indications for UKA have expanded. Exact thresholds for UKA inclusion, however, remain unclear.

The modern literature is overturning the traditional idea that UKA is not indicated for patients under age 60 years.²³ Using KSS, Thompson and colleagues²⁴ found that younger patients did better than older patients 2 years after UKA using various types of implants. Analyzing survivorship results, Heyse and colleagues²⁵ concluded that UKA can be successful in patients under age 60 years and reported a 15-year survivorship rate of 85.6% and excellent outcome scores. Other authors have had similar findings.^26-28

Evaluating the influence of weight, Thompson and colleagues²⁴ found obese patients did not have a higher revision rate but did have slower progression of improvement 2 years after UKA. Cavaignac and colleagues²⁹ concluded that, at minimum follow-up of 7 years (range, 7-22 years), weight did not influence UKA survivorship. Other authors^30-33 have found no significant influence of BMI on survival.

Reports on preoperative radiographic parameters that can potentially influence UKA results are limited. In 113 medial UKAs studied by Niinimäki and colleagues,³⁴ mild medial compartment degeneration, seen on preoperative radiographs, was associated with significantly higher failure rates. The authors concluded that other treatment options should be favored in the absence of severe isolated compartment OA.

Although the classic indications defined by Kozinn and Scott²³ have yielded good to excellent UKA results, improvements in implants and surgical techniques^35-38 have extended the criteria. The modern literature demonstrates that age and BMI should not be used as criteria for excluding UKA candidates. Radiographically, there should be significant isolated compartment degeneration in order to optimize patient-reported outcome and survivorship.

Outcomes

Improved implant designs and modern minimally invasive techniques have effected a change in outcome results and a renewed interest in implants. Over the past decade, multiple authors have described the various modern UKA implants and their survivorship. Reports published since UKA was introduced in the 1970s show a continual increase in implant survival. Koskinen and colleagues,³⁹ using Finnish Arthroplasty Register data on 1819 UKAs performed between 1985 and 2003, found 10-year survival rates of 81% for Oxford implants (Zimmer Biomet), 79% for Miller-Galante II (Zimmer Biomet), 78% for Duracon (Howmedica), and 53% for PCA unicompartmental knee (Howmedica). Heyse and colleagues²⁵ reported 10- and 15-year survivorship data (93.5% and 86.3%, respectively) for 223 patients under age 60 years at the time of their index surgery (Genesis Unicondylar implant, Smith & Nephew), performed between 1993 and 2005. KSS was good to excellent. Similar numbers in cohorts under age 60 years were reported by Schai and colleagues²⁶ using the PFC system (Johnson & Johnson) and by Price and colleagues²⁷ using the medial Oxford UKA. Both groups reported excellent survivorship rates: 93% at 2- to 6-year follow-up and 91% at 10-year follow-up. The outcome in older patients seems satisfactory as well. In another multicenter report, by Price and colleagues,⁴⁰ medial Oxford UKAs had a 15-year survival rate of 93%. Berger and colleagues⁴¹ reported similar numbers for the Miller-Galante prosthesis. Survival rates were 98% (10 years) and 95.7% (13 years), and 92% of patients had good to excellent Hospital for Special Surgery knee scores.

Although various modern implants have had good to excellent results, the historical question of what type of UKA to use (mobile or fixed-bearing) remains unanswered. To try to address it, Peersman and colleagues⁴² performed a systematic review of 44 papers (9463 knees). The 2 implant types had comparable revision rates. Another recent retrospective study tried to determine what is crucial for implant survival: implant design or surgeon experience.⁴³ The authors concluded that prosthetic component positioning is key. Other authors have reported high-volume centers are crucial for satisfactory UKA results and lower revision rates.^44-46

Results of these studies indicate that, where UKAs are being performed in volume, 10-year survivorship rates higher than 90% and good to excellent outcomes can be expected.

UKA vs HTO

Cohort studies that have directly compared the 2 treatment modalities are scarce, and most have been retrospective. In a prospective study, Stukenborg-Colsman and colleagues⁴⁷ randomized patients with medial compartment OA to undergo either CWHTO (32 patients) with a technique reported by Coventry⁴⁸ or UKA (28 patients) with the unicondylar knee sliding prosthesis, Tübingen pattern (Aesculap), between 1988 and 1991. Patients were assessed 2.5, 4.5, and 7.5 years after surgery. More postoperative complications were noted in the HTO group. At 7- to 10-year follow-up, 71% of the HTO group and 65% of the UKA group had excellent KSS. Mean ROM was 103° after UKA (range, 35°-140°) and 117° after HTO (range, 85°-135°) during the same assessment. Although differences were not significant, Kaplan-Meier survival analysis was 60% for HTO and 77% for UKA at 10 years. Results were not promising for the implants used, compared with other implants, but the authors concluded that, because of improvements in implant designs and image-guided techniques, better long-term success can be expected with UKA than with HTO.

In another prospective study, Börjesson and colleagues⁴⁹ evaluated pain during walking, ROM, British Orthopaedic Association (BOA) scores, and gait variables at 1- and 5-year follow-up. Patients with moderate medial OA (Ahlbäck¹⁴ grade I-III) were randomly selected to undergo CWHTO or UKA (Brigham, DePuy). There were no significant differences in BOA scores, ROM, or pain during walking between the 2 groups at 3 months, 1 year, and 5 years after surgery. Gait analysis showed a significant difference in favor of UKA only at 3 months after surgery. At 1- and 5-year follow-up, no significant differences were noted.

To clarify current ambiguities, Fu and colleagues⁵⁰ performed a systematic review of all (11) comparative studies. These studies had a total of 5840 (5081 UKA, 759 HTO) patients. Although ROM was significantly better for the HTO group than the UKA group, the UKA group had significantly better functional results. Walking after surgery was significantly faster for the UKA group. The authors suggested the difference might be attributed to the different postoperative regimens—HTO patients wore a whole-leg plaster cast for 6 weeks, and UKA patients were allowed immediate postoperative weight-bearing. Regarding rates of survival and complications, pooled data showed no significant differences. Despite these results, the authors acknowledged the limitation of available randomized clinical trials and the multiple techniques and implants used. We share their assertion that larger prospective controlled trials are needed. These are crucial to getting a definitive answer regarding which of the 2 treatment strategies should be used for isolated compartment OA.

Current Trends in Use of UKA and HTO

Evaluation of national registries and recent reports showed a global shift in use of both HTO and UKA. Despite the lack of national HTO registries, a few reports have described use of TKA, UKA, and HTO in Western populations over the past 2 decades. Using 1998-2007 data from the Swedish Knee Arthroplasty Register, W-Dahl and colleagues⁵¹ found a 3-fold increase in UKA use, whereas HTO use was halved over the same period. Niinimäki and colleagues⁵² reported similar findings with the Finnish National Hospital Discharge Register. They noted a steady 6.8% annual decrease in osteotomies, whereas UKA use increased sharply after the Oxford UKA was introduced (Phase 3; Biomet). These findings are consistent with several reports from North America. In their epidemiologic analysis covering the period 1985-1990, Wright and colleagues⁵³ found an 11% to 14% annual decrease in osteotomies among the elderly, compared with an annual decrease of only 3% to 4% among patients younger than 65 years. Nwachukwu and colleagues⁵⁴ recently compared UKA and HTO practice patterns between 2007 and 2011, using data from a large US private payer insurance database. They noted an annual growth rate of 4.7% in UKA use, compared with an annual 3.9% decrease in HTO use. Furthermore, based on their subgroup analysis, they speculated there was a demographic shift toward UKA, as opposed to TKA, particularly in older women. Bolognesi and colleagues⁵⁵ investigated further. Evaluating all Medicare beneficiaries who underwent knee arthroplasty in the United States between 2000 and 2009, they noted a 1.7-fold increase in TKA use and a 6.2-fold increase in UKA use. As there were no substantial changes in patient characteristics over that period, the authors hypothesized that a possible broadening of inclusion criteria may have led to the increased use of UKA.

