nonasbestos agents (e.g., erionite, silicates, and manmade fibers), rib fractures, drug-induced pleuritis, rheumatoid pleurisy, uremic pleurisy and Hemothorax2.
New Drug Information
DABIGATRAN ETEXILATE - A DIRECT THROMBIN INHIBITOR. VV JAIN *, S YELWATKAR*, JYOTI JAIN**
Anticoagulants play a major role in thrombosis prevention. For more than 60yrs since its development, Warfarin has ruled the domain of anticoagulation. But the journey has been marred with many problems, like a narrow therapeutic range, delayed onset of action, difficulty with reversal, many interactions with drugs, dietary effects and the need for frequent monitoring. 1 The development of newer anticoagulants has been constructive to overcome some of these difficulties. Dabigatran etexilate is one such new drug in the armamentarium against thrombosis, acting at the end of the coagulation cascade. Although Ximelagatran was the first oral direct thrombin inhibitor to complete phase III clinical trials, including large stroke prevention in AF trials, it has been dropped from further development because of hepatotoxicity. Like Ximelagatran, Dabigatran is an oral prodrug administered once or twice daily and which gets readily converted to active competitive direct thrombin inhibitor. It has a very rapid onset of action, within 2 hrs and has a 14-17hr half life. It has a bioavailability of about 6.5% and majority of the drug is renally excreted. It is a reversible inhibitor of free thrombin and also clot bound thrombin. Recently Dabigatran etexilate received European and Canadian regulators' approval for VTE prevention following orthopaedic surgery based on two studies` ( RE-NOVATE and RE
MODEL) that showed noninferiority to enoxaparin when the latter was given according to a European dosing regimen (40 mg daily beginning 12 hours preoperatively) 2,3,4. The RE-NOVATE trial (Phase III trial) was a double-blind study that included 3494 patients undergoing total hip replacement who were randomized to receive dabigatran 220 mg or 150 mg once daily, starting with a half dose 1 to 4 hours after surgery or enoxaparin 40 mg once daily starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolic events (including both symptomatic VTE and asymptomatic DVT detected by venography) and all-cause mortality. This occurred in 60/897 (6.7%) of patients receiving enoxaparin versus 53/880 (6.0%) of patients in the dabigatran 220 mg group and 75/874 (8.6%) of those in the 150 mg group. The results in both dabigatran groups were non-inferior to enoxaparin based on pre-specified criteria, and there was no significant difference in the rates of VTE or bleeding among the groups 5. Dabigatran did not achieve noninferiority; however, in the other double blind trial, where enoxaparin was dosed 30 mg BID beginning postoperatively. This third Phase III orthopedic study (RE-MOBILIZE) was conducted in North America. This study included 2615 patients undergoing total knee replacement who were randomized to receive 12-15 days of treatment with dabigatran 150 mg daily, dabigatran 220 mg
*Assistant Prof.,**Prof., Dept. of Medicine, M.G.I.M.S.
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VV Jain & et al
A long-acting agent like dabigatran also offers the potential for a better option for stroke prevention. This strong rationale for using a thrombin inhibitor for stroke prevention underpinned the RE-LY study, which looked at patients with atrial fibrillation plus one stroke risk factor 8. Warfarin, Compared with Dabigatran in 18, 113 patients with AF and an additional stroke risk factor. Two doses of dabigatran etexilate (110 mg twice daily and 150 mg twice daily), administered in a blinded fashion, were compared with adjusted dose warfarin administered in an unblinded manner. The primary outcome was systemic embolism or stroke (including hemorrhagic stroke); the safety outcome was major hemorrhage defined as a reduction in the hemoglobin level of at least 2 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. All outcomes were adjudicated by independent committees blinded as to treatment. The stroke or systemic embolism rate was significantly lower with Dabigatran etexilate at a dose of 150 mg twice daily (1.11%; RR [relative risk] 0.66; 95% CI, 0.53- 0.82; P_ .001 for superiority), compared with warfarin, and the 110 mg BID dose was noninferior (1.53%; RR 0.91; 95% CI, 0.74 -1.11, P _ .001 for noninferiority), compared with warfarin (1.69%). The rate of major bleeding with the 150-mg dose was not different from that with warfarin (3.11% vs 3.36%; RR 0.93; 95% CI, 0.81-1.07; P _ .31), although it was significantly lower with the 110 mg dose, compared with warfarin (2.71% vs 3.36%; RR 0.80; 95% CI, 0.69-0.93; P_ .003). The rates of hemorrhagic stroke with the 110- and 150-mg dabigatran etexilate doses (0.12% and 0.10%) were both significantly lower than with warfarin (0.38%), as were the rates of intracranial hemorrhage (0.23
daily or enoxaparin 30 mg twice daily. Dabigatran was given as a half dose 6 to 12 hours postoperatively, and enoxaparin was started 12 to 24 hours after surgery. As in the prior studies, the primary efficacy end point was the composite of symptomatic VTE, all-cause mortality and asymptomatic DVT detected by screening venography. This end point was reached in 188 of 604 (31.1%) patients in the dabigatran 220 mg group, 219 of 649 (33.7%) in the 150 mg group and 163 of 643 (25.3%) in the enoxaparin group. Both dabigatran dose regimens failed to show non-inferiority to enoxaparin based on the prespecified margin of 9.2%. The rate of the primary end point was significantly higher in the 220 mg group (P = .02) and in the 150 mg group (P = .0009) compared with enoxaparin. Major bleeding events were uncommon in all three groups and did not differ significantly 6. The RE-COVER trial was a blinded, noninferiority trial of dabigatran etexilate, 150 mg BID, compared with INR (international normalized ratio)-adjusted Warfarin (INR 2-3) for 6 months in more than 2500 patients with acute VTE, all of whom were initially treated with a 5- to 10-day course of standard parenteral heparin therapy. Recurrent VTE occurred in 2.4% of dabigatran-treated patients versus 2.1% of warfarin patients (HR [hazard ratio] 1.10; 95% CI, 0.651.84). Major bleeding occurred at a rate of 1.6% versus 1.9% in dabigatran and warfarin patients, respectively. The results showed highly significant non-inferiority of dabigatran in the treatment of VTE after initial use of low-molecular weight heparin 7. Overall, the results of these studies indicate that dabigatran appears safe following major orthopedic surgery and is effective in reducing the rate of VTE. 61
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Dabigatran Etexilate - A Direct Thrombin Inhibitor.
