Total hip arthroplasty in patients with classic hemophilia: a matched comparison of 90-day outcomes and five-year implant survival

Abstract

Background:

Patients with classic hemophilia can develope joint hemarthroses, degenerative changes, and eventually require total hip arthroplasty (THA). Little data exist concerning THA outcomes in this population, and evidence-based guidelines specifically addressing venous thromboembolism (VTE) prophylaxis in this population are lacking.

Methods:

A retrospective study was conducted using the 2010-2020 PearlDiver MHip database. Patients undergoing primary THA were identified, and those with classic hemophilia were matched 1:10 with non-hemophilia patients based on age, sex, and Elixhauser Comorbidity Index (ECI). Ninety-day serious, minor, and any adverse events (SAEs, MAEs, and AAEs, respectively) were compared with multivariate analysis. Reoperation at five years was assessed using Kaplan-Meier analysis.

Results:

518 classic hemophilia THA patients were matched 1:10 with 5,193 non-hemophilia patients. On multivariate analysis, those with classic hemophilia had greater odds of aggregated AAEs (OR=1.76), SAEs (OR=2.30), and MAEs (OR=1.52) (P<0.001 for each). Patients with classic hemophilia had greater odds of bleeding issues (transfusion, OR=1.98; hematoma, OR=4.23; P<0.001 for both), VTE (DVT, OR=2.67; PE, OR=4.01; P<0.001 for both), and AKI (OR=1.63; P=0.03). Five-year implant survival was lower in hemophilia patients (91.9%) relative to matched controls (95.3%; P = 0.009).

Conclusion:

Hemophilia patients undergoing THA had elevated risks of both 90-day bleeding complications (transfusion and hematoma) and VTE (DVT and PE) relative to matched controls. These findings emphasize the need to balance factor replacement and VTE prophylaxis. Although the five-year implant survival was lower in hemophilia patients, this represented a difference of 3.4% at five years, suggesting that THA remains effective in this cohort.

INTRODUCTION

Hemophilia A, also known as classic hemophilia, is the most prevalent form of hemophilia and occurs in approximately 1 in 5,000 male live births [1,2]. This X-linked recessive bleeding disorder is caused by mutations in Factor VIII of the intrinsic blood coagulation pathway [3]. Due to the potential for recurrent hemarthroses, those with hemophilia are at increased risk of synovitis, cartilage damage, and eventual degenerative changes [4,5]. In fact, hemophilic arthropathy of the knee has been observed in approximately 90% of hemophilia patients by the third decade [4]. The repeated intra-articular bleeds and resulting synovitis in hemophilia frequently results in target joints, which have continuous swelling and reduced range of motion [6]. Recurrent hemarthroses can lead to irreversible damage of these target joints, causing chronic pain and poor physical functioning. Given this, orthopaedic interventions, particularly in the form of total joint arthroplasty (TJA) of affected hip and knee joints, are often considered in this population [5,7].

The challenges of elective TJA in hemophilia patients are considerable. In particular, reports document increased risks of perioperative bleeding and infection in these patients [3,8,9]. To help address these risks, infusion of the deficient factor is considered in the perioperative and postoperative periods [4,10]. However, despite the established high risk of venous thromboembolism (VTE) following TJA in the general population [11,12], the risk of VTE after TJA in hemophilia patients remains incompletely understood, with suggestions that the risk in this group may be similar to [13] or perhaps lower than [14] that of non-hemophilia patients. As a consequence, formal VTE prophylaxis guidelines remain poorly defined for this population [10,12,15,16].

With these unique concerns, outcomes following total hip arthroplasty (THA) in patients with hemophilia have been explored to some extent but have been limited by small sample sizes. One report of 94 patients with hemophilia A or B documented elevated 72-hour rates of blood transfusion for those with hemophilia (19.2%) versus controls (10.4%) [17]. Another short-term THA study of 31 patients with hemophilia A or B recorded significantly elevated 30-day bleeding complications (38.7% versus 16.1%) and blood transfusion (19.4% versus 7.7%) relative to controls, but no difference in surgical site infections [9]. Only 2 studies have assessed mid- and long-term follow-up in THA patients with hemophilia A, both with small sample sizes. One study of 20 patients with hemophilia A found no difference in perioperative complications and 100% implant survivorship at a mean follow-up of 113 months after index THA [18]. Another study of 37 THA patients with hemophilia A, B, or C found no differences in 30- and 90-day major and minor complication rates (other than transfusion adjusted hazard ration of 5.26 versus controls), 1-year infection rate, or 1-year reoperation rate [19].