There is a possible multifactorial explanation for the current global shift in favor of UKA. First, UKA was once a technically demanding procedure, but improved surgical techniques, image guidance, and robot assistance⁵⁶ have made it relatively less difficult. Second, UKA surgery is associated with lower reported perioperative morbidities.⁵⁷ We think these factors have contributed to the global trend of less HTO use and more UKA use in the treatment of unicompartmental OA.

Conclusion

The modern literature suggests the inclusion criteria for HTO have been well investigated and defined; the UKA criteria remain a matter of debate but seem to be expanding. Long-term survival results seem to favor UKA, though patient satisfaction with both procedures is good to excellent. The broadening range of inclusion criteria and consistent reports of durable outcomes, coupled with excellent patient satisfaction, likely explain the shift toward UKA in the treatment of isolated compartment degeneration.

Am J Orthop. 2016;45(6):E355-E361. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Imatinib (Gleevec) tablet

cut in half with a pill splitter

Photo by Patrick Pelletier

Significant out-of-pocket costs may delay treatment for Medicare beneficiaries with chronic myeloid leukemia (CML), according to a study published in the Journal of Clinical Oncology.

Researchers studied 393 patients with CML who had federally funded health insurance—specifically, a Medicare Part D plan.

Nearly a third of these patients did not start tyrosine kinase inhibitor (TKI) treatment within 6 months of their diagnosis.

However, patients who had access to subsidies that help cover treatment costs had a shorter median time to the start of therapy.

“There are 2 troubling findings here,” said study author Aaron Winn, a doctoral student at the University of North Carolina at Chapel Hill.

“First, we are seeing that more than 30% of people aren’t starting therapy within 6 months. Second, we are seeing long delays in starting drugs for people without subsidies. This is very concerning as these delays may be an indicator that the patient is trying to find funds to pay for their first treatment.”

Medicare Part D and TKIs

Previous studies have shown that patients insured through Medicare Part D have out of-pocket costs of nearly $3000 for the first month’s supply of a TKI.

According to researchers, the high upfront costs are due to the Medicare Part D benefit design, which requires patients to pay a larger share of medication costs until they have paid at least $4850 out-of-pocket in a year (cost in 2016). After that, patients pay 5% of the monthly drug costs.

In order to qualify for Medicare Part D’s low-income subsidy, an individual must have an annual income of less than $17,820 and assets of less than $13,640 (figures for 2016).

“Once you’re on Medicare Part D, there really aren’t ways to minimize these out-of-pocket costs, other than subsidies,” said Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.

“One of the challenges is that when the Medicare benefit was designed, I don’t think they were really considering these very expensive therapies. The benefit design makes a lot more sense when you’re looking at drugs that cost several hundred dollars versus several thousand dollars or more. We really need to think carefully about how much these high out-of-pocket costs are impacting patients’ access to life-saving drugs.”

Study results

For this study, Dr Dusetzina and her colleagues evaluated data on 393 patients who were diagnosed with CML between 2007 and 2011. The patients’ median age was 77, 47% were married, 48% were male, and 85% were white.

All of the patients were enrolled in Medicare Part D, and 40% qualified for subsidies to lower drug costs.

Of all the patients, there were 32% who had not started treatment with a first-line TKI (imatinib, nilotinib, or dasatinib) within 6 months of diagnosis.

However, having access to subsidies was associated with a shorter time to the start of treatment. The median time to the start of treatment was 58 days for patients with subsidies and 108 days for patients without them.

While the gap between the 2 groups widened after diagnosis, eventually, patients without subsidies did catch up, Dr Dusetzina said.

Ninety days from diagnosis, 48% of patients without subsidies had started treatment, compared to 63% of patients with subsidies. At 6 months from diagnosis, 64% of patients without subsidies had started treatment, compared to 65% of patients with subsidies.

Dr Dusetzina said patients without subsidies could be catching up as they find the financial resources to help cover those initial costs. But overall, patients with subsidies were 35% more likely to start TKI treatment faster.

“We recognize that people have a high cost to even start therapy, and this study really demonstrates the difference between people with and without a subsidy in initiating therapy,” Dr Dusetzina said. “The out-of-pocket costs may be delaying people starting these life-saving drugs.”

Imatinib (Gleevec) tablet

cut in half with a pill splitter

Photo by Patrick Pelletier

Significant out-of-pocket costs may delay treatment for Medicare beneficiaries with chronic myeloid leukemia (CML), according to a study published in the Journal of Clinical Oncology.

Researchers studied 393 patients with CML who had federally funded health insurance—specifically, a Medicare Part D plan.

Nearly a third of these patients did not start tyrosine kinase inhibitor (TKI) treatment within 6 months of their diagnosis.

However, patients who had access to subsidies that help cover treatment costs had a shorter median time to the start of therapy.

“There are 2 troubling findings here,” said study author Aaron Winn, a doctoral student at the University of North Carolina at Chapel Hill.

“First, we are seeing that more than 30% of people aren’t starting therapy within 6 months. Second, we are seeing long delays in starting drugs for people without subsidies. This is very concerning as these delays may be an indicator that the patient is trying to find funds to pay for their first treatment.”

Medicare Part D and TKIs

Previous studies have shown that patients insured through Medicare Part D have out of-pocket costs of nearly $3000 for the first month’s supply of a TKI.

According to researchers, the high upfront costs are due to the Medicare Part D benefit design, which requires patients to pay a larger share of medication costs until they have paid at least $4850 out-of-pocket in a year (cost in 2016). After that, patients pay 5% of the monthly drug costs.

In order to qualify for Medicare Part D’s low-income subsidy, an individual must have an annual income of less than $17,820 and assets of less than $13,640 (figures for 2016).

“Once you’re on Medicare Part D, there really aren’t ways to minimize these out-of-pocket costs, other than subsidies,” said Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.

“One of the challenges is that when the Medicare benefit was designed, I don’t think they were really considering these very expensive therapies. The benefit design makes a lot more sense when you’re looking at drugs that cost several hundred dollars versus several thousand dollars or more. We really need to think carefully about how much these high out-of-pocket costs are impacting patients’ access to life-saving drugs.”

Study results

For this study, Dr Dusetzina and her colleagues evaluated data on 393 patients who were diagnosed with CML between 2007 and 2011. The patients’ median age was 77, 47% were married, 48% were male, and 85% were white.

All of the patients were enrolled in Medicare Part D, and 40% qualified for subsidies to lower drug costs.

Of all the patients, there were 32% who had not started treatment with a first-line TKI (imatinib, nilotinib, or dasatinib) within 6 months of diagnosis.

However, having access to subsidies was associated with a shorter time to the start of treatment. The median time to the start of treatment was 58 days for patients with subsidies and 108 days for patients without them.

While the gap between the 2 groups widened after diagnosis, eventually, patients without subsidies did catch up, Dr Dusetzina said.

Ninety days from diagnosis, 48% of patients without subsidies had started treatment, compared to 63% of patients with subsidies. At 6 months from diagnosis, 64% of patients without subsidies had started treatment, compared to 65% of patients with subsidies.

Dr Dusetzina said patients without subsidies could be catching up as they find the financial resources to help cover those initial costs. But overall, patients with subsidies were 35% more likely to start TKI treatment faster.

“We recognize that people have a high cost to even start therapy, and this study really demonstrates the difference between people with and without a subsidy in initiating therapy,” Dr Dusetzina said. “The out-of-pocket costs may be delaying people starting these life-saving drugs.”

