Interpretation of the phase 3 trials
The trials have shown that the new anticoagulants are either non-inferior to or superior to conventional therapy for the indications thromboprophylaxis after total hip or knee replacement surgery, prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation, treatment of acute venous thrombosis, even though only rivaroxaban has been approved for this indication as yet. In these trials, the incidence of serious bleeding was the same as or lower than that experienced with conventional anticoagulation therapy. In cases of atrial fibrillation, all three drugs showed a significantly lower incidence of intracranial haemorrhages than warfarin (14, 15, 27).
After the completion of anticoagulation treatment for acute venous thrombosis, there is a considerable risk of recurrence, but because warfarin also entails a significant risk of haemorrhage, the duration of the therapy, particularly after the first episode, is often limited. Secondary prophylaxis with new anti-coagulants can reduce the risk of recurrence by about 70 – 80 % compared with a placebo, without a significant increase in the number of severe haemorrhages (19) – (21).
Trials conducted with standard dose dabigatran, standard dose apixaban and low dose rivaroxaban with acute coronary disease showed inconsistent results as regards clinical efficacy and bleeding risk (22) – (24). Only low dose rivaroxaban resulted in lower mortality without a significant increase in the number of severe haemorrhages (23). Extended thromboprophylaxis with apixaban or rivaroxaban for acutely ill in-hospital medical patients resulted in significantly higher bleeding rates and hence no benefit compared with ten-day treatment with enoxaparin (25, 26).
All clinical trials on these drugs were conducted without adjusting the dose with respect to anticoagulation effect. This means that treatment with dabigatran, rivaroxaban and apixaban can be carried out without monitoring the anticoagulation effect. However, all three have a relatively short half-life. Lack of patient compliance is therefore a potential problem when these drugs are to be used in practice. As a rule, patients taking part in clinical trials are motivated and are closely monitored, which probably leads to greater compliance. It also contributes to more rapid identification and treatment of intercurrent conditions that may arise during treatment.
One such example is deterioration in kidney function/development of kidney failure, which in turn can cause a greater concentration of the drug and risk of bleeding. Expected poor patient compliance was one of the exclusion criteria in most trials, in addition to slight or moderately elevated liver transaminases and bilirubin and uncontrolled hypertension. We therefore know little about patients who belong to one of these groups. The same applies to patients with cancer. A high age was not an exclusion criterion, but there are limited clinical data on patients aged over 75.