Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 4293  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (969 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  Coagulation Medi...
 »  Existing Therapy...
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed345    
    Printed6    
    Emailed0    
    PDF Downloaded75    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
REVIEW ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 5  |  Page : 1200-1212

Critical Issues and Recent Advances in Anticoagulant Therapy: A Review


1 Department of Pharmacology, Maulana Azad Medical College, New Delhi, India
2 Department of Pharmacology, Baroda Medical College and SSG Hospital, Vadodara, Gujarat, India

Date of Web Publication19-Nov-2019

Correspondence Address:
Dr. Bhupinder S Kalra
Department of Pharmacology, Maulana Azad Medical College, New Delhi - 110 002
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.271256

Rights and Permissions

 » Abstract 


As the population is aging, clinicians are coming across more patients with atrial fibrillation and venous thromboembolism requiring anticoagulation to prevent stroke and systemic embolisms. Due to a high prevalence and unfavorable consequences, managing thromboembolic diseases have become areas of clinical concern. Traditional anticoagulants like heparin, low molecular weight heparin and warfarin have been used for the prevention and treatment of venous and arterial thromboses. But, issues of bleeding, parenteral route of administration, or the need for frequent monitoring due to variability in response respectively limit their use. The article gives an overview of coagulation along with existing therapy available for anticoagulation and to present an update on utility and recent advances of new oral anticoagulants (NOACs) beginning from their nomenclature, advantages, disadvantages, precautions and contraindications compared with those of vitamin K antagonists (VKAs) based on a large number of recent studies and clinical trials.


Keywords: Atrial fibrillation, new oral anticoagulants, venous thromboembolism, vitamin K antagonist
Key Message: Recent research and results of various landmark trials have led to the approval of new oral anticoagulants. They have turned out to be immensely fruitful and an outstanding alternative to warfarin in treatment of various arterial and thrombotic disorders. Therefore, an understanding of the basics in terms of need, nomenclature, trial data, advantages and limitations of these agents is important for clinicians prescribing them.


How to cite this article:
Batta A, Kalra BS, Khirasaria R. Critical Issues and Recent Advances in Anticoagulant Therapy: A Review. Neurol India 2019;67:1200-12

How to cite this URL:
Batta A, Kalra BS, Khirasaria R. Critical Issues and Recent Advances in Anticoagulant Therapy: A Review. Neurol India [serial online] 2019 [cited 2019 Dec 7];67:1200-12. Available from: http://www.neurologyindia.com/text.asp?2019/67/5/1200/271256




The process of forming a clot to stop bleeding is known as coagulation. To stop bleeding, the body relies on the interaction of primary and secondary hemostasis:

Primary hemostasis involves two processes.

  1. Vasoconstriction: Vasoconstriction is the body's first response to injury in the vascular wall. When injury occurs, vessel walls constrict to cause reduced blood flow to the site of injury.
  2. Platelet plug formation: Platelets aggregate to the site of the injury. They stick to each other forming a “plug.” Platelets also activate the process which causes a fibrin clot to form, known as secondary hemostasis.


  3. Secondary hemostasis.

  4. Platelets alone are not enough to secure the damage in the vessel wall. A clot must form at the site of injury. Synthesis of a clot depends upon various mediators called clotting factors. These factors are designated by roman numerals I through XIII. These factors or proenzymes activate each other in what is known as the clotting cascade. The outcome is the synthesis of fibrinogen, a soluble plasma protein, which is cleaved into fibrin, a nonsoluble plasma protein. The fibrin proteins intercalate with each other forming a clot.


Clotting is a complex cascade of enzymatic reactions in which each clotting factor activates another factor in a fixed sequence till a fibrin clot is formed. The clotting cascade occurs through two separate pathways that interact; the intrinsic and the extrinsic pathway as depicted in [Figure 1].
Figure 1: Pathway of coagulation cascade showing site of action of various anticoagulants

Click here to view


Extrinsic pathway is triggered by external trauma that results in blood to escape from the vascular system. This pathway is quicker than the intrinsic pathway. It involves activation of factor VII. The intrinsic pathway is actuated by trauma inside the vascular system and is activated by platelets, exposed endothelium, chemicals, or collagen. This pathway is slower and involves factors XII, XI, IX, and VIII. The common pathway is the merging point and terminate the pathway of clot production. The common pathway involves factors I, II, V, and X.