Imatinib (Gleevec) tablet

cut in half with a pill splitter

Photo by Patrick Pelletier

Significant out-of-pocket costs may delay treatment for Medicare beneficiaries with chronic myeloid leukemia (CML), according to a study published in the Journal of Clinical Oncology.

Researchers studied 393 patients with CML who had federally funded health insurance—specifically, a Medicare Part D plan.

Nearly a third of these patients did not start tyrosine kinase inhibitor (TKI) treatment within 6 months of their diagnosis.

However, patients who had access to subsidies that help cover treatment costs had a shorter median time to the start of therapy.

“There are 2 troubling findings here,” said study author Aaron Winn, a doctoral student at the University of North Carolina at Chapel Hill.

“First, we are seeing that more than 30% of people aren’t starting therapy within 6 months. Second, we are seeing long delays in starting drugs for people without subsidies. This is very concerning as these delays may be an indicator that the patient is trying to find funds to pay for their first treatment.”

Medicare Part D and TKIs

Previous studies have shown that patients insured through Medicare Part D have out of-pocket costs of nearly $3000 for the first month’s supply of a TKI.

According to researchers, the high upfront costs are due to the Medicare Part D benefit design, which requires patients to pay a larger share of medication costs until they have paid at least $4850 out-of-pocket in a year (cost in 2016). After that, patients pay 5% of the monthly drug costs.

In order to qualify for Medicare Part D’s low-income subsidy, an individual must have an annual income of less than $17,820 and assets of less than $13,640 (figures for 2016).

“Once you’re on Medicare Part D, there really aren’t ways to minimize these out-of-pocket costs, other than subsidies,” said Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.

“One of the challenges is that when the Medicare benefit was designed, I don’t think they were really considering these very expensive therapies. The benefit design makes a lot more sense when you’re looking at drugs that cost several hundred dollars versus several thousand dollars or more. We really need to think carefully about how much these high out-of-pocket costs are impacting patients’ access to life-saving drugs.”

Study results

For this study, Dr Dusetzina and her colleagues evaluated data on 393 patients who were diagnosed with CML between 2007 and 2011. The patients’ median age was 77, 47% were married, 48% were male, and 85% were white.

All of the patients were enrolled in Medicare Part D, and 40% qualified for subsidies to lower drug costs.

Of all the patients, there were 32% who had not started treatment with a first-line TKI (imatinib, nilotinib, or dasatinib) within 6 months of diagnosis.

However, having access to subsidies was associated with a shorter time to the start of treatment. The median time to the start of treatment was 58 days for patients with subsidies and 108 days for patients without them.

While the gap between the 2 groups widened after diagnosis, eventually, patients without subsidies did catch up, Dr Dusetzina said.

Ninety days from diagnosis, 48% of patients without subsidies had started treatment, compared to 63% of patients with subsidies. At 6 months from diagnosis, 64% of patients without subsidies had started treatment, compared to 65% of patients with subsidies.

Dr Dusetzina said patients without subsidies could be catching up as they find the financial resources to help cover those initial costs. But overall, patients with subsidies were 35% more likely to start TKI treatment faster.

“We recognize that people have a high cost to even start therapy, and this study really demonstrates the difference between people with and without a subsidy in initiating therapy,” Dr Dusetzina said. “The out-of-pocket costs may be delaying people starting these life-saving drugs.”

Do you have a patient with back pain? Suggest acupuncture and yoga. Osteoarthritis? Acupuncture and tai chi. Those are some of the approaches that are safe and effective in treating chronic pain, according to researchers from the National Center for Complementary and Integrative Health (NCCIH). They also gave a nod to massage for neck pain and relaxation techniques for severe headaches and migraine.

The researchers reviewed 105 U.S. randomized controlled trials from the past 50 years, focusing on 7 complementary treatments: acupuncture, spinal manipulation or osteopathic manipulation, massage therapy, tai chi, yoga, and relaxation techniques (such as mindfulness meditation). They also evaluated findings from studies involving natural product supplements: chondroitin, glucosamine, methylsulfonylmethane (MSM), S-adenosylmethionine (SAMe), and omega-3 fatty acids.

The researchers rated those treatments in 5 painful conditions often seen in primary care: back pain, osteoarthritis, neck pain, fibromyalgia, and severe headaches and migraine.

Although evidence was weaker, they also found that massage, spinal manipulation, and osteopathic manipulation may help in some back pain, and relaxation and tai chi may help patients with fibromyalgia.

No trial reported a serious adverse event linked to a complementary treatment. Most adverse events were gastrointestinal problems from glucosamine, chondroitin, MSM, or SAMe, or minor soreness from exercise.

Do you have a patient with back pain? Suggest acupuncture and yoga. Osteoarthritis? Acupuncture and tai chi. Those are some of the approaches that are safe and effective in treating chronic pain, according to researchers from the National Center for Complementary and Integrative Health (NCCIH). They also gave a nod to massage for neck pain and relaxation techniques for severe headaches and migraine.

The researchers reviewed 105 U.S. randomized controlled trials from the past 50 years, focusing on 7 complementary treatments: acupuncture, spinal manipulation or osteopathic manipulation, massage therapy, tai chi, yoga, and relaxation techniques (such as mindfulness meditation). They also evaluated findings from studies involving natural product supplements: chondroitin, glucosamine, methylsulfonylmethane (MSM), S-adenosylmethionine (SAMe), and omega-3 fatty acids.

The researchers rated those treatments in 5 painful conditions often seen in primary care: back pain, osteoarthritis, neck pain, fibromyalgia, and severe headaches and migraine.

Although evidence was weaker, they also found that massage, spinal manipulation, and osteopathic manipulation may help in some back pain, and relaxation and tai chi may help patients with fibromyalgia.

No trial reported a serious adverse event linked to a complementary treatment. Most adverse events were gastrointestinal problems from glucosamine, chondroitin, MSM, or SAMe, or minor soreness from exercise.

Do you have a patient with back pain? Suggest acupuncture and yoga. Osteoarthritis? Acupuncture and tai chi. Those are some of the approaches that are safe and effective in treating chronic pain, according to researchers from the National Center for Complementary and Integrative Health (NCCIH). They also gave a nod to massage for neck pain and relaxation techniques for severe headaches and migraine.

The researchers reviewed 105 U.S. randomized controlled trials from the past 50 years, focusing on 7 complementary treatments: acupuncture, spinal manipulation or osteopathic manipulation, massage therapy, tai chi, yoga, and relaxation techniques (such as mindfulness meditation). They also evaluated findings from studies involving natural product supplements: chondroitin, glucosamine, methylsulfonylmethane (MSM), S-adenosylmethionine (SAMe), and omega-3 fatty acids.

The researchers rated those treatments in 5 painful conditions often seen in primary care: back pain, osteoarthritis, neck pain, fibromyalgia, and severe headaches and migraine.

Although evidence was weaker, they also found that massage, spinal manipulation, and osteopathic manipulation may help in some back pain, and relaxation and tai chi may help patients with fibromyalgia.

No trial reported a serious adverse event linked to a complementary treatment. Most adverse events were gastrointestinal problems from glucosamine, chondroitin, MSM, or SAMe, or minor soreness from exercise.

The Case

A 74-year-old man with Alzheimer’s dementia presents with urinary tract infection (UTI), hypovolemia, and hypernatremia. He also has chronic dysphagia with a history of aspiration pneumonia and has been on thickened liquids at home for the past five months. As his infection is treated, he improves and requests water to drink.

Background

The diagnosis of dysphagia is clinical, and assessments from patients and family are often sufficient. The optimal test to assess the severity of dysphagia is a bedside swallow evaluation using small amounts of water.1 Video-assisted fluoroscopic examinations can identify problem areas within the oropharynx and esophagus and may help determine the etiology of dysphagia.

What evidence supports various treatment options for dysphagia?