Small sample sizes of patients with hemophilia A make single institution or regional outcome studies of TJA procedures in this population challenging. A better understanding of the TJA data in patients with classic hemophilia may help optimize patient counseling, care pathways, and contribute to improvement in clinical outcomes in this population. Thus, the present study was performed to assess both the 90-day postoperative complications and five-year implant survival in a large national cohort of hemophilia THA patients relative to matched controls. More specifically, this study aimed to identify the VTE rates for this large cohort of patients to more expertly determine the clinical need for postoperative VTE prophylaxis in this population. We hypothesized that patients with hemophilia would have more bleeding events and fewer instances of VTE in the first 90 postoperative days and lower five-year implant survival, when compared to matched controls.

METHODS

Study population

A retrospective study was performed with data from the January 2010 to April 2020 MHip PearlDiver database (PearlDiver Inc., Fort Wayne, IN, USA), a commercially available administrative United States database containing 121 million patients. All the data in the database are de-identified and Health Insurance Portability and Accountability Act (HIPAA)-compliant. Based on the fact that all data are de-identified in the PearlDiver database, our Institutional Review Board (IRB) has deemed this study “Not Human Research” and has thus provided an exemption.

Patients who underwent primary THA were queried by Current Procedural Terminology (CPT) code CPT-27130 and filtered based on first instance of primary THA. Patients with a diagnosis of classic hemophilia were identified based on International Classification of Diseases (ICD) codes ICD-9-D-2860 and ICD-10-D-D66. These codes pertain to hereditary factor VIII deficiency, but to due to limitations in hemophilia diagnosis coding, some female carriers may be captured. The hemophilia cohort was matched with the non-hemophilia cohort at 1:10 based on age, sex, and Elixhauser Comorbidity Index (ECI) score, variables which were abstracted from the dataset. We chose to match at 1:10 as prior studies assessing similarly rare conditions have matched at this ratio [20,21].

Postoperative complications

The incidence of 90-day postoperative adverse events was assessed. Individual adverse events were assessed based on ICD codes, and these were aggregated as serious adverse events (SAEs), minor adverse events (MAEs), and any adverse events (AAEs).

SAE was noted if there was the occurrence of cardiac arrest, myocardial infarction, sepsis, surgical site infection, and VTE, including deep vein thrombosis (DVT) or pulmonary embolism (PE). MAE was noted if there was the occurrence of pneumonia, wound dehiscence, urinary tract infection (UTI), acute kidney injury (AKI), transfusion, or hematoma. AAE was noted if there was the occurrence of any SAE or MAE.

Five-year reoperation rates

The five-year survival of THA was investigated. Reoperation was noted if there was CPT coding of a single or dual component revision of the THA. Kaplan Meier survival curves were used to depict THA implant survival in patients with classic hemophilia versus controls.

Statistical analysis

Patient demographic data were tabulated and compared using an independent t-test and Pearson’s chi-square test for continuous and categorical variables, respectively.

The risk of various postoperative complications for patients with hemophilia, relative to matched controls, was assessed by multivariate logistic regression, controlling for age, sex, and ECI score. Adjusted odds ratios [ORs] and 95% confidence intervals [CIs] were tabulated. Kaplan-Meier curves for the hemophilia versus control cohort were compared with a log-rank test.

All statistical analyses were performed using the PearlDiver software or GraphPad Prism, version 9 (GraphPad Software, San Diego, CA). Significance was defined as P < 0.05.

RESULTS

Study population

Based on 1:10 matching (hemophilia to non-hemophilia), the study population consisted of 518 patients with classic hemophilia and 5,193 controls, matched on age, sex, and ECI. For the hemophilia cohort, mean age (± SD) was 62.8 (± 11.6) years, females made up 53.9%, and mean ECI was 5.69 (±4.02). The matched, non-hemophilia population (62.77 ± 11.64 years, 53.8% female, 5.72 ± 4.04 ECI) was not significantly different for any of these demographic variables (P > 0.05 for each) (Table 1).

Table 1.

Characteristics of study population.

	Total		Non-Hemophilia		Classic Hemophilia		P-value
	N	%	N	%	N	%
Overall	5,711	100.0 %	5,193	90.9%	518	9.1%
Age (mean ± SD)	62.77 ± 11.64		62.77 ± 11.64		62.78 ± 11.64		0.99
Age group							1.00
<40	226	4.0%	226	4.4%	22	4.2%
40-49	395	6.9%	359	6.9%	36	6.9%
50-59	1379	24.1%	1254	24.1%	125	24.1%
60-69	1786	31.3%	1624	31.3%	162	31.3%
70-79	1771	31.0%	1610	31.0%	161	31.1%
≥80	154	2.7%	120	2.3%	12	2.3%
Sex							0.98
Male	2,643	46.3%	2,404	46.4%	239	46.1%
Female	3,068	53.7%	2,789	53.8%	279	53.9%
ECI (mean ± SD)	5.71 ± 4.04		5.72 ± 4.04		5.69 ± 4.02		0.91

Hemophilia patients were matched with non-hemophilia patients at 1:10 by age, sex, and Elixhauser Comorbidity Index (ECI). Cohort characteristics were compared by independent t-test (for age and ECI) and Pearson’s chi-square test (for age group and sex) for continuous and categorical variables, respectively. Bold font indicates statistical significance (P < 0.05).