prevention of strokes in patients with atrial fibrillation 9. But of course dabigatran would be more expensive than our good old warfarin. But there will be obvious cost reduction from the reduced number of strokes.
vs 0.30 for dabigatran vs warfarin; P_.001). The study has been criticized because of the relatively high rate of major bleeding experienced in the warfarin group, compared with other large AF trials. The investigators attribute this to the greater use of aspirin in this study and to differences in the definition of major bleeding from other studies. The most bothersome side effect with dabigatran etexilate was dyspepsia, which occurred significantly more commonly with Dabigatran etexilate (11.8% and 11.3% in the 110- and 150-mg dabigatran groups) than with warfarin (5.8%) (P_.001 for both). Myocardial infarction also occurred more commonly with dabigatran (0.72% and 0.74% with 110 and 150 mg of dabigatran etexilate, respectively, compared with 0.53% with warfarin (P_.07 and .048, respectively). The pathophysiology for this difference is unclear, although the authors suggest that it may be due to a greater efficacy of warfarin for the prevention of myocardial infarction. There was no evidence of hepatotoxicity with dabigatran, during the 2-year median duration of the study. In conclusion, dabigatran, 150 mg twice daily, was superior to warfarin in preventing stroke and noninferior to warfarin with regard to major bleeding. Dabigatran, 110 mg twice daily, was superior to warfarin with regard to major bleeding and noninferior to warfarin with regard to preventing stroke. Both doses resulted in a significant reduction of intracranial hemorrhage, compared with warfarin, whereas they also resulted in an increase in myocardial infarctions, although this increase was only statistically significant for the 150-mg BID dose of dabigatran etexilate.
References : 1.
2. 3.
4.
5.
6.
7.
8.
All this was achieved with no need for monitoring. Dabigatran is likely to replace warfarin as the treatment of choice for both prevention of venous thromboembolism and
9.
Meddahi S, Samama MM. Direct inhibitors of thrombin, hirudin, bivalirudin, and dabigatran etexilate. J Mal Vasc. 2011 Jan 14. Jack Ansell. Warfarin versus New Agents: Interpreting the Data. Hematology 2010:221 Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Friedman RJ; the RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011 Jan 12;105(4). The RE-MOBILIZE Writing Committee. The oral thrombin inhibitor dabigatran etexilate vs. the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009 Jan; 24(1):1-9. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran.Am Heart J.2009 May;157(5):805-10, 810.e1-2. A. John Camm. The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapy: dabigatran vs. Warfarin. European Heart Journal (2009) 30, 2554-2555.
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PICTORIAL CME VV JAIN *, OP GUPTA **, H PAWADE ***, SAMEER***
Fifty yr old male presented to us with complaints of distention of abdomen, breathlessness and weight loss since 15-20 days. He had a history of pulmonary tuberculosis 20 yrs back for which he had taken treatment for about 1 year. On investigation we found a homogenous ovoid opacity in right mid and lower zone of his chest X ray. There were calcifications present in this opacity and there was loss of lung volume on right side with crowding of ribs suggestive of tuberculosis with pleural calcification.
Hemothorax, chronic empyema or pyothorax and tuberculous pleural effusion usually heal with formation of broad, continuous or multiple discrete plaques, which usually extends from midzone posteriorly along the major fissure 1 . The differential diagnosis of pleural calcifications includes tuberculous pleural effusion, asbestosis, and exposure to nonasbestos agents (e.g., erionite, silicates, and manmade fibers), rib fractures, drug-induced pleuritis, rheumatoid pleurisy, uremic pleurisy and Hemothorax 2. Our patient did not have any history of asbestos exposure or any other history suggestive for other causes. Patient was reassured about his respiratory condition and was discharged.
Fig 1 : Chest X ray P/A view showing a homogenous ovoid opacity in the right mid zone and lower zone with calcifications suggestive of Pleural calcification.
References : 1.
Anubhav Thukral, Digvijay Nath Tiwari, Kamlakar Tripathi. Extensive Pleural Calcification. JAPI. 2010 May; vol 58:314.
2. Clarke CC, Mowat FS, Klesh MA, Roberts MA. Pleural plaques: a review of diagnostic issues and possible nonasbestos factors. Arch Environ Occup Health. 2006 Jul-Aug; 61(4):183-92.
*Assistant Prof., ** Professor, ***Resident, Department of Medicine, MGIMS, Sewagram ,Wardha -442102.
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