Access to Water

Water is a thin liquid with low viscosity, which allows for rapid transit through the oropharynx. In debilitated and elderly patients, thin liquids easily reach the epiglottis and enter the trachea before pharyngeal muscles compensate. As such, access to water and other thin liquids is often restricted in patients suspected to have dysphagia.4

However, allowing access to water improves patient satisfaction, reduces the development of dehydration, and does not increase the incidence of AP. Bedside therapy interventions such as correct positioning and chin-tuck and sipping technique as well as attention to oral hygiene are recommended prior to more noxious options such as thickened liquids.1 The Frazier water protocol may help provide logistical guidance for facilities interested in improving access to water for patients with dysphagia.

Liquid Modification

Many clinicians manage dysphagia through restricting access to all thin liquids. In the hospital setting where video fluoroscopy and speech therapy are readily available, clinicians frequently employ the use of modified diets with thickened liquids in order to minimize the risk of aspiration despite the lack of high-quality evidence supporting liquid modification.2 Patients associate thickened liquids and restricted diets with a reduction in quality of life. Compliance studies have shown that only a minority of patients are compliant with thickened liquids at five days. In addition, thickening liquids has not been shown to decrease the risk of AP nor improve nutritional status, and it may actually cause harm by increasing the risk of dehydration and UTI.4

Tube Feeding

In patients with severe dysphagia in whom conservative management is not feasible or has failed, maintaining adequate nutrition can be a challenge. There are encouraging data with nutritionally enriching and modifying the texture of solid foods.1 Alternative methods of enteral nutrition delivery are often also considered. The most common vehicles of delivery are nasogastric tubes, post-pyloric feeding tubes, and percutaneous endoscopic gastrostomy (PEG) tubes. In theory, bypassing the pharynx and esophagus could result in fewer aspiration events and less AP.3 However, nasogastric, post-pyloric, or PEG feeding does not decrease the risk of AP. For patients with advanced dementia, there have been no randomized trials demonstrating an improvement in mortality with tube feeds.4 Tube feeding also carries with it a slight procedural risk and a high incidence of associated diarrhea, plus is associated with electrolyte derangements such as hypernatremia. The decision to pursue tube feeding should be weighed heavily in every patient and is highly influenced by the etiology and anticipated duration of dysphagia.

Selective Digestive Decontamination

Selective digestive decontamination (SDD) is a protocol-based treatment that aims to eradicate potentially pathogenic gut flora, particularly aerobic gram-negatives, in critically ill patients to reduce the impact of aspiration events. The utilization of SDD and the available literature center firmly on critically ill and ventilated patients. Subsequent studies have demonstrated recolonization after protocol cessation, and long-term effects are currently undefined.5 Until it can be studied in broader populations and proven to have clinical benefit, employing SSD in non-critically ill patients with dysphagia remains unsupported.

Multimodal Approach

Many rehabilitation centers incorporate a therapist-driven swallowing treatment program. Evidence suggests patient and family counseling alone may not be effective, so these programs variably incorporate diet/liquid modification, strengthening exercises, sensory processing techniques, and even neuromuscular electrical stimulation for muscle building.1 Accordingly, these programs are resource-intensive.

Management

Dysphagia remains a significant clinical problem for hospitalized patients. The existing literature and practice guidelines generally support a “less is more” approach. Though liquid/diet modification is common practice, it is not based in solid evidence and may contribute to unnecessary tube feeding. The best current evidence supports allowing access to water and ice chips. The ideal management plan for each patient will differ and should incorporate patient and family preferences in a multidisciplinary approach.

Back to the Case

Our patient requests water. He coughs after drinking during a bedside swallow evaluation. The risks of potential aspiration and AP are explained, and he expresses his understanding. He reiterates his choice to be allowed access to water as it is important to his quality of life. The speech therapy team is consulted and provides instruction on chin-tuck positioning, oral care, and timing water between meals rather than while eating food. He does well for the remainder of the hospital stay, and by time of discharge, his electrolytes are corrected, and he is much more comfortable being allowed to drink water. He is discharged home and encouraged to continue with these conservative measures.

Bottom Line

Evidence to support many common interventions for dysphagia is lacking; patients with dysphagia are best managed via a multidisciplinary, multimodal approach that provides access to water whenever possible. TH

Vijay G. Paryani, MD, is an internal medicine resident in the department of internal medicine at the University of Kentucky. Joseph R. Sweigart, MD, is a hospitalist and assistant professor of hospital medicine in the division of hospital medicine at the University of Kentucky. Laura C. Fanucchi, MD, is a hospitalist and assistant professor of hospital medicine in the division of hospital medicine at the University of Kentucky.

References

1. Karagiannis MJ, Chivers L, Karagiannis TC. Effects of oral intake of water in patients with oropharyngeal dysphagia. BMC Geriatr. 2011;11(2):9.
2. Foley N, Teasell R, Salter K, Kruger E, Martino R. Dysphagia treatment post stroke: a systematic review of randomized controlled trials. Age Ageing. 2008;37(3):258-264.
3. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671.
4. Loeb MB, Becker M, Eady A, Walker-Dilks C. Interventions to prevent aspiration pneumonia in older adults: a systematic review. J Am Geriatr Soc. 2003;51(7):1018-1022.
5. Gosney M, Martin MV, Wright AE. The role of selective decontamination of the digestive tract in acute stroke. Age Ageing 2006;35(1):42-47.

The Case

A 74-year-old man with Alzheimer’s dementia presents with urinary tract infection (UTI), hypovolemia, and hypernatremia. He also has chronic dysphagia with a history of aspiration pneumonia and has been on thickened liquids at home for the past five months. As his infection is treated, he improves and requests water to drink.

Background

The diagnosis of dysphagia is clinical, and assessments from patients and family are often sufficient. The optimal test to assess the severity of dysphagia is a bedside swallow evaluation using small amounts of water.1 Video-assisted fluoroscopic examinations can identify problem areas within the oropharynx and esophagus and may help determine the etiology of dysphagia.

What evidence supports various treatment options for dysphagia?

Access to Water

Water is a thin liquid with low viscosity, which allows for rapid transit through the oropharynx. In debilitated and elderly patients, thin liquids easily reach the epiglottis and enter the trachea before pharyngeal muscles compensate. As such, access to water and other thin liquids is often restricted in patients suspected to have dysphagia.4

However, allowing access to water improves patient satisfaction, reduces the development of dehydration, and does not increase the incidence of AP. Bedside therapy interventions such as correct positioning and chin-tuck and sipping technique as well as attention to oral hygiene are recommended prior to more noxious options such as thickened liquids.1 The Frazier water protocol may help provide logistical guidance for facilities interested in improving access to water for patients with dysphagia.

Liquid Modification

Many clinicians manage dysphagia through restricting access to all thin liquids. In the hospital setting where video fluoroscopy and speech therapy are readily available, clinicians frequently employ the use of modified diets with thickened liquids in order to minimize the risk of aspiration despite the lack of high-quality evidence supporting liquid modification.2 Patients associate thickened liquids and restricted diets with a reduction in quality of life. Compliance studies have shown that only a minority of patients are compliant with thickened liquids at five days. In addition, thickening liquids has not been shown to decrease the risk of AP nor improve nutritional status, and it may actually cause harm by increasing the risk of dehydration and UTI.4

Tube Feeding

In patients with severe dysphagia in whom conservative management is not feasible or has failed, maintaining adequate nutrition can be a challenge. There are encouraging data with nutritionally enriching and modifying the texture of solid foods.1 Alternative methods of enteral nutrition delivery are often also considered. The most common vehicles of delivery are nasogastric tubes, post-pyloric feeding tubes, and percutaneous endoscopic gastrostomy (PEG) tubes. In theory, bypassing the pharynx and esophagus could result in fewer aspiration events and less AP.3 However, nasogastric, post-pyloric, or PEG feeding does not decrease the risk of AP. For patients with advanced dementia, there have been no randomized trials demonstrating an improvement in mortality with tube feeds.4 Tube feeding also carries with it a slight procedural risk and a high incidence of associated diarrhea, plus is associated with electrolyte derangements such as hypernatremia. The decision to pursue tube feeding should be weighed heavily in every patient and is highly influenced by the etiology and anticipated duration of dysphagia.