 » Coagulation Medical Disorders: Need for Anticoagulation Top


The most common abnormality of hemostasis is thrombosis, i.e. the formation of an unwanted clot within a blood vessel. Atrial fibrillation (AF) poses a major challenge in the medical world. Not only it is associated with a greater risk of stroke (five folds), but is also accompanied with increased mortality when compared to patients in normal sinus rhythm. As the population ages, the incidence of AF is expected to increase, thereby increasing the incidence of stroke and systemic embolism.[1] Cardioversion and catheter ablation (CA) are also treatment modalities available for AF. To minimize the risk of periprocedural thromboembolism without increasing the risk of bleeding during CA is a major challenge. Cardioversion (both electric and pharmacological) is also associated with a definitive risk of thrombotic complications in patients of AF.[1]

Due to a high prevalence and unfavorable consequences, thromboembolic diseases are also of major clinical concern which is often fatal. Venous thromboembolism (VTE) is a term used to describe both deep vein thrombosis (DVT) and pulmonary embolism (PE). It is a global health problem as it affects all races, age groups, and genders.[2] After coronary heart disease and stroke, the third most common cardiovascular disorder is VTE.[3] Treatment of venous and arterial thrombotic phenomena remains a major medical challenge, and the discovery of anticoagulant drugs represents a revolution in medicine. Thrombotic disorders also include acute myocardial infarction (MI) and acute ischemic stroke. These conditions are also treated with drugs such as anticoagulants and fibrinolytics.


 » Existing Therapy for Coagulation Top


Parenteral anticoagulants

Heparin has been used in the management of acute thrombotic episodes. Heparin therapy prevents extension of thrombus and subsequently reduces the risk of nonfatal and fatal PE. However in venography studies, complete lysis of clot with heparin therapy has been seen in less than 10% of acute DVT patients after treatment. Unfractionated heparin (UFH) was the standard of care for initial treatment of acute DVT until the introduction of low molecular weight heparin (LMWH). It furnishes specific anti-Xa activity, has a long duration of action, and better predictability of anticoagulant response than UFH. LMWH can be given once or twice daily subcutaneously without the need of activated partial thromboplastin time monitoring. Also, the rate of heparin-induced thrombocytopenia with LMWH is less as compared with UFH.[2] Fondaparinux is a synthetic and selective inhibitor of factor Xa which was found to be at least as effective and safe as enoxaparin in the initial treatment of symptomatic deep vein thrombosis.

Limitations

Bleeding is the most common adverse effect of anticoagulant therapy. Heparin-induced thrombocytopenia and osteoporosis are the nonhemorrhagic adverse effects of UFH/LMWH therapy. They are caused by the nonspecific protein binding of UFH and are less common with LMWH, owing to decreased molecular charge. Osteoporosis is an adverse effect of long-term use of UFH or LMWH therapy.[1] This is not a major issue of concern in most patients with DVT, who receive only short-term treatment; however, long-term use of heparin can result in substantial bone loss.

Oral anticoagulants (OAC)

For the last 60 years, coumarin derivatives like warfarin and acenocoumarol are the only orally acting vitamin K antagonists (VKAs), which have been used.[3] The mechanism of action of warfarin involves inhibition of vitamin K epoxide reductase (VKOR) which is responsible for the cyclic conversion of vitamin K epoxide to vitamin K hydroquinone (reduced form). Inhibition of this enzyme results in decreased activation of vitamin K-dependent coagulation factors II, VII, IX, and X production by the liver.[2] The structure (racemic mixture) and pharmacokinetic (PK) properties (hepatic metabolism, high protein binding) makes warfarin more prone for the drug interactions. Warfarin has two isomers S-isomer and R-isomer, of which “S” form is more potent. Both the isomers are metabolized primarily by cytochromeP(CYP)2C9 (S-isomer) and CYP1A2 and 3A4 (R-isomer) isozymes.[2]

Warfarin has several limitations like delayed onset (due to long half-life of factor II) and off set of action, drug–drug interactions, and genetic polymorphism leading to variable response. Due to such limitations, warfarin requires frequent monitoring of INR International Normalised Ratio to keep a balance between effectiveness and safety in clinical practice.[2] It is also prone to various drug–food interactions. For example, high intake of green leafy vegetables like cabbage, cauliflower, spinach, and other foods rich in vitamin K in diet would interfere with target INR in patients on warfarin/acenocoumarol and cause labile INR values. Habitual intake of over the counter medications like nonsteroidal anti-inflammatory drugs (NSAIDs)/tramadol or alternative herbal products/foods like garlic, fenugreek for various disorders would increase the anticoagulant action of the VKA and may cause bleeding. Various drug interactions of warfarin have been summarized in [Table 1]. Warfarin along with other VKAs has several limitations that make it challenging to use in clinical practice:

