Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels

Abstract

Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques. This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example. In total, 433 patients with moderate (27%) and mild (73%) haemophilia A treated on demand were included in this study. One year of self-reported data on joint bleed frequency and baseline clotting factor activity were analysed using Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial distributions. Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy. This model showed 18% reduction [Rate ratio (RR) 0.82; 95%confidence interval (CI) 0.77-0.86] of bleeding frequency with every IU dL -1 increase in residual FVIII activity. The actual association is expected to be higher because of exclusion (30 out of 463 patients) of patients on prophylaxis (baseline FVIII levels 0.01-0.06 IU mL )1 ). The best way to analyse low frequency bleeding data is using a negative binomial distribution.

The frequency of joint hemorrhages and procedures in nonsevere hemophilia A vs B

“…In addition, recent data suggest that hemophilia B is associated with a less severe bleeding phenotype than hemophilia A, although the data are inconsistent between studies. [2][3][4][5][6] In a study by den Uijl et al, 7 rates of joint bleeding were found to decrease by 18% for each 1% increase in baseline FA level among 433 Dutch patients with moderate or mild hemophilia A who were receiving on-demand therapy. Limitations of the study were the small number of patients studied, the single data capture point for each patient, and the lack of data from patients with hemophilia B.…”

Recombinant full‐length factor VIII (FVIII) and extended half‐life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling

“…Limits of the middle 50% of the data (IQR limits)* with mild haemophilia showing that those with endogenous FVIII levels below 3% were at high risk of bleeding and consequently of arthropathy, while those with levels above 10% had a significantly lower risk [4]. Moreover, Ahlberg looking at the Swedish cohort of patients on prophylaxis suggested that a FVIII trough level of about 3% would be enough to lower the incidence of arthropathy in most cases [7].…”

“…It has been shown that joint bleeds are absent in patients with endogenous factor VIII (FVIII) levels approaching 12%. Patients with low baseline FVIII levels (<3%) seem to have the highest risk for joint bleeds and those with clotting factor activity levels of 10% and higher seem to have a very low risk [4]. Already in 1965 Ahlberg showed that in patients on prophylaxis with plasma trough levels above 3% arthropathy was rare and milder [7].…”

“…This premise is based on the observation that patients with mild/moderate haemophilia (i.e. with residual plasma coagulation factor levels ≥1%) bleed less frequently and show lower and/or delayed occurrence of arthropathy [4]. Regular administration of factor concentrates every 2-3 days therefore aims to maintain a factor trough level of ≥1%.…”

“…age, joint status, level of physical activity). Therefore, thresholds of 3 and 10 IU dL À1 were chosen in accordance with previously published evidence indicating that (i) a trough level of 1% (1 IU dL À1 ) may not be sufficient to prevent bleeds and chronic arthropathy in all patients [4,7] and (ii) that patients with FVIII levels above 10% had a very low risk for joint bleeds [4]. Recently it was proposed that prophylaxis should aim for a trough a level of 3% instead of 1% [5].…”