Selective Digestive Decontamination

Selective digestive decontamination (SDD) is a protocol-based treatment that aims to eradicate potentially pathogenic gut flora, particularly aerobic gram-negatives, in critically ill patients to reduce the impact of aspiration events. The utilization of SDD and the available literature center firmly on critically ill and ventilated patients. Subsequent studies have demonstrated recolonization after protocol cessation, and long-term effects are currently undefined.5 Until it can be studied in broader populations and proven to have clinical benefit, employing SSD in non-critically ill patients with dysphagia remains unsupported.

Multimodal Approach

Many rehabilitation centers incorporate a therapist-driven swallowing treatment program. Evidence suggests patient and family counseling alone may not be effective, so these programs variably incorporate diet/liquid modification, strengthening exercises, sensory processing techniques, and even neuromuscular electrical stimulation for muscle building.1 Accordingly, these programs are resource-intensive.

Management

Dysphagia remains a significant clinical problem for hospitalized patients. The existing literature and practice guidelines generally support a “less is more” approach. Though liquid/diet modification is common practice, it is not based in solid evidence and may contribute to unnecessary tube feeding. The best current evidence supports allowing access to water and ice chips. The ideal management plan for each patient will differ and should incorporate patient and family preferences in a multidisciplinary approach.

Back to the Case

Our patient requests water. He coughs after drinking during a bedside swallow evaluation. The risks of potential aspiration and AP are explained, and he expresses his understanding. He reiterates his choice to be allowed access to water as it is important to his quality of life. The speech therapy team is consulted and provides instruction on chin-tuck positioning, oral care, and timing water between meals rather than while eating food. He does well for the remainder of the hospital stay, and by time of discharge, his electrolytes are corrected, and he is much more comfortable being allowed to drink water. He is discharged home and encouraged to continue with these conservative measures.

Bottom Line

Evidence to support many common interventions for dysphagia is lacking; patients with dysphagia are best managed via a multidisciplinary, multimodal approach that provides access to water whenever possible. TH

Vijay G. Paryani, MD, is an internal medicine resident in the department of internal medicine at the University of Kentucky. Joseph R. Sweigart, MD, is a hospitalist and assistant professor of hospital medicine in the division of hospital medicine at the University of Kentucky. Laura C. Fanucchi, MD, is a hospitalist and assistant professor of hospital medicine in the division of hospital medicine at the University of Kentucky.

References

1. Karagiannis MJ, Chivers L, Karagiannis TC. Effects of oral intake of water in patients with oropharyngeal dysphagia. BMC Geriatr. 2011;11(2):9.
2. Foley N, Teasell R, Salter K, Kruger E, Martino R. Dysphagia treatment post stroke: a systematic review of randomized controlled trials. Age Ageing. 2008;37(3):258-264.
3. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671.
4. Loeb MB, Becker M, Eady A, Walker-Dilks C. Interventions to prevent aspiration pneumonia in older adults: a systematic review. J Am Geriatr Soc. 2003;51(7):1018-1022.
5. Gosney M, Martin MV, Wright AE. The role of selective decontamination of the digestive tract in acute stroke. Age Ageing 2006;35(1):42-47.

The Case

A 74-year-old man with Alzheimer’s dementia presents with urinary tract infection (UTI), hypovolemia, and hypernatremia. He also has chronic dysphagia with a history of aspiration pneumonia and has been on thickened liquids at home for the past five months. As his infection is treated, he improves and requests water to drink.

Background

The diagnosis of dysphagia is clinical, and assessments from patients and family are often sufficient. The optimal test to assess the severity of dysphagia is a bedside swallow evaluation using small amounts of water.1 Video-assisted fluoroscopic examinations can identify problem areas within the oropharynx and esophagus and may help determine the etiology of dysphagia.

What evidence supports various treatment options for dysphagia?

Access to Water

Water is a thin liquid with low viscosity, which allows for rapid transit through the oropharynx. In debilitated and elderly patients, thin liquids easily reach the epiglottis and enter the trachea before pharyngeal muscles compensate. As such, access to water and other thin liquids is often restricted in patients suspected to have dysphagia.4

However, allowing access to water improves patient satisfaction, reduces the development of dehydration, and does not increase the incidence of AP. Bedside therapy interventions such as correct positioning and chin-tuck and sipping technique as well as attention to oral hygiene are recommended prior to more noxious options such as thickened liquids.1 The Frazier water protocol may help provide logistical guidance for facilities interested in improving access to water for patients with dysphagia.

Liquid Modification

Many clinicians manage dysphagia through restricting access to all thin liquids. In the hospital setting where video fluoroscopy and speech therapy are readily available, clinicians frequently employ the use of modified diets with thickened liquids in order to minimize the risk of aspiration despite the lack of high-quality evidence supporting liquid modification.2 Patients associate thickened liquids and restricted diets with a reduction in quality of life. Compliance studies have shown that only a minority of patients are compliant with thickened liquids at five days. In addition, thickening liquids has not been shown to decrease the risk of AP nor improve nutritional status, and it may actually cause harm by increasing the risk of dehydration and UTI.4

Tube Feeding

In patients with severe dysphagia in whom conservative management is not feasible or has failed, maintaining adequate nutrition can be a challenge. There are encouraging data with nutritionally enriching and modifying the texture of solid foods.1 Alternative methods of enteral nutrition delivery are often also considered. The most common vehicles of delivery are nasogastric tubes, post-pyloric feeding tubes, and percutaneous endoscopic gastrostomy (PEG) tubes. In theory, bypassing the pharynx and esophagus could result in fewer aspiration events and less AP.3 However, nasogastric, post-pyloric, or PEG feeding does not decrease the risk of AP. For patients with advanced dementia, there have been no randomized trials demonstrating an improvement in mortality with tube feeds.4 Tube feeding also carries with it a slight procedural risk and a high incidence of associated diarrhea, plus is associated with electrolyte derangements such as hypernatremia. The decision to pursue tube feeding should be weighed heavily in every patient and is highly influenced by the etiology and anticipated duration of dysphagia.

Selective Digestive Decontamination

Selective digestive decontamination (SDD) is a protocol-based treatment that aims to eradicate potentially pathogenic gut flora, particularly aerobic gram-negatives, in critically ill patients to reduce the impact of aspiration events. The utilization of SDD and the available literature center firmly on critically ill and ventilated patients. Subsequent studies have demonstrated recolonization after protocol cessation, and long-term effects are currently undefined.5 Until it can be studied in broader populations and proven to have clinical benefit, employing SSD in non-critically ill patients with dysphagia remains unsupported.

Multimodal Approach

Many rehabilitation centers incorporate a therapist-driven swallowing treatment program. Evidence suggests patient and family counseling alone may not be effective, so these programs variably incorporate diet/liquid modification, strengthening exercises, sensory processing techniques, and even neuromuscular electrical stimulation for muscle building.1 Accordingly, these programs are resource-intensive.

Management

Dysphagia remains a significant clinical problem for hospitalized patients. The existing literature and practice guidelines generally support a “less is more” approach. Though liquid/diet modification is common practice, it is not based in solid evidence and may contribute to unnecessary tube feeding. The best current evidence supports allowing access to water and ice chips. The ideal management plan for each patient will differ and should incorporate patient and family preferences in a multidisciplinary approach.

