Pradaxa - First New Oral Medication To Stop Blood Clotting In Over 50 Years Launched In Ireland Today

Main Category: Blood / Hematology
Also Included In: Vascular;  Regulatory Affairs / Drug Approvals;  Cardiovascular / Cardiology
Article Date: 02 Oct 2008 - 6:00 PDT

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The first new oral medication to stop blood  clotting  since  the  launch of warfarin in the early 1950s has been launched  today.   Pradaxa*  (dabigatran  etexilate)  is the first of a new class  of  oral  anticoagulants  - a direct thrombin inhibitor - to be made available  in  Ireland  by  Boehringer Ingelheim.  One of the most commonly used  anti-clotting agents in this patient group currently is low molecular weight  heparin (LMWH), which must be administered - often by the patient - as  an  injection.   As  Pradaxa*  is  given  as an oral dose it avoids the patient  having  to  get an injection and can be taken conveniently both in and  out  of  the  hospital  setting. In addition Pradaxa* does not require coagulation  monitoring**,  so  a  patient  does not have to go for regular blood  tests  to  determine  that  the  clotting tendency of their blood is within the appropriate limits.

The  initial  licence  for Pradaxa* is for the primary prevention of venous thromboembolic  events  (VTE) in adult patients who have undergone elective hip  replacement  surgery or elective knee replacement surgery.(1) A venous thrombosis  is  a  blood  clot that forms within a vein and thrombosis is a specific term for a blood clot that remains in the place where it formed.

Many  of  the  5,000  Irish patients (2) in public hospitals who every year undergo  total  hip  or  knee  replacement  are at high risk of a deep vein thrombosis  (DVT) where a blood clot forms inside a deep vein, partially or totally  blocking  flow of blood.  Without thromboprophylaxis (treatment to prevent  VTE)  as  many as 60 per cent will go on to develop DVT (deep vein thrombosis;  which  may  or  may not be associated with any symptoms).  One quarter  to  one  third  of  these thrombi involve the proximal deep veins, resulting  in a greater likelihood of symptoms and PE (pulmonary embolism - a blood clot in the lungs which is potentially fatal).(3)

Guidelines,  including those published by National Institute for Health and Clinical  Excellence  (NICE)  in  the UK last year, recommend that patients undergoing  elective  hip replacement surgery with one or more risk factors for  VTE  (e.g.  over  the  age  of  60  years)  should continue to receive thromboprophylaxis  for  four weeks after their operation.(4) Similarly, it is  recommended  that  patients  undergoing  total knee replacement surgery receive up to 10 days thromboprophylaxis.(3)

However  a paper published in The Lancet this January concluded that whilst a  large proportion of hospital patients are at risk of VTE, there is a low rate  of  appropriate  preventative measures used.  Findings from the study revealed  that  in  Ireland  less  than  half  of  medical patients receive recommended prophylaxis.(5)

Moreover,  a  recent report published in the UK highlighted that VTE caused in  excess  of  25,000  deaths  per  annum  in  hospitals in England alone, exceeding the combined total of deaths from breast cancer, AIDS and traffic accidents.(6)   If rates are similar in Ireland, this translates into 2,000 deaths.

Pradaxa*  does  not  require  coagulation  monitoring**(7,8),  which  means patients  do  not  need  to  have  regular blood tests to check coagulation activity.   Pradaxa*  also  does  not  interact  with  food  and  has a low potential  for  interactions  with  drugs  metabolised  by  cytochrome P450 enzymes.(9)

Pradaxa*  works  by  targeting and inhibiting thrombin, the central and key enzyme implicated in the formation of blood clots.(10,11)

The  granting  of the licence for Pradaxa* by the European Medicines Agency (EMEA)  follows the submission of efficacy and safety data in February 2007 from  the  phase  III  RE-NOVATE  and RE-MODEL studies.(12,13)   Oral, once daily administration of both 150 mg and 220 mg Pradaxa* was demonstrated to be  as  effective  and  well  tolerated as injectable enoxaparin (40 mg) in preventing  VTE  and  all  cause  mortality following total hip replacement surgery  and  total  knee replacement surgery in the RE-NOVATE and RE- MODEL trials, respectively.(12,13)

With  all  anticoagulant  agents it is important to optimise the balance of efficacy  and  safety.   In  addition  to the critically important bleeding profile,  hepatic  and  cardiac  safety  needs to be considered, as well as tolerability.  In both the RE-NOVATE and RE-MODEL trials, the incidence and severity  of  major  bleeding  (including  those  occurring at the surgical site), observed with Pradaxa* was comparable to enoxaparin.