  1. Slow onset and offset of action
  2. Unpredictable response
  3. Narrow therapeutic window
  4. Frequent dose adjustments
  5. Routine coagulation monitoring
  6. Numerous drug–drug interactions
  7. Numerous food–drug interactions
  8. Intracranial bleeding
  9. Warfarin resistance CYP 2C9, VKORC1 genetic polymorphisms
  10. Long half-life (troublesome in cases of emergency surgery required)
  11. kin necrosis if started without LMWH.


Need for new anticoagulants

Despite the discovery and application of many parenteral (unfractionated and low-molecular weight heparins) and oral anticoagulant VKA, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years.
Table 1: Examples of various drug interactions of warfarin

Click here to view


Frequent laboratory monitoring is one of the major challenges with VKAs. Therefore, an oral anticoagulant with wide therapeutic window without routine laboratory monitoring would be a good alternative to VKAs in the treatment as well as secondary prevention of DVT to ensure therapeutic efficacy and minimize bleeding complications.

Newer anticoagulants

In the recent past, a few novel drugs have been released in the market namely dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban for management of thrombosis. These drugs are popularly known as non-vitamin K antagonist oral anticoagulant (NOAC).

New oral anticoagulants and dilemma in their nomenclature

Originally dabigatran (Pradaxa) was assigned the term “novel” in 2010 when it was introduced to the US market.[4] Unlike warfarin, it does not reduce clotting factor production and neither does it bind to antithrombin III to augment its effect like heparin. Dabigatran directly binds to clotting factor IIa (thrombin). This was a novel mechanism for an oral anticoagulant and even for most parenteral anticoagulants. In 2011, rivaroxaban (Xarelto) got approval by the Food and Drug Administration (FDA). Rivaroxaban directly binds to clotting factor Xa which is responsible for activating prothrombin to thrombin. Over the next 4 years, two more direct factor Xa inhibitors (apixaban [Eliquis] and edoxaban [Savaysa]) got approved. The idea of these oral anticoagulants being called novel did not seem relevant after 6 years. Thus, various organizations proposed more reliable names to refer to this important class of oral anticoagulants.

The “N” in NOAC

It stands for “non-vitamin K” in the newest American College of Chest Physicians (CHEST) guidelines which initially stood for “novel.”[5] By adopting NOAC (non-vitamin K), the CHEST guidelines preserved the well-known acronym but updated it to avoid controversies with these agents no longer being novel. Using the same acronym helps include terms within Internet searches and literature evaluations for “NOAC” even though the meaning has been modified. Experts of the NOAC terminology believe that NOAC may be misunderstood to mean “NO anticoagulants,” which could potentially be a life-threatening mistake as “non-vitamin K” contains several letters not captured in the acronym.

Also, there are various alternative acronyms being used. One such terminology being famous and challenging is “DOAC,” which stands for direct oral anticoagulant. This term reflects the novel mechanism of the these anticoagulants (directly binding to specific clotting factors), which might reflect future of oral anticoagulants that have not been developed yet, like those directly binding to other clotting factors (apart from Xa or IIa) within the coagulation pathway. Although the CHEST guidelines have recommended the term NOAC, the International Society on Thrombosis and Haemostasis (ISTH) approved the DOAC acronym in a 2015 recommendations statement largely based on a small survey of 77 board members on thrombosis, hemostasis, anticoagulation, and vascular medicine societies from North America and Europe. In the survey, respondents slightly preferred DOAC (29.9%) over NOAC (28.6%), although the survey asked several questions regarding the safety concerns of the acronym NOAC (being misconstrued as “no anticoagulant”), which likely biased the participants.[6] Specific oral direct anticoagulant, target-specific oral anticoagulant, and oral direct inhibitor are also the terminologies reported and were also present in the ISTH survey, but seems less likely to be adopted in the future.[6]

According to the ISTH survey, terminology was standardized and 89.6% of respondents agreed that a single consensus term is necessary to describe the newest oral anticoagulant drug class.[6] CHEST 2016 guidelines has now adopted NOAC which was the first terminology used, but has major constraints regarding the meaning of “N” and safety issues. Therefore, DOAC seems to be a very reasonable term moving ahead that may be accepted by clinicians to describe these new oral anticoagulants.