Back to the Case

Our patient requests water. He coughs after drinking during a bedside swallow evaluation. The risks of potential aspiration and AP are explained, and he expresses his understanding. He reiterates his choice to be allowed access to water as it is important to his quality of life. The speech therapy team is consulted and provides instruction on chin-tuck positioning, oral care, and timing water between meals rather than while eating food. He does well for the remainder of the hospital stay, and by time of discharge, his electrolytes are corrected, and he is much more comfortable being allowed to drink water. He is discharged home and encouraged to continue with these conservative measures.

Bottom Line

Evidence to support many common interventions for dysphagia is lacking; patients with dysphagia are best managed via a multidisciplinary, multimodal approach that provides access to water whenever possible. TH

Vijay G. Paryani, MD, is an internal medicine resident in the department of internal medicine at the University of Kentucky. Joseph R. Sweigart, MD, is a hospitalist and assistant professor of hospital medicine in the division of hospital medicine at the University of Kentucky. Laura C. Fanucchi, MD, is a hospitalist and assistant professor of hospital medicine in the division of hospital medicine at the University of Kentucky.

References

1. Karagiannis MJ, Chivers L, Karagiannis TC. Effects of oral intake of water in patients with oropharyngeal dysphagia. BMC Geriatr. 2011;11(2):9.
2. Foley N, Teasell R, Salter K, Kruger E, Martino R. Dysphagia treatment post stroke: a systematic review of randomized controlled trials. Age Ageing. 2008;37(3):258-264.
3. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671.
4. Loeb MB, Becker M, Eady A, Walker-Dilks C. Interventions to prevent aspiration pneumonia in older adults: a systematic review. J Am Geriatr Soc. 2003;51(7):1018-1022.
5. Gosney M, Martin MV, Wright AE. The role of selective decontamination of the digestive tract in acute stroke. Age Ageing 2006;35(1):42-47.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.

The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).

Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.

The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).

AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.

But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.

Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.

The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.

UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.

Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.

The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.

“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.

The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).

Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.

The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).

AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.

But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.

Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.

The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.

UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.

Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.

The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.

“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.

The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).

Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.

The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).

AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.

But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.

Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.

The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.

UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.

Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.

The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.

“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.

Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.

These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.

Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.

According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.

Previous results from TITAN

TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.

These and other results from TITAN were published in NEJM earlier this year.

Post-hoc analyses

Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.

The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.

There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.

There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.

There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.

Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.

When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.

When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.

“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.

“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”

“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.

Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.

These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.

Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.

According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.

Previous results from TITAN

TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.

These and other results from TITAN were published in NEJM earlier this year.

Post-hoc analyses

Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.

The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.

There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.

There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.

There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.

Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.

When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.

When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.

“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.

“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”

“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.

Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.

These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.

Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.

According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.

Previous results from TITAN

TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.

These and other results from TITAN were published in NEJM earlier this year.

Post-hoc analyses

Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.

The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.

There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.

There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.

There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.

Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.

When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.

When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.

“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.

“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”

“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”

Yoshinori Ohsumi, PhD

Photo by Mari Honda

The 2016 Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, PhD, for his discoveries related to autophagy.

The concept of autophagy emerged during the 1960s, but little was known about the process until the early 1990s.

That’s when Dr Ohsumi used yeast cells to identify genes essential for autophagy. He cloned several of these genes in yeast and mammalian cells and described the function of the encoded proteins.

According to The Nobel Assembly at Karolinska Institutet, Dr Ohsumi’s discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes.

The man

Dr Ohsumi was born in 1945 in Fukuoka, Japan. He received a PhD from University of Tokyo in 1974.

After spending 3 years at Rockefeller University in New York, he returned to the University of Tokyo, where he established his research group in 1988. Since 2009, he has been a professor at the Tokyo Institute of Technology.

The research

The Belgian scientist Christian de Duve coined the term autophagy in 1963. However, the process was still not well understood when Dr Ohsumi began his research on autophagy.

In the early 1990s, Dr Ohsumi decided to study autophagy using the budding yeast Saccharomyces cerevisae as a model system.

He was not sure whether autophagy existed in this organism. However, he reasoned that, if it did, and he could disrupt the degradation process in the vacuole while autophagy was active, autophagosomes should accumulate within the vacuole.

Dr Ohsumi cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells.

Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes, and the experiment proved that autophagy exists in yeast cells.

The experiment also provided a method to identify and characterize genes involved in autophagy.

Dr Ohsumi noted that the accumulation of autophagosomes should not occur if genes important for autophagy were inactivated.

So he exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. In this way, he identified 15 genes essential for autophagy in budding yeast.

In his subsequent studies, Dr Ohsumi cloned several of these genes in yeast and mammalian cells and characterized the function of the proteins encoded by these genes.

He found that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.

Insights provided by Dr Ohsumi’s work enabled subsequent research that has revealed the role of autophagy in human physiology and disease.

For more information on Dr Ohsumi and his work, visit the Nobel Prize website.

Yoshinori Ohsumi, PhD

Photo by Mari Honda

The 2016 Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, PhD, for his discoveries related to autophagy.

The concept of autophagy emerged during the 1960s, but little was known about the process until the early 1990s.

That’s when Dr Ohsumi used yeast cells to identify genes essential for autophagy. He cloned several of these genes in yeast and mammalian cells and described the function of the encoded proteins.

According to The Nobel Assembly at Karolinska Institutet, Dr Ohsumi’s discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes.

The man

Dr Ohsumi was born in 1945 in Fukuoka, Japan. He received a PhD from University of Tokyo in 1974.

After spending 3 years at Rockefeller University in New York, he returned to the University of Tokyo, where he established his research group in 1988. Since 2009, he has been a professor at the Tokyo Institute of Technology.

The research

The Belgian scientist Christian de Duve coined the term autophagy in 1963. However, the process was still not well understood when Dr Ohsumi began his research on autophagy.

In the early 1990s, Dr Ohsumi decided to study autophagy using the budding yeast Saccharomyces cerevisae as a model system.

He was not sure whether autophagy existed in this organism. However, he reasoned that, if it did, and he could disrupt the degradation process in the vacuole while autophagy was active, autophagosomes should accumulate within the vacuole.

Dr Ohsumi cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells.

Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes, and the experiment proved that autophagy exists in yeast cells.

The experiment also provided a method to identify and characterize genes involved in autophagy.

Dr Ohsumi noted that the accumulation of autophagosomes should not occur if genes important for autophagy were inactivated.

So he exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. In this way, he identified 15 genes essential for autophagy in budding yeast.

In his subsequent studies, Dr Ohsumi cloned several of these genes in yeast and mammalian cells and characterized the function of the proteins encoded by these genes.

He found that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.

Insights provided by Dr Ohsumi’s work enabled subsequent research that has revealed the role of autophagy in human physiology and disease.

For more information on Dr Ohsumi and his work, visit the Nobel Prize website.

Yoshinori Ohsumi, PhD

Photo by Mari Honda

The 2016 Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, PhD, for his discoveries related to autophagy.

The concept of autophagy emerged during the 1960s, but little was known about the process until the early 1990s.

That’s when Dr Ohsumi used yeast cells to identify genes essential for autophagy. He cloned several of these genes in yeast and mammalian cells and described the function of the encoded proteins.

According to The Nobel Assembly at Karolinska Institutet, Dr Ohsumi’s discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes.

The man

Dr Ohsumi was born in 1945 in Fukuoka, Japan. He received a PhD from University of Tokyo in 1974.

After spending 3 years at Rockefeller University in New York, he returned to the University of Tokyo, where he established his research group in 1988. Since 2009, he has been a professor at the Tokyo Institute of Technology.

The research

The Belgian scientist Christian de Duve coined the term autophagy in 1963. However, the process was still not well understood when Dr Ohsumi began his research on autophagy.

In the early 1990s, Dr Ohsumi decided to study autophagy using the budding yeast Saccharomyces cerevisae as a model system.