Ninety-day postoperative complications

The incidence of adverse events occurring within the 90-day postoperative period in the two cohorts is depicted in Table 2. Based on multivariate analysis, those with classic hemophilia were at greater odds of aggregated AAEs (OR=1.76), SAEs (OR=2.30), and MAEs (OR=1.52) (P<0.001 for each).

Table 2.

90-day complications following THA, comparing classic hemophilia patients versus matched control cohort.

Complication	Non-Hemophilia		Classic Hemophilia		Odds Ratio	95% Confidence Interval	P-value
	N	%	N	%
Sample size	5,193	91.11%	518	9.09%
Any adverse event (AAE)	899	17.31%	136	26.25%	1.76	1.41-2.18	P < 0.001
Serious adverse event (SAE)	348	6.70%	72	13.90%	2.30	1.74-3.02	P < 0.001
Cardiac arrest	6	0.12%	0	0.00%	na	na	P = 1.00
Myocardial infarction	44	0.85%	3	0.58%	0.68	0.16-1.88	P = 0.52
Sepsis	80	1.54%	11	2.12%	1.41	0.70-2.56	P = 0.30
Surgical site infection	97	1.87%	14	2.70%	1.47	0.79-2.51	P = 0.19
Deep vein thrombosis	156	3.00%	39	7.53%	2.67	1.83-3.81	P < 0.001
Pulmonary embolism	66	1.27%	25	4.83%	4.01	2.50-6.44	P < 0.001
Minor adverse event (MAE)	697	13.42%	94	18.15%	1.52	1.19-1.94	P < 0.001
Pneumonia	117	2.25%	12	2.32%	1.03	0.54-1.82	P = 0.92
Wound dehiscence	48	0.92%	5	0.97%	1.05	0.36-2.42	P = 0.92
Urinary tract infection	247	4.76%	29	5.60%	1.19	0.78-1.75	P = 0.39
Acute kidney injury	154	2.97%	24	4.63%	1.63	1.02-2.51	P = 0.03
Transfusion	231	4.45%	43	8.30%	1.98	1.39-2.76	P < 0.001
Hematoma	45	0.87%	18	3.47%	4.23	2.36-7.28	P < 0.001

For total counts (i.e., any, serious, or minor adverse events), each qualifying patient was only counted once regardless of the number of events the patient experienced in that category. Comparisons were made using multivariate logistic regression, controlling for age, sex, and ECI. Bold font indicates statistical significance (P < 0.05).

Several individual MAEs and SAEs occurred at higher rates in the hemophilia cohort relative to the matched controls. Specifically, for SAEs, VTE including DVT (OR, 2.67; 95% CI, 1.83-3.81; P < 0.001) and PE (OR, 4.01; 95% CI, 2.50-6.44; P < 0.001) were both significantly more common in the hemophilia cohort. For MAEs, risks of transfusion (OR, 1.98; 95% CI, 1.39-2.76; P < 0.001), hematoma (OR, 4.23; 95% CI, 2.36-7.28; P < 0.001), and acute kidney injury (OR, 1.63; 95% CI, 1.02-2.51; P = 0.03) were higher in the hemophilia cohort. Figure 1 depicts odds ratios and 95% confidence intervals of all tabulated adverse events in a Forest plot. These results were preserved when stratifying hemophilia patients by sex.

Figure 1.

90-day complications in classic hemophilia versus controls following THA. Forest plot of odds ratios ± 95% confidence intervals of individual serious and minor adverse events, as well as combined odds ratios of any, serious, and minor adverse events in the hemophilia relative to control cohort. Bold font indicates statistical significance (P < 0.05).

Five-year reoperation rates

THA revision codes were utilized to determine 5-year rates of implant failure using a Kaplan-Meier analysis. There were 209 observed revisions in the control group and 35 observed revisions in the hemophilia group. Five-year implant survival was significantly lower in the hemophilia cohort relative to the control cohort (91.9% vs. 95.3%; P = 0.009). Figure 2 depicts the Kaplan-Meier implant survival curves for the two cohorts.

Figure 2.

Five-year Kaplan Meier survival of THA prosthesis in patients with and without classic hemophilia. Failure is defined as either a single or dual component revision of the THA. Survival curves for hemophilia versus control cohort analyzed by log-rank test, with cumulative prosthesis survival of 0.953 for non-hemophilia patients versus 0.919 for hemophilia patients (P = 0.009).