Dabigatran

It was the first approved NOAC in the year 2008 by the EU and by the FDA in 2010. The results of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial which compared dabigatran with warfarin formed the basis of the acceptance of the drug.[7] An oral, direct thrombin inhibitor that prevents clot formation by preventing the conversion of fibrinogen to fibrin, dabigatran is indicated to reduce the risk of stroke and systemic embolism in patients with NVAF.[8] Defining “nonvalvular AF” is a matter of debate and is difficult to differentiate from “valvular AF.” It varies from one trial to another and even between North American and European guidelines, which is a source of uncertainity in clinical practice.[9] Currently, “valvular AF” refers to patients with mitral stenosis or artificial heart valves (and valve repair in North American guidelines only) and should be treated with VKAs.[10]

It is a prodrug (dabigatran etexilate) which gets quickly converted to dabigatran in liver by enzymatic reactions after oral ingestion. It can be given with or without food. Its half-life is 12–14 hours and is independent of dose. It does not inhibit CYP450; therefore, its potential for drug–drug interactions is low. Unlike VKA, dabigatran does not require routine coagulation monitoring as it exhibits a predictable dose response.[11] The primary route for dabigatran elimination in humans is renal (80%).[8],[12] Hence, assessment of renal function through the measurement of creatinine clearance (CrCl) prior to initiation of dabigatran is recommended in routine clinical practice.[1]

There are several comparisons of the effects of dabigatran (110 mg) with those of warfarin, and the RE-LY trial showed that dabigatran is not inferior to warfarin with respect to the prevention of stroke or systemic embolism in patients with NVAF. In this trial, dabigatran was compared with warfarin and was associated with similar rates of stroke and systemic embolism. It also showed lower rates of major hemorrhage [Table 2]. Additionally, a higher dose of dabigatran (150 mg) was associated with lower rates of stroke and systemic embolism when compared with warfarin, but with similar rates of major hemorrhage.[7] Also, dabigatran reduced the risk of ischemic stroke, intracranial hemorrhage as well as death but increased the risk of major gastrointestinal bleeding as compared with warfarin in elderly patients with NVAF as shown by a study of Graham et al.[13] The RE-COVER trial showed a rate of recurrent VTE in patients treated with dabigatran (150 mg twice daily) of 2.4% compared with those treated with warfarin, for which the rate was 2.1%. These results showed that dabigatran when compared with warfarin was noninferior for the prevention of recurrent VTE [difference risk 0.4%, 95% confidence interval (CI), 0.8–1.5, P, 0.001 for the prespecified noninferiority margin].[14] The results of both the trials have been compiled in [Table 2]. One of the most common nonbleeding side-effect of dabigatran observed in RE-LY trial was gastroesophageal-reflux-disease like symptoms with dyspepsia resulting in stoppage of therapy.
Table 2: Important clinical trials of dabigatran

Click here to view


Rivaroxaban

Rivaroxaban, the second NOAC approved in 2008 by the European Medicine Agency and by the FDA, was based on the results of the rivaroxaban versus warfarin in nonvalvularv atrial fibrillation (ROCKET AF) trial [Table 3].[15] Rivaroxaban is an oxazolidinone derivative[16] and a selective direct inhibitor of Xa.[17] Activated factor Xa plays an important role in the coagulation pathway because it not only links the intrinsic and extrinsic coagulation cascade but also acts as a rate-limiting step in thrombin generation. Being a nonbasic compound, it is rapidly absorbable and has a high bioavailability (60%–80%) after oral administration.[18] Metabolism of this drug occurs in the liver, primarily via the CYP isozyme CYP3A4.[19] Although there is a lack of information in the literature regarding the use of rivaroxaban in elderly patients, in order to prevent thromboembolic events 5 mg doses of rivaroxaban can be used twice daily in patients above 75 years of age. The role of rivaroxaban in the treatment of VTE was investigated in three large randomized trials in the EINSTEIN programs (EINSTEIN-DVT, EINSTEIN-PE, and EINSTEIN-extension study).[20],[21] In the EINSTEIN-DVT and EINSTEIN-PE trials, rivaroxaban was found equivalent to the standard treatment in the overall population, as well as in older individuals and those with renal compromise[22] [Table 3].
Table 3: Important clinical trials of rivaroxaban