He was not sure whether autophagy existed in this organism. However, he reasoned that, if it did, and he could disrupt the degradation process in the vacuole while autophagy was active, autophagosomes should accumulate within the vacuole.

Dr Ohsumi cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells.

Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes, and the experiment proved that autophagy exists in yeast cells.

The experiment also provided a method to identify and characterize genes involved in autophagy.

Dr Ohsumi noted that the accumulation of autophagosomes should not occur if genes important for autophagy were inactivated.

So he exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. In this way, he identified 15 genes essential for autophagy in budding yeast.

In his subsequent studies, Dr Ohsumi cloned several of these genes in yeast and mammalian cells and characterized the function of the proteins encoded by these genes.

He found that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.

Insights provided by Dr Ohsumi’s work enabled subsequent research that has revealed the role of autophagy in human physiology and disease.

For more information on Dr Ohsumi and his work, visit the Nobel Prize website.

A 25-year-old woman who is 16 weeks pregnant with her first child is experiencing increased vaginal discharge associated with vaginal itching. A microscopic examination of the discharge confirms your suspicions of vaginal candidiasis. Is oral fluconazole or a topical azole your treatment of choice?

Because of the increased production of sex hormones, vaginal candidiasis is common during pregnancy, affecting up to 10% of pregnant women in the United States.^1,2 Treatment options include oral fluconazole and a variety of topical azoles. Although the latter are recommended as firstline therapy, the ease of oral therapy makes it an attractive option.^3,4

However, the safety of oral fluconazole during pregnancy has recently come under scrutiny. Case reports have linked high-dose use with congenital malformation.^5,6 These case reports led to epidemiologic studies in which no such association was found.^7,8

A large cohort study involving 1,079 fluconazole-exposed pregnancies and 170,453 unexposed pregnancies found no increased risk for congenital malformation or stillbirth; rates of spontaneous abortion and miscarriage were not evaluated.⁹ A prospective cohort study of 226 pregnant women found no association between fluconazole use during the first trimester and miscarriage.¹⁰ However, the validity of both studies’ findings was limited by small numbers of participants.

The current study is the largest to date to evaluate whether use of fluconazole in early pregnancy is associated with increased rates of spontaneous abortion and stillbirth, compared to topical azoles.

STUDY SUMMARY

Increased risk for miscarriage, but not stillbirth

This nationwide cohort study, conducted using the Medical Birth Register in Denmark, evaluated more than 1.4 million pregnancies occurring from 1997 to 2013 for exposure to oral fluconazole between 7 and 22 weeks’ gestation. Each oral fluconazole–exposed pregnancy was matched with up to four unexposed pregnancies (based on propensity score, maternal age, calendar year, and gestational age) and to pregnancies exposed to intravaginal formulations of topical azoles. Exposure to fluconazole was documented by filled prescriptions from the National Prescription Register. Primary outcomes were rates of spontaneous abortion (loss before 22 weeks) and stillbirth (loss after 23 weeks).

Rates of spontaneous abortion. Of the total cohort, 3,315 pregnancies were exposed to oral fluconazole between 7 and 22 weeks’ gestation. Spontaneous abortion occurred in 147 of these pregnancies and in 563 of 13,246 unexposed, matched pregnancies (hazard ratio [HR], 1.48).

Rates of stillbirth. Of 5,382 pregnancies exposed to fluconazole from week 7 to birth, 21 resulted in stillbirth; 77 stillbirths occurred in the 21,506 unexposed matched pregnancies (HR, 1.32). In a sensitivity analysis, however, higher doses of fluconazole (350 mg) were four times more likely than lower doses (150 mg) to be associated with stillbirth (HRs, 4.10 and 0.99, respectively).

Oral fluconazole vs topical azole. Use of oral fluconazole in pregnancy was associated with an increased risk for spontaneous abortion, compared to topical azole use (130 of 2,823 pregnancies vs 118 of 2,823 pregnancies; HR, 1.62)—but not an increased risk for stillbirth (20 of 4,301 pregnancies vs 22 of 4,301 pregnancies; HR, 1.18).

 

 

WHAT'S NEW

A sizeable study with a treatment comparison

The authors found that exposure in early pregnancy to oral flu­conazole, as compared to topical azoles, increases the risk for spontaneous abortion. By comparing treatments in a sensitivity analysis, the researchers were able to eliminate Candida infections causing spontaneous abortion as a confounding factor. In addition, this study challenges the balance between ease of use and safety.

CAVEATS

A skewed population?

This cohort study using a Danish hospital registry may not be generalizable to a larger, non-Scandinavian population. Those not seeking care through a hospital were likely missed; if those seeking care through the hospital had a higher risk for abortion, the results could be biased. However, this would not have affected the results of the comparison between the two active treatments.

In addition, the study focused on women exposed from 7 to 22 weeks’ gestation; the findings may not be generalizable to fluconazole exposure prior to 7 weeks. Likewise, the registry is unlikely to capture very early spontaneous abortions that are not recognized clinically.

In all, given the large sample size and the care taken to match each exposed pregnancy with up to four unexposed pregnancies, these limitations likely had little influence on the overall findings.

CHALLENGES TO IMPLEMENTATION

Balancing ease of use with safety

Given the ease of using oral fluconazole, compared with daily topical azole therapy, many clinicians and patients may still opt for oral treatment.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(9):624-626.

A 25-year-old woman who is 16 weeks pregnant with her first child is experiencing increased vaginal discharge associated with vaginal itching. A microscopic examination of the discharge confirms your suspicions of vaginal candidiasis. Is oral fluconazole or a topical azole your treatment of choice?

Because of the increased production of sex hormones, vaginal candidiasis is common during pregnancy, affecting up to 10% of pregnant women in the United States.^1,2 Treatment options include oral fluconazole and a variety of topical azoles. Although the latter are recommended as firstline therapy, the ease of oral therapy makes it an attractive option.^3,4

However, the safety of oral fluconazole during pregnancy has recently come under scrutiny. Case reports have linked high-dose use with congenital malformation.^5,6 These case reports led to epidemiologic studies in which no such association was found.^7,8

A large cohort study involving 1,079 fluconazole-exposed pregnancies and 170,453 unexposed pregnancies found no increased risk for congenital malformation or stillbirth; rates of spontaneous abortion and miscarriage were not evaluated.⁹ A prospective cohort study of 226 pregnant women found no association between fluconazole use during the first trimester and miscarriage.¹⁰ However, the validity of both studies’ findings was limited by small numbers of participants.

The current study is the largest to date to evaluate whether use of fluconazole in early pregnancy is associated with increased rates of spontaneous abortion and stillbirth, compared to topical azoles.

STUDY SUMMARY

Increased risk for miscarriage, but not stillbirth

This nationwide cohort study, conducted using the Medical Birth Register in Denmark, evaluated more than 1.4 million pregnancies occurring from 1997 to 2013 for exposure to oral fluconazole between 7 and 22 weeks’ gestation. Each oral fluconazole–exposed pregnancy was matched with up to four unexposed pregnancies (based on propensity score, maternal age, calendar year, and gestational age) and to pregnancies exposed to intravaginal formulations of topical azoles. Exposure to fluconazole was documented by filled prescriptions from the National Prescription Register. Primary outcomes were rates of spontaneous abortion (loss before 22 weeks) and stillbirth (loss after 23 weeks).

Rates of spontaneous abortion. Of the total cohort, 3,315 pregnancies were exposed to oral fluconazole between 7 and 22 weeks’ gestation. Spontaneous abortion occurred in 147 of these pregnancies and in 563 of 13,246 unexposed, matched pregnancies (hazard ratio [HR], 1.48).

