Health & Medical Lung Health

Treatment of Venous Thromboembolism With Dabigatran

Treatment of Venous Thromboembolism With Dabigatran

Comparisons With Other New Agents


The results from the dabigatran studies in VTE can mainly be compared with those from the rivaroxaban trials, although there is some general information available also for apixaban and edoxaban.

Efficacy


In the initial treatment studies – two for each of dabigatran and rivaroxaban – the dabigatran trials were almost identical, whereas one rivaroxaban trial included patients with DVT alone (Einstein DVT) and the second one enrolled only patients with symptomatic pulmonary embolism (with or without DVT; Einstein PE), which hampers direct comparison. This is particularly so as the results in Einstein DVT and Einstein PE differed somewhat. In terms of efficacy, neither dabigatran nor rivaroxaban demonstrated superiority against warfarin, although for rivaroxaban in the treatment of DVT there was a strong trend toward better efficacy, which was not seen in Einstein PE. Although the subgroup analysis of RE-COVER indicates similar directions of the efficacy results, the numbers are small and are in the opposite direction in RE-COVER II. A cautious conclusion that the two drugs by indirect comparison appear to have similar efficacy for the initial treatment of VTE is, therefore, probably justified.

The placebo-controlled extension studies RESONATE and Einstein Extension had many features in common in their design and allow for a fair comparison. Both dabigatran and rivaroxaban demonstrated convincing hazard ratios for efficacy versus placebo −0.08 [95% confidence interval (CI), 0.02−0.25] and 0.18 (95% CI 0.09−0.39), respectively.

The extended warfarin-controlled RE-MEDY study does not have any counterpart. It showed that for an average treatment duration of 16 months after 6 months of initial treatment, dabigatran has a similar efficacy as warfarin, maintaining a low annual recurrence rate of approximately 1%.

Safety: Bleeding


Bleeding is the main complication of any anticoagulant therapy. The definition of major bleeding has in the past differed substantially between studies. In the dabigatran studies and in the Einstein program, major bleeding was defined in the same way, adhering to the recommendations of the International Society on Thrombosis and Haemostasis. In the three warfarin-controlled trials with dabigatran, the risk for major bleeding was numerically lower in the dabigatran groups with a trend to superiority in RE-MEDY and hazard ratios between 0.52 and 0.82. Similarly, in Einstein DVT and Einstein PE, there was a reduction in the rivaroxaban groups with hazard ratios of 0.65 and 0.49, respectively, the latter being statistically significant. In both placebo-controlled extension studies, there were a few major bleeding events with dabigatran (n = 2; 0.3%) and rivaroxaban (n = 4; 0.7%) and none in the placebo groups.

Clinically relevant bleeding includes major bleeding, but the nonmajor component is less strictly defined, and therefore a comparison across studies becomes more problematic. Treatment with dabigatran in the three warfarin-controlled studies was consistently associated with a significant reduction of the risk for this type of bleeding with hazard ratios between 0.54 and 0.63. In the Einstein DVT and Einstein PE studies, the corresponding hazard ratios were nonsignificant, 0.97 and 0.90, respectively.

In the placebo-controlled studies, treatment with either drug was at the cost of significantly more events of clinically relevant bleeding with hazard ratios of 2.92 for dabigatran and 5.19 for rivaroxaban.

The only specific bleeding that was more common with dabigatran than with warfarin was gastrointestinal, which occurred in 53 versus 35 patients (not statistically significant) in RE-COVER. The results were similar, reaching statistical significance with the 150mg twice daily dose in the much larger atrial fibrillation trial. The difference compared with warfarin is related to an increase of lower rather than upper gastrointestinal bleeding. This, in turn, seems to be explained by the high concentration of active dabigatran in feces. Rivaroxaban also demonstrated a increase of gastrointestinal bleeding in the study in atrial fibrillation.

In conclusion, dabigatran has in comparison with warfarin a favorable profile regarding the risk of bleeding and probably more consistent than in the rivaroxaban studies.