Click here to view


Apixaban

In 2011, another NOAC was got approved by the FDA and by the European Medicine Agency. Apixaban is also a reversible direct Xa antagonist.[23] It exerts a similar anticoagulant activity as rivaroxaban: by the direct inhibition of factor Xa, which is formed by both intrinsic and extrinsic coagulation pathways. Results of the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial led to its approval, which have been summarized in [Table 4].[24] It is absorbed after oral administration quickly with approximately 66% bioavailability and its absorption is not affected by food. It has a time maximum plasma concentration (short tmax), similar to other NOACs, with a half-life of 8–15 hours; however, compared with other new NOACs, apixaban is the most renal friendly drug with renal clearance of only 25%.[25]
Table 4: Important clinical trials of apixaban, edoxaban, and betrixaban

Click here to view


It has a favourable PK and pharmacodynamic (PD) profile. Similar to rivaroxaban, apixaban is metabolized in the liver in the CYP-dependent isozyme pathway (CYP3A4).[19] As noted above, the ARISTOTLE trial was a randomized double-blind trial that compared apixaban with the dose-adjusted warfarin INR of 2.0–3.0 (5 mg twice daily). The authors concluded that apixaban was superior to warfarin for preventing stroke and systemic embolism in patients with AF (1.27% per year compared with 1.60% in the warfarin group). Mortality rates were decreased in the apixaban group when compared with the warfarin group.[24] [Table 4] Moreover, when effectiveness and safety of dabigatran, rivaroxaban, and apixaban in patients with NVAF were compared with that of warfarin individually; apixaban was associated with lower risks of both stroke and major bleeding as per the retrospective analysis done by Yao et al.[26]

Edoxaban (DU-176b)

It was approved in July 2011 in Japan for the prevention of VTE following lower-limb orthopedic surgery. It is an oral, direct specific inhibitor of factor Xa with an approximate 10,000-fold selectivity for factor Xa over thrombin.[27] The FDA gave its approval in January 2015.[28] ENGAGE AF-TIMI 48 trial was undertaken which compared edoxaban with warfarin. It was approved in patients of AF for stroke systemic embolism prevention.[29] In addition, HOKUSAI-VTE was the trial done comparing edoxaban with warfarin for prevention of VTE.[30] The results of both the trials have been highlighted in [Table 4]. It has a half-life of 9–11 hours. The route of elimination is by two pathways; one-third via the kidney and the remaining by feces.[31] Similar to dabigatran and rivaroxaban, edoxaban is also a substrate for the efflux transporter P-glycoprotein (P-gp). So, reduction of the edoxaban dosage by 50% is required when used in combination with strong P-gp inhibitors, such as verapamil.[32] Edoxaban is considered to be a noninferior alternative to warfarin for preventing stroke and systemic embolisms in patients with NVAF, with a lower rate of intracranial bleeding.[33] In addition, edoxaban is approved in cancer-associated venous thromboembolism patients. In these patients, LMWH has been the standard treatment of choice.[34]

Betrixaban

Recently in June 2017, the U.S. FDA approved to betrixaban for the prophylaxis of VTE in adult patients hospitalized for an acute medical illness who are at risk for developing thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. The results of APEX trial were the basis of its approval mentioned in [Table 4].[35] It is a potent, orally active and highly selective and reversible direct factor Xa inhibitor. The primary route of excretion is biliary with a long half-life of 19–27 hours. High fatty food is a hindrance in its bioavailability. Since it is minimally excreted via kidney (5%–7%), its unique pharmacological profile may allow broader use to include patients with renal impairment (CrCl <30 mL/min), a population excluded from previous NOAC trials and with limited anticoagulant option.[36]

It is unlikely to have drug–drug interactions with CYP450 isoenzymes as it undergoes minimal hepatic metabolism. It is believed that betrixaban has low the human Ether-à-go-go-related gene (hERG) affinity, which codes for α subunit of K+ channel. It contributes in coordination of action potential in cardiac muscle. Many drugs act by inhibiting this channel and may caus QT prolongation and sudden death. It has been shown in expert study and a single dose cross-over toxicology study that betrixaban had no significant effect on prolongation of QT interval.[36],[37]

