RE-COVER II - RE-COVER II

Dec 20, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Boehringer Ingelheim Pharmaceuticals
Date Published:
01/01/2013
Date Updated:
12/20/2013
Original Posted Date:
12/20/2013
References

Description:

In the RE-COVER trial, dabigatan, an orally active direct thrombin inhibitor, demonstrated similar efficacy and lower bleeding as compared with warfarin in the treatment of patients with symptomatic venous thromboembolism (VTE). However, this trial had low event rates. Accordingly, the current trial sought to extend these findings in another patient population.

Hypothesis:

Dabigatran would be noninferior to warfarin for the treatment of acute VTE, with a superior safety profile.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patient Populations:

  • Age >18 years
  • Acute symptomatic, objectively verified proximal DVT of the legs, or PE
  • Appropriate candidate for 6 months of anticoagulation

    Number of enrollees: 2,568
    Duration of follow-up: 6 months
    Mean patient age: 55 years
    Percentage female: 39%

Exclusions:

  • Persistent symptoms of VTE
  • PE requiring urgent intervention
  • Use of vena cava filter
  • Contraindications to anticoagulant therapy
  • Allergy to study medications
  • Elevated aspartate-aminotransferase (AST) or ALT >3x ULN or known liver disease expected to have an impact on survival
  • Severe renal impairment
  • Patients considered unsuitable for inclusion

Primary Endpoints:

  • Recurrent nonfatal or fatal VTE

Secondary Endpoints:

  • Symptomatic DVT
  • Symptomatic nonfatal PE
  • Fatal PE
  • All-cause mortality

Drug/Procedures Used:

Patients with acute VTE received parental anticoagulation per local practice. Thereafter, they received dabigatran 150 mg twice daily orally, in addition to placebo or warfarin (goal international normalized ratio [INR] 2-3), in addition to placebo for 6 months, in a double-dummy fashion. Stratification was by pulmonary embolism (PE) and cancer.

Concomitant Medications:

Low molecular weight heparin (89%), fondaparinux (2%), and aspirin (9%)

Principal Findings:

A total of 2,568 patients were randomized, 1,279 to dabigatran, and 1,289 to warfarin. Baseline characteristics were fairly similar between the two arms. Parenteral anticoagulation was given for 9.5 days in both arms. Time in therapeutic range in the warfarin arm was 56.9%. Average estimated creatinine clearance was 108 ml/min in both arms. The main indications for use of anticoagulation were deep vein thrombosis (DVT) (68%), PE (23%), and both DVT and PE (9%). Approximately 18% of the patients had a history of VTE, and 4% had cancer at baseline.

The primary outcome of recurrent VTE or death due to recurrent VTE was noted in 2.3% of patients in the dabigatran arm, and 2.2% of patients in the warfarin arm (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.64-1.80, p < 0.001 for noninferiority). All-cause mortality was also similar between the two arms (2.0% vs. 1.9%, p > 0.05). There were three fatal PEs in the dabigatran arm versus none in the warfarin arm. Acute coronary syndrome/myocardial infarction events were numerically higher in the dabigatran arm (0.3% vs. 0.2%).

The secondary endpoint of major bleeding was similar between the dabigatran and warfarin arms (1.2% vs. 1.7%, HR 0.69, 95% CI 0.36-1.32). The combined endpoint of major or clinically relevant nonmajor bleeding was lower in the dabigatran arm (5.0% vs. 7.9%, HR 0.62; 95% CI 0.45-0.84). There were two intracranial hemorrhages in the dabigatran arm versus six in the warfarin arm. There was a significant interaction with age (p = 0.01), with higher bleeding with dabigatran in patients >85 years of age.

An adverse event leading to study discontinuation was similar (7.8% vs. 7.8%). Common adverse events included dyspepsia. The incidence of liver damage (alanine-aminotransferase [ALT] >3 upper limit of normal [ULN], bilirubin >2 x ULN, 0.1% vs. 0.2%) was similar between the two arms.

Pooled analysis: On pooled analysis of patients from RE-COVER and RE-COVER II (n = 5,107), efficacy for the primary endpoint was similar between the dabigatran and warfarin arms at 6 months (2.4% vs. 2.2%, HR 1.09; 95% CI 0.76-1.57). Similarly, major bleeding was similar (1.4% vs. 2.0%, HR 0.73; 95% CI 0.48-1.11). Major or clinically relevant nonmajor bleeding was lower in the dabigatran arm (5.3% vs. 8.5%, HR 0.62; 95% CI 0.50-0.76).

Interpretation:

The results of the RE-COVER II study indicate that dabigatran 150 mg bid orally is noninferior in efficacy to warfarin in patients with acute VTE, with a similar to slightly better bleeding profile. In addition, toxic effects on the liver, as noted with ximelagatran, were not present.

These findings are almost identical to those noted in the RE-COVER trial in a slightly different patient population. Similar results have been reported for apixaban (AMPLIFY), rivaroxaban (EINSTEIN-PE, EINSTEIN-DVT), and edoxaban (Hokusai-VTE). These novel anticoagulants are likely to significantly change the management of patients with acute VTE. It is important to note that dabigatran and edoxaban were both studied with an initial course of parenteral anticoagulation, and thus, need to be used as such when indicated. Long-term safety data are necessary.

References:

Schulman S, Kakkar AK, Goldhaber SZ, et al., on behalf of the RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-72.

Keywords: Follow-Up Studies, Morpholines, Warfarin, Thiazoles, Venous Thromboembolism, Creatinine, International Normalized Ratio, beta-Alanine, Azetidines, Benzylamines, Benzimidazoles, Confidence Intervals, Pyridones, Myocardial Infarction, Neoplasms, Acute Coronary Syndrome, Pulmonary Embolism, Bilirubin, Pyrazoles, Pyridines, Dyspepsia, Intracranial Hemorrhages, Liver, Venous Thrombosis


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