DISCUSSION

The current study assesses 90-day postoperative complications and five-year implant survival in hemophilia A patients following THA. Despite increased risks of arthritis-related changes in this population, little to no mid- and long-term data currently exist on THA outcomes in patients with hemophilia, and previous studies have been limited by small sample sizes and short follow-up.

Our study found a higher risk of several 90-day adverse events following THA in patients with hemophilia. Based on multivariate analysis, we found that patients with hemophilia had greater odds of bleeding events, namely blood transfusion (OR=1.98) and hematoma (OR=4.23). These findings match prior literature [9,17,19], and highlight the importance of preparing for the likelihood of post-operative blood transfusion following THA in patients with hemophilia and of appropriate factor VIII administration pre-, intra-, and post-operatively to maintain the factor level in the target range (80-100 IU/dl pre- and intra-operatively and 60-80 IU/dl down to 30-50 IU/dl in the 14 post-operative days) [22].

Furthermore, contradicting our hypothesis, we found that those with hemophilia were at greater odds of VTE, including both DVT (OR=2.67) and PE (OR=4.01), relative to matched controls. The inherent risk of bleeding in hemophilia has previously led to contradictory guidance regarding VTE prophylaxis [10,12,15], including explicit recommendations against providing routine pharmacologic VTE prophylaxis [14] and uncertainty about proper VTE prophylaxis due to a paucity of evidence [10,12,15]. The finding of elevated VTE risk in the current large data study provides significant new evidence on this subject, suggesting that surgeons might indeed consider the routine use of VTE prophylaxis for TJA in hemophilia patients.

In addition to noting a greater risk of bleeding, prior studies had suggested an increased risk of infection following joint replacement in patients with hemophilia [23,24], However, the present study failed to demonstrate an increased risk of surgical site infection in hemophilia patients relative to matched controls, a finding borne out by prior smaller studies [9,18,19].

In terms of longer-term outcomes, the current study found those with hemophilia to have a lower 5-year prosthesis survivorship by a difference of 3.4% (91.9% versus 95.3% at five years). Kaplan-Meier analysis shows that hemophilia patients’ prosthesis survivorship fell below that of controls beginning at 6 months following THA and remained inferior throughout the 5-year period following surgery. Based on these trends, we postulate that this difference may persist, or even worsen, over time with longer-term follow-up. This is a critical metric speaking to long-term results, one which has not been explored previously with a robust sample size. Wu et al. and Wang et al. both assessed reoperation rate/prosthesis survivorship and found no prosthesis failure at 113 months following surgery [18] and no difference in 1-year revision rates versus controls [19], respectively; both studies had THA cohorts of less than 40 patients. Nonetheless, the difference in survival observed in the present analysis amounted to 3.4% at 5 years and the TJA survival for both groups remains acceptable (>90%) at a 5-year timeframe, suggesting that THA is generally effective and durable over 5 years in patients with hemophilia A.

There are limitations to the present study that should be noted. Foremost among them is its design as a large database retrospective cohort study. Matching for age, sex, and ECI score was used to control for covariate imbalance; however, it remains possible that there were unrecognized differences between the groups. Second, there are intrinsic limitations associated with administrative data from the PearlDiver database, including lack of data granularity and functional outcome metrics. Third, the study cannot determine the dosing regimen or route of administration for tranexamic acid (TXA) for patients undergoing TJA in the database. The use of TXA in modem TJA surgery has dramatically reduced the risk of postoperative bleeding events and blood transfusions, which likely also benefits patients with hemophilia undergoing these same procedures. Fourth, while female carriers of hemophilia A typically have normal hemostasis and thus are phenotypically normal, a wide range in factor VIII levels has been observed in carriers [25], and thus our dataset likely includes some female carriers of hemophilia, in addition to males and females with a pure hemophilia genotype (X_aY males and X_aX_a females). We were unable to conduct analyses particular to the carrier status. Finally, the precise indications for THA revision in this population, whether based upon clinical or radiographic factors, could not be determined.

CONCLUSION

To the authors’ knowledge, the current national database study is the largest study to date examining 90-day postoperative complications and implant survival at five years in patients with classic hemophilia who underwent THA. Hemophilia patients undergoing THA had elevated risks of both 90-day bleeding complications (transfusion and hematoma) as well as VTE (DVT and PE) relative to matched controls, emphasizing the need to simultaneously balance factor replacement and also consider the use of postoperative VTE prophylaxis. Although the five-year implant survival was lower in hemophilia patients, this difference was less than 4% at five years, suggesting that THA remains effective and durable over five years in patients with classic hemophilia.