**7. Discussion**

#### **7.1 Danaparoid dosing**

Danaparoid dosed at 1250 U b.d., i.v. in adults and 30 U/kg body weight b.d., i.v. in children, appears to be effective and safe for the treatment of PVT or prevention of SOS and TA-TMA. Despite the relatively high danaparoid dosing intensity used in children there were no reports of bleeding complications in any of the studies and case reports supporting its safety in these vulnerable subjects.

Nevertheless, the intermittent dosing regimen based on DIC treatment used for both adults and children is unlikely to be optimal since it takes 2–3 days to reach steady state drug levels, produces post-injection peak levels of drug that could cause bleeding in high risk patients and pre-injection troughs with insufficient thrombosis protection. The antithrombotic action of danaparoid is shared between the 5% by weight HA-HS and the 80% by weight NA-HS subfractions of danaparoid with greatly different half-lives—25 and 7 h respectively. Hence by the time the next 12 hourly danaparoid injection is due there is much less of the NA-HS left in the circulation even at steady-state pharmacokinetics. This subfraction is largely responsible for the

anti-inflammatory and immunosuppressive actions of danaparoid [34]. Hence for TE treatment PK modelling was used to determine a dosing regimen that provided circulating therapeutic danaparoid levels as quickly as possible and maintained the natural ratios of the HS-HS and NA-HS constituents continuously. The ideal regimen was found to be an i.v. loading dose of 2250 U (body weight adjusted—1250 U if <55 kg and 3000 U if >90 kg), followed by a continuous i.v. infusion of 400 U/h × 4 hours, followed by 300 U/h × 4 hours, followed by the maintenance infusion rate of 150– 200 U/h for as long as considered necessary. This regimen immediately attains and maintains the target plasma anti-Xa activity range of 0.4 and 0.8 U/mL and outside Japan is approved for patients with thrombosis. This can be important for increasing the efficacy of danaparoid not only for PVT treatment but also for SOS/TA-TMA prevention since the inflammatory disturbances should respond better to the continuous presence of the NA-HS subfraction of danaparoid. If a bleeding risk is present then the daily danaparoid dosing intensity, can be lowered by reducing the loading dose size by 25%–50% and the maintenance infusion rate to 100–125 U/h.

## **7.2 PVT treatment**

Due to differences in detail between guidelines for the management of PVT, some confusion remains surrounding attempts to evaluate and compare its alternative treatment strategies. Many clinical factors such as the distribution of Child-Pugh status, the cause of cirrhosis, the frequency of cirrhosis, varices or hepatocellular carcinoma, the distribution of PVST and grade of vessel obstruction at the time of antithrombotic initiation, the age of the thrombus, the presence of infection, the inclusion of different antithrombotics and their combination with either AT or UDCA. Furthermore there is a need to standardise what is considered a 'good clinical treatment outcome' for PVT. Is it complete recanalisation only [94], or ≥70% partial recanalisation [58] or is ≥50% [95] sufficient. What assessment criteria for an effect on PVT is best**—**reduction thrombus size, in vessel volume or in portal hypertension or a combination of these possible outcomes? For how long should study end-points be assigned to the original treatment drug**—**2 weeks, 4 weeks or 3 months after switching to an alternative long-term antithrombotic? Such details are crucial for adequate drug comparisons. Even age and gender distributions of studies are not usually considered in the choice of studies included in meta-analyses but can have a profound effect on the clinical responses to treatment. For these reasons I am not convinced of the value of treatment assessment meta-analyses that are more concerned with the mechanics of study design [5, 14] than many of the above clinical issues.

The pooled results of danaparoid treatment suggest that it possesses at least the same efficacy as AT and its performance does not seem to be enhanced by the addition of AT. Danaparoid appears to be safe even in patients with moderate to severe hepatic dysfunction and extensive varices. A Japan-wide survey performed in 2018 [132], revealed that 46% of the 539 patients included in the responses were treated with danaparoid alone or + AT. A comparison of the outcomes of the six most common treatment regimens i.e. heparin, warfarin, danaparoid, heparin + warfarin, danaparoid + antithrombin and no anticoagulant, showed that warfarin produced the highest complete PVT disappearance rate (about 50% compared with danaparoid at 30%). However, the rate of PVT disappearance plus reduction (not defined) was highest for danaparoid about 80% compared with just over 70% for warfarin. The rates of no change and PVT extension were both lowest for danaparoid at about 18% and 2%

respectively. Furthermore, PVT disappearance rates with danaparoid + AT while better than those of heparin were inferior to those achieved with danaparoid alone.

### **7.3 SOS/TA-TMA prevention**

Apart from one study [108] there appears to be agreement on the prophylactic dosing regimens of danaparoid used for adults or children to prevent SOS/TMA. Children above 2 years appear to require almost double the dosing intensity used in adults to achieve the same plasma anti-Xa levels [116], but it does not appear to have compromised safety in terms of bleeding and side-effects.