Rates of stillbirth. Of 5,382 pregnancies exposed to fluconazole from week 7 to birth, 21 resulted in stillbirth; 77 stillbirths occurred in the 21,506 unexposed matched pregnancies (HR, 1.32). In a sensitivity analysis, however, higher doses of fluconazole (350 mg) were four times more likely than lower doses (150 mg) to be associated with stillbirth (HRs, 4.10 and 0.99, respectively).

Oral fluconazole vs topical azole. Use of oral fluconazole in pregnancy was associated with an increased risk for spontaneous abortion, compared to topical azole use (130 of 2,823 pregnancies vs 118 of 2,823 pregnancies; HR, 1.62)—but not an increased risk for stillbirth (20 of 4,301 pregnancies vs 22 of 4,301 pregnancies; HR, 1.18).

 

 

WHAT'S NEW

A sizeable study with a treatment comparison

The authors found that exposure in early pregnancy to oral flu­conazole, as compared to topical azoles, increases the risk for spontaneous abortion. By comparing treatments in a sensitivity analysis, the researchers were able to eliminate Candida infections causing spontaneous abortion as a confounding factor. In addition, this study challenges the balance between ease of use and safety.

CAVEATS

A skewed population?

This cohort study using a Danish hospital registry may not be generalizable to a larger, non-Scandinavian population. Those not seeking care through a hospital were likely missed; if those seeking care through the hospital had a higher risk for abortion, the results could be biased. However, this would not have affected the results of the comparison between the two active treatments.

In addition, the study focused on women exposed from 7 to 22 weeks’ gestation; the findings may not be generalizable to fluconazole exposure prior to 7 weeks. Likewise, the registry is unlikely to capture very early spontaneous abortions that are not recognized clinically.

In all, given the large sample size and the care taken to match each exposed pregnancy with up to four unexposed pregnancies, these limitations likely had little influence on the overall findings.

CHALLENGES TO IMPLEMENTATION

Balancing ease of use with safety

Given the ease of using oral fluconazole, compared with daily topical azole therapy, many clinicians and patients may still opt for oral treatment.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(9):624-626.

A 25-year-old woman who is 16 weeks pregnant with her first child is experiencing increased vaginal discharge associated with vaginal itching. A microscopic examination of the discharge confirms your suspicions of vaginal candidiasis. Is oral fluconazole or a topical azole your treatment of choice?

Because of the increased production of sex hormones, vaginal candidiasis is common during pregnancy, affecting up to 10% of pregnant women in the United States.^1,2 Treatment options include oral fluconazole and a variety of topical azoles. Although the latter are recommended as firstline therapy, the ease of oral therapy makes it an attractive option.^3,4

However, the safety of oral fluconazole during pregnancy has recently come under scrutiny. Case reports have linked high-dose use with congenital malformation.^5,6 These case reports led to epidemiologic studies in which no such association was found.^7,8

A large cohort study involving 1,079 fluconazole-exposed pregnancies and 170,453 unexposed pregnancies found no increased risk for congenital malformation or stillbirth; rates of spontaneous abortion and miscarriage were not evaluated.⁹ A prospective cohort study of 226 pregnant women found no association between fluconazole use during the first trimester and miscarriage.¹⁰ However, the validity of both studies’ findings was limited by small numbers of participants.

The current study is the largest to date to evaluate whether use of fluconazole in early pregnancy is associated with increased rates of spontaneous abortion and stillbirth, compared to topical azoles.

STUDY SUMMARY

Increased risk for miscarriage, but not stillbirth

This nationwide cohort study, conducted using the Medical Birth Register in Denmark, evaluated more than 1.4 million pregnancies occurring from 1997 to 2013 for exposure to oral fluconazole between 7 and 22 weeks’ gestation. Each oral fluconazole–exposed pregnancy was matched with up to four unexposed pregnancies (based on propensity score, maternal age, calendar year, and gestational age) and to pregnancies exposed to intravaginal formulations of topical azoles. Exposure to fluconazole was documented by filled prescriptions from the National Prescription Register. Primary outcomes were rates of spontaneous abortion (loss before 22 weeks) and stillbirth (loss after 23 weeks).

Rates of spontaneous abortion. Of the total cohort, 3,315 pregnancies were exposed to oral fluconazole between 7 and 22 weeks’ gestation. Spontaneous abortion occurred in 147 of these pregnancies and in 563 of 13,246 unexposed, matched pregnancies (hazard ratio [HR], 1.48).

Rates of stillbirth. Of 5,382 pregnancies exposed to fluconazole from week 7 to birth, 21 resulted in stillbirth; 77 stillbirths occurred in the 21,506 unexposed matched pregnancies (HR, 1.32). In a sensitivity analysis, however, higher doses of fluconazole (350 mg) were four times more likely than lower doses (150 mg) to be associated with stillbirth (HRs, 4.10 and 0.99, respectively).

Oral fluconazole vs topical azole. Use of oral fluconazole in pregnancy was associated with an increased risk for spontaneous abortion, compared to topical azole use (130 of 2,823 pregnancies vs 118 of 2,823 pregnancies; HR, 1.62)—but not an increased risk for stillbirth (20 of 4,301 pregnancies vs 22 of 4,301 pregnancies; HR, 1.18).

 

 

WHAT'S NEW

A sizeable study with a treatment comparison

The authors found that exposure in early pregnancy to oral flu­conazole, as compared to topical azoles, increases the risk for spontaneous abortion. By comparing treatments in a sensitivity analysis, the researchers were able to eliminate Candida infections causing spontaneous abortion as a confounding factor. In addition, this study challenges the balance between ease of use and safety.

CAVEATS

A skewed population?

This cohort study using a Danish hospital registry may not be generalizable to a larger, non-Scandinavian population. Those not seeking care through a hospital were likely missed; if those seeking care through the hospital had a higher risk for abortion, the results could be biased. However, this would not have affected the results of the comparison between the two active treatments.

In addition, the study focused on women exposed from 7 to 22 weeks’ gestation; the findings may not be generalizable to fluconazole exposure prior to 7 weeks. Likewise, the registry is unlikely to capture very early spontaneous abortions that are not recognized clinically.

In all, given the large sample size and the care taken to match each exposed pregnancy with up to four unexposed pregnancies, these limitations likely had little influence on the overall findings.

CHALLENGES TO IMPLEMENTATION

Balancing ease of use with safety

Given the ease of using oral fluconazole, compared with daily topical azole therapy, many clinicians and patients may still opt for oral treatment.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(9):624-626.

Federal health officials are wasting no time in putting to use long-awaited congressional funding aimed at strengthening Zika prevention and advancing research efforts.

The country’s health care agencies will split the $1.1 billion in funding approved by Congress on Sept. 28, dividing the money among Zika vaccine development, mosquito control, and response to virus outbreaks in the United States and globally, Sylvia Burwell, Health and Human Services secretary, said during an Oct. 3 press conference.

Courtesy HHS

agallegos@frontlinemedcom.com

On Twitter @legal_med

Federal health officials are wasting no time in putting to use long-awaited congressional funding aimed at strengthening Zika prevention and advancing research efforts.

The country’s health care agencies will split the $1.1 billion in funding approved by Congress on Sept. 28, dividing the money among Zika vaccine development, mosquito control, and response to virus outbreaks in the United States and globally, Sylvia Burwell, Health and Human Services secretary, said during an Oct. 3 press conference.

Courtesy HHS

agallegos@frontlinemedcom.com

On Twitter @legal_med

Federal health officials are wasting no time in putting to use long-awaited congressional funding aimed at strengthening Zika prevention and advancing research efforts.

The country’s health care agencies will split the $1.1 billion in funding approved by Congress on Sept. 28, dividing the money among Zika vaccine development, mosquito control, and response to virus outbreaks in the United States and globally, Sylvia Burwell, Health and Human Services secretary, said during an Oct. 3 press conference.

Courtesy HHS

agallegos@frontlinemedcom.com

On Twitter @legal_med