Safety: All-cause Mortality


Unlike the study with idraparinux for pulmonary embolism, which showed a significant increase of all-cause mortality with the experimental drug, there was no such signal in the dabigatran trials ( Table 2 ). In Einstein DVT, there was a statistical trend toward lower mortality in the rivaroxaban group (hazard ratio 0.67; 95% CI 0.44–1.02) but going slightly in the opposite direction in Einstein PE (hazard ratio 1.13; 95% CI, 0.77–1.65). It is reasonable to believe that both drugs are well tolerated in this respect.

Safety: Acute Coronary Syndromes


There were few events of acute coronary syndromes in this population with venous disease, although in the RE-MEDY trial a statistically significant difference was seen, with 13 events (0.9%) in the dabigatran group versus three events (0.2%) (P = 0.02) in the warfarin group. In RE-COVER that absolute increase in risk was only 0.1%. This effect has been described also in a recent meta-analysis of the dabigatran trials. In the placebo-controlled RESONATE study, there was one event in each group. It is, thus, possible that dabigatran is less protective against myocardial infarction than warfarin but that the drug does not generate acute coronary syndromes. This will obviously require additional studies. There has not been any signal of this kind in the studies on VTE with rivaroxaban or in the studies on arterial indications with any of the neworal factor Xa inhibitors. A secondary analysis of the results from the phase III dabigatran trial in atrial fibrillation showedthat patients with a history of coronary artery disease did not have a higher risk of such events on dabigatran than patients without such history. No recommendation can, therefore, be issued regarding selection of patients with coronary artery disease for treatment with a particular drug.

Safety: Other Adverse Events


The only nonhemorrhagic adverse event that has specifically been ascribed to dabigatran is dyspepsia. This occurred in 2.9% with dabigatran compared with 0.6% with warfarin in RE-COVER and will cause discontinuation of therapy in some patients. Clinical experience indicates that ingestion together with food reduces this occurrence. It is important to provide patients starting on dabigatran with an early follow-up appointment or at least a telephone contact to verify that the treatment is well tolerated and has not been discontinued by the patient.

Convenience


The main difference between the new oral anticoagulants and warfarin is that they can be used without coagulation laboratory monitoring and dose adjustments. The number of interactions with other drugs or food is far smaller than that of warfarin. Furthermore, the elimination is less or not at all dependent on hepatic microsomal enzymes. Dabigatran also has a low degree of binding to albumin. Instead, the elimination of dabigatran is dependent upto 80% on renal excretion, and exclusion of severe renal impairment is necessary before starting on treatment with this drug as well as annually while on treatment, as recently recommended by regulatory authorities. The proportion of patients with VTE that would be excluded due to a creatinine clearance of less than 30 ml/min is approximately 5%, as reported from a large registry on VTE. Notably, the same exclusion criterion was applied in the Einstein studies.

The initial treatment in RE-COVER and RECOVER II was with parenteral anticoagulants and there is, thus, no data on immediate start with dabigatran when VTE is diagnosed. The patients received treatment with unfractionated or low-molecularweight heparin or with fondaparinux for a median of 9 days fromdiagnosis.While there is no theoretical reason why dabigatran, with a time to maximum concentration of 2 h, could not be used as the sole anticoagulant, this cannot be recommended. Edoxaban is the only factor Xa inhibitor that is studied for the treatment of VTE with a similar protocol, using initial parenteral anticoagulation, whereas rivaroxaban and apixaban are given from start or after 1–2 doses of heparin. It is understandable if apixaban or rivaroxaban will be favored by some physicians for this reason, although a reduction of the dose of these drugs is required after1 or3 weeks, respectively. Alternatively, other physicians might prefer initial treatment with a well documented parenteral anticoagulant for patients with extensive DVT or pulmonary embolism. For most patients, a short course of subcutaneous injections once daily is not a major problem. The manufacturers of dabigatran and edoxaban might also decide to perform or support investigators to carry out additional studies with immediate start of oral anticoagulation.



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