The study [109] that did not use UDCA co-medication recorded a higher rate of acute GvHD (grades II–IV) for both danaparoid alone and dalteparin alone compared with the much lower rates recorded for both drugs when combined with UCDA in the other major comparative study [110]. Whether this reveals a true effect of UDCA or a centre/patient cohort treatment bias requires further investigation. Acute GvHD is a risk factor for TA-TMA, thus it is unfortunate that the investigators [109] comparing a low intensity danaparoid + UDCA with dalteparin + UDCA and UDCA alone, although detailing measures taken to prevent GvHD, did not refer to it again.

Two comparative studies concluded that danaparoid: 'reduces the incidence of transplant associated microangiopathies' in adults [105] or 'lowers TRM after stemcell transplantation in children' [110] since in both studies danaparoid was superior to dalteparin with or without UDCA. Whether or not these results are due to the antithrombotic action of danaparoid alone or a combination with its anti-inflammatory effects has not been investigated. The latter is likely in view of the positive results of danaparoid use in HIT [133], sepsis [134], APS [135, 136] and paroxysmal nocturnal haemoglobinuria [137].

#### **7.4 HIT development**

Although one patient exposed to danaparoid developed thrombocytopenia it was not reported to be due to HIT. However, of 214 control patients receiving UFH or a LMWH in the danaparoid studies a case of HIT was recorded [109].

#### **7.5 Alternative therapies**

Long term antithrombotic treatment appears to be crucial for preventing PVT recurrences and the VKAs have until recently been the method of choice. However, despite one investigator [56] calculating that warfarin doubled the time of PVT recurrence from 1 to 2 years, eight others [55–59, 61, 62, 67] reported that follow-up treatment with warfarin after initial danaparoid failed to maintain PVT reductions achieved when danaparoid was discontinued. A comparison of warfarin v edoxaban following danaparoid PVT reduction showed that only edoxaban maintained or reduced the already achieved vessel volume reduction.

Whether any pharmaceutical prophylaxis for SOS/TATMA is effective remains controversial, but it appears possible with current therapy options and UDCA is now recommended by the EBMT Handbook and the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines. It is unclear if UDCA improves the efficacy of danaparoid but it appears to improve the safety of DF in patients with a high risk of developing SOS. It is also unclear who should receive prophylaxis and which treatment is most likely to offer the best

risk–benefit ratio so it is interesting that danaparoid is especially effective in reducing both SOS and TRM in children and increases their OS.

DF appears to be efficacious in preventing SOS but at the expense of a high bleeding rate (perhaps related to its pro-fibrinolytic activity). A large prospective Phase III controlled trial of DF v best management without DF was discontinued in 2018. The manufacturers report of the interim analysis of that study concluded 'it would be highly unlikely to reach statistical significance for the primary end-point of SOS survival at Day +30 post HSCT in the final analysis if the study were to complete enrolment' [138]. So that there remains confusion around the evidence for DFG suitability for SOS prophylaxis. Danaparoid however, appears to be safe even when compared with UDCA.

#### **7.6 Cost calculations**

It is difficult to generalise about the cost effectiveness of different pharmacological strategies for SOS prevention due to the unclear duration of drug administration and inter-country differences in basic drug and hospitalisation costs. In Europe the current price of 10 × 750 U ampoules of danaparoid sodium varies between € 975 and € 1250 (price discounting not considered), having been much less when originally approved for DVT prophylaxis. Thus per patient treatment of PVT at 3 A/day for 2 weeks could cost about € 5250. For SOS/TA-TMA prophylaxis danaparoid administration at 3–4 A/ day for the median 2 months treatment duration would cost between € 17,500 and € 30,000. This assumes long term follow-up treatment with a VKA or DOAC to prevent recurrence of the PVT. For DF dosed at 25 mg/kg/day divided into 4 doses the drug cost is about the same as danaparoid. DF is known to reduce hospital stay but this effect is somewhat offset by the fact that unlike danaparoid many patients do not complete their treatment due to adverse events, particularly bleeding and these events incur the costs of additional investigations and treatment. One single centre study [139] found an SOS incidence of 7.4% and a TRM of 19%. Their cost effectiveness analysis led to the conclusion that 'prophylactic DF for children at risk of SOS was not cost-effective with respect to TRM and length of hospital stay'. By contrast the UDCA cost per patient (in 2013) was about € 400 for 2 months treatment [140]. UDCA can be a lifelong treatment but and its cost price may have risen since then. Which is the most cost-effective for the management of SOS/TA-TMA hinges on the desired outcome mere prevention or reducing TRM and increasing OS.
