Kent M. Samuelson

Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation

Background— Pharmacogenetic-guided dosing of warfarin is a promising application of “personalized medicine” but has not been adequately tested in randomized trials. Methods and Results— Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic=30.7%, standard=33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic=29%, standard=39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of ≥4 (P=0.03). Conclusions— An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

Background— Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results— A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ⩽1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. Conclusions— These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

The patellofemoral joint in total knee prostheses: Design considerations

Abstract Some desirable design features of the patellofemoral joint in a total knee arthroplasty condylar prosthesis are proposed. These are that the femoral element should be grooved, have a high anterior flange, and be ciruclar as viewed from the side. The groove should be about 5 mm deep and have relatively vertical walls. The patellar component should have a saddle-shaped articular surface matching the femur and should be countersunk into the patella. The components should be placed so as to position the joint automatically. Results with such a design are reproted; loosening, wear, dislocation, and fracture have been rare. Osteolysis of the patella has not been seen after 9 years, so that the cementless press-fit fixation of an H.D.P. patellar prosthesis to date seems safe and efficacious.

Analysis of foot position in ankle arthrodesis and its influence on gait.

This study was carried out on 24 patients who underwent 25 ankle fusions. Twenty-four of 25 ankles operated upon by eight different surgeons achieved a solid fusion. A review showed that when the ankle was fused in a neutral position, the patient would, on the average, have 10° of plantar flexion occurring in the midfoot. This motion allowed him to wear most normal foot gear. In gait, the plantar flexion in the foot approximated the plantar flexion in the normal ankle, giving little difficulty. In contrast, those individuals whose ankle was fused in 10° of plantar flexion who also had 10° of plantar motion in the midfoot and no dorsiflexion motion in the midfoot were, in effect, in 10° of equinus. These patients showed a vaulting pattern while ambulating barefoot, but were usually able to accommodate this position while wearing shoes. The patient with a neutral position of the foot and ankle showed a very satisfactory gait in shoes and a much improved barefoot gait. It is concluded that fusion in a neutral position is indicated and that midtarsal motion occurs in the plantar direction but that no dorsiflexion is present in the midtarsal area.

Investigation of Lateral Ankle Ligament Reconstruction

The problem of chronic instability of lateral ankle ligaments has been approached with both conservative and surgical measures. Many operative procedures have been devised to correct this problem, and of these the Watson-Jones, modified Elmslie and Evans procedures are the most commonly used in our community. This paper was designed to: 1) compare the results of the three procedures; 2) investigate subtalar motion in a population of uninjured ankles; and 3) compare these results to subtalar motion in ankles after lateral ligament reconstruction. We found that each of the three procedures had a surprisingly high incidence of postoperative pain. All procedures had a high rate of return to preinjury activity level, and the majority of the patients were satisfied with the results of the operation. Postoperatively, the Watson-Jones repair exhibited the highest percentage of subjective instability. Twenty-four per cent of the Watson-Jones repairs had a postoperative talar tilt greater than 5°. It was determined that subtalar motion was affected by the type of reconstructive procedure, and although this fact had been theorized in the literature, it had not been documented by objective data.

Analysis of Lymph Nodes for Polyethylene Particles in Patients Who Have Had a Primary Joint Replacement

Polarized light microscopy has been used for more than forty years to identify polyethylene particles in histological specimens; however, few investigators have assessed the specificity of this technique. We examined specimens from dissected lymph nodes for the presence of strongly birefringent particles resembling polyethylene. Twenty-seven patients had dissection of lymph nodes after a total joint replacement (Group 1), and a control group of eighteen patients had dissection of lymph nodes before a total joint replacement (Group 2). Specimens from both groups of lymph nodes were examined under plain and polarized light. The presence of strongly birefringent particulate debris was graded from 0 to 4. Twenty-one (78 per cent) of the twenty-seven patients in Group 1 and eight of the eighteen patients in Group 2 had strongly birefringent particles in the lymph nodes. Our results demonstrate that, in the assessment of the systemic dissemination of polyethylene in the lymphoreticular system, polarized light microscopy has important limitations. More refined techniques employing polarized light and other methods of physical and chemical analysis may be necessary to identify polyethylene particles accurately within the lymphoreticular system and periprosthetic tissue.

Bone grafting and noncemented revision arthroplasty of the knee.

Revision of failed cemented total knee arthroplasties with cementless stemmed components and allogeneic bone grafts was performed on 22 patients, with clinical results comparable to those in primary arthroplasty. On roentgenograms, most of the allogeneic grafts appeared to be incorporated in the host bone. Various bone reactions not fitting any particular pattern, occurred around the stems.

Development and Evolution of the ICLH Ankle Replacement

In 1972 the original ICLH ankle was first used clinically, and since then the authors have implanted 75 ICLH ankles. The overall percentage of acceptable results in this series is about 70%. The most frequent complication seen was delayed wound healing. Talomalleolar contact with resultant pain was a significant problem early in the series. Partial collapse of the talus has occurred in five ankles. Our experience has shown that it is possible to replace the ankle and initially achieve a functioning, pain-free arthroplasty. There are many factors that may adversely influence the ultimate outcome; and thus, the procedure should be approached with caution.

Flat-top talus. A long-term report of twenty club feet.

Twelve adult patients who had been treated for talipes equinovarus were studied. A flat-top talus was found in all of the twenty ankles involved. The mean age of the patients was forty-two years. All patients had a measurably decreased range of motion in the ankle, but it caused them little or no pain. Only one patient had significant pain and limitation of activity.

Implant arthroplasty in the adult hindfoot.

In patients with mild to moderate valgus deformity and localized pain due to lateral impingement, the subtalar implant has been effective in controlling position and relieving localized pain. When used in conjunction with a talonavicular resurfacing prosthesis in the absence of talonavicular subluxation, the implant has been effective in relieving pain and maintaining the foot in a normal or nearly normal position. In feet with valgus deformity and talonavicular subluxation, both the subtalar implant and the talonavicular prosthesis with a built-in stop must be used. Use of these implants requires that the foot be supple and correctable to at least neutral position at surgery. The valgus hindfoot with a subluxated but otherwise normal talonavicular joint presents a greater problem. In this condition correction can be maintained only if the subtalar implant is used in conjunction with the modified talonavicular joint with a built-in stop. External supports in the shoe have not been routinely used in all patients after operation for a variety of reasons (mostly nonmedical). It may be advisable in patients who have had correction of a deformity to continue to use some sort of support in the shoe for most ambulation. Arthroplasty early in the disease course, before severe deformities develop, may prevent progression of the disorder, but more experience is necessary to validate clinical impressions.