In  terms  of  cardiac  safety  profile, no incidences of adjudicated acute coronary syndrome (ACS) events were reported during 3 months follow up with Pradaxa*  220  mg,  suggesting no rebound coagulation effect once treatment ends.(12,13)

Patients were frequently monitored and assessed for liver enzyme elevations by  an independent data safety monitoring committee.  Rates of liver enzyme alanine  aminotransferase  (ALT)  elevations  greater  than three times the upper limit of normal (ULN) were comparable to enoxaparin.(12,13)

The  incidence  of other adverse reactions across all categories (i.e. from very  rare to very common events) for both doses of Pradaxa* was comparable to  enoxaparin.(13,14)   In  addition,  treatment  discontinuation for both doses of Pradaxa* was similar to that seen with enoxaparin.(12.13)

NICE has recently recommended Pradaxa*, within its marketing authorisation, as  an option for the primary prevention of venous thromboembolic events in adults  who  have  undergone  elective  total  hip  or  elective total knee replacement surgery throughout the National Health Service (NHS) of England and  Wales(15).  NICE  highlighted  that  oral  administration of Pradaxa*, without  the need for monitoring, would reduce administration costs and may support  the  adherence  to  treatment(15).  This  NICE  recommendation  of Pradaxa*  provides widely recognised endorsement for the product's clinical efficacy, safety and cost effectiveness.

Boehringer  Ingelheim  continues  to  evaluate  the  efficacy and safety of Pradaxa*  in  a range of thromboembolic disease conditions. RE-VOLUTION (TM) is  an  extensive  clinical  trial  programme  involving  more  than 38,000 patients worldwide.

*Pradaxa is a registered trademark
**Please  refer to prescribing information for further information on close clinical surveillance
#  Drug  interactions for Pradaxa*: anticoagulants and platelet aggregation agents;  amiodarone  (reduce  Pradaxa*  dose to 150mg); caution with strong P - glycoprotein  inhibitors  (e.g.  verapamil,  clarithromycin)  or inducers (e.g. rifampicin, St John's wort). Contraindicated with quinidine

References

1.  CHMP press office http://www.emea.europa.eu/whatsnewp.htm

2. HIPE data 2004, from Activity in Acute Public Hospitals in Ireland, 2004 Annual Report, published Dec 2007

3.   Geerts   WH,  Heit  JA,  Glagett  GP  et  al.   Prevention  of  Venous Thromboembolism.  Chest 2004; 126:338S-400S

4.  Reducing  the  risk  of venous thromboembolism in inpatients undergoing surgery.  NICE clinical guideline 46

5.  Cohen  AT,  Tapson VF, Bergmann J-F et al.  Venous thromboembolism risk and  prophylaxis  in  the  acute  hospital care setting (ENDORSE study):  a multinational cross-sectional study Lancet 2008; 371(9610):387-394

6.  The  prevention  of  venous  thromboembolism  in hospitalised patients. Department of Health, House of Commons Health Committee report.  March 2005

7.  Stangier  J,  Rathgen  K,  Staehle  H  et  al.   The  pharmacokinetics, pharmacodynamics  and  tolerability  of  dabigatran  etexilate,  a new oral direct  thrombin inhibitor, in healthy male subjects.  Br J Clin Pharmacol. 2007; 64:292-303

8.  Stangier  J et al.  Pharmacokinetics and pharmacodynamics of the direct oral  thrombin  inhibitor  dabigatran  in  healthy  elderly subjects.  Clin Pharmacokinet 2008; 47:47-59

9.  Blech  S  et  al.   The  metabolism  and disposition of the oral direct thrombin  inhibitor, dabigatran, in humans.  Drug Metab Dispo. 2008; 36:386 -399

10.   Di  Nisio  M  et  al.  Direct thrombin inhibitors.  N Eng J Med. 2005; 353:1028-1040

11.  van Ryn J et al.  Dabigatran inhibits both clot -bound and fluid phase thrombin  in  vitro:   Effects  compared  to heparin and hirudin.  Abstract Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Atlanta, GA, USA, May 2008

12.  Eriksson  BI,  Dahl  OE,  Kurth AA et al Oral dabigatran etexilate vs. Enoxaparin  for  the  prevention of venous thromboembolism after total knee replacement:  the  RE-MODEL  randomized  trial  J.Thromb  Haemost  2007; 5: 2178-2185

13.  Eriksson BI, Dahl OE, Rosenoir N et al.  Dabigatran etexilate compared with  enoxaparin  for  the  extended  prevention  of venous thromboembolism following total hip replacement.  Lancet 2007; 370: 949-956

14. Summary of Product Characteristics for Pradaxa* March 2008

15. http://http:www.nice.org.uk/TA157

About Boehringer Ingelheim

The   Boehringer   Ingelheim  group  is  one  of  the  world's  20  leading pharmaceutical companies.  Headquartered in Ingelheim, Germany, it operates globally  with  144  affiliates  in  47  countries  and  more  than  38,000 employees.   Since  it was founded in 1885, the privately-owned company has been  committed  to  researching,  developing,  manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In  2007,  Boehringer Ingelheim posted net sales of 10.9 billion euro while spending  nearly  one  fifth  of net sales in its largest business segment, Prescription   Medicines,   on   research  and  development.   For  further information about global clinical trials sponsored by Boehringer Ingelheim, please visit:  http://www.boehringer-ingelheim.com

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