Current status of NOAC and ongoing research

As per the guidelines of European Society of Cardiology in collaboration with European Association for Cardio-Thoracic Surgery 2016, indications for the start of anticoagulation therapy with NOACs in nonvalvular AF are summarized in a flow diagram [Figure 2].[38] There are various other comorbid conditions in which NOAC are being tried. Patients with AF and coronary artery disease (CAD) are a commonly encountered situation and the combination of these diseases are associated with high mortality. VKA is protective after an acute coronary syndrome (ACS). It is well known that warfarin plus aspirin reduces the risk of recurrent ischemic events in these patients. Triple therapy of dual antiplatelet therapy (DAPT) and NOACs doubles the risk of major bleeding after an ACS. However, there have been trials evaluating combinations of NOAC or VKA plus antiplatelet agents postpercutaneous intervention (PCI) and stent placement which have been outlined in [Table 5].[39],[40],[41] They evaluated whether single antiplatelet therapy (SAPT)/DAPT plus NOAC is safer than SAPT/DAPT plus VKA or vice versa.
Figure 2: Flowchart showing use of NOAC in NVAF.#CHA2DS2: Congestive heart failure, hypertension, age = 75 (doubled), diabetes, stroke (doubled), vascular disease, age 65-74, and sex (female)

Click here to view
Table 5: Clinical trials showing results of NOAC use in patients undergoing PCI with stent placement

Click here to view


Pharmaceutical companies emphasize the use of NOACs plus SAPT as a better alternative to warfarin plus DAPT in patients who have undergone PCI to reduce the pill burden and improve compliance to therapy. Rivaroxaban (2.5 mg BID) along with DAPT significantly improves ischemic outcome after ACS, but is accompanied with increased major and intracranial bleeding as per the findings of  Atlas More Details ACS 2-TIMI 51 trial.[42] According to the RE-DUAL PCI trial which compared dabigatran with warfarin, patients with AF who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.[40] The results of COMPASS trial showed that patients with stable atherosclerotic vascular disease, rivaroxaban (2.5 mg BID) plus aspirin had better cardiovascular outcomes but more major bleeding events than those assigned to aspirin alone. The primary outcome was a composite of cardiovascular death, stroke, or MI. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.[43]

In patients of AF, anticoagulants are recommended at least 3 weeks prior and 4 weeks after cardioversion. Evidence for considering the use of NOAC in cardioversion was scarce. However, data have been generated from the post-hoc analysis of the three major pivotal trials namely RE-LY (dabigatran), ROCKET-AF (rivaroxaban), Aristotle (apixaban). NOAC versus warfarin in the setting of cardioversion was compared for the bleeding and thromboembolism rates from the post-hoc analysis. The results of these analyses showed NOAC being a reasonable alternative to warfarin in the patients who are planning to undergo cardioversion.[44],[45],[46] Also, electrical cardioversion in patients treated with NOACs had a similar (and very low) thromboembolic risk as under warfarin.

Since anticoagulation is a must during cardiac ablation, the use of NOAC in these patients has also emerged. Studies have been published investigating dabigatran versus warfarin and rivaroxaban versus warfarin in patients undergoing CA for AF for showing reduced bleeding events. The results of VENTURE-AF trial and RECIRCUIT trial are mentioned in [Table 6].[47],[48] They concluded that in patients undergoing ablation for atrial fibrillation, anticoagulation with uninterrupted dabigatran or rivaroxaban was associated with fewer bleeding complications than uninterrupted warfarin.
Table 6: Clinical trials showing results of NOAC use in patients undergoing CA

Click here to view


In addition, the net clinical and mortality benefit of dabigatran over VKA was maintained in AF patients with a previous MI, as no further increase in incidence of MI was observed in a meta-analysis conducted by Clemens et al.[49] The recently published Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation showed that in the nonvalvular AF patient population, with up to two years of follow-up, the use of dabigatran led to a low incidence of ischemic stroke, major bleeding, and MI in routine clinical care, confirming the sustained safety and effectiveness of dabigatran in clinical practice over two years of follow-up.[50] NOACs are also being tried in patients of heart failure and other cardiac events.[51] Data of these ongoing trials have been summarized in brief in [Table 7].[52],[53],[54]
Table 7: Ongoing trials of NOAC

Click here to view


The rationale for maintenance of therapy varies from patient to patient. Anticoagulation with either warfarin or one of the NOACs is indicated for patients with AF with prior stroke, transient ischemic attack, or a CHA2 DS2-VASc score of 2 or greater.[55] Multiple randomized studies and meta-analyses have shown that the NOACs decrease thromboembolic events and mortality compared to warfarin. However, the risk of bleeding associated with NOACs is not negligible with rates of major bleeding for dabigatran and rivaroxaban being similar to those seen with warfarin. Further, these agents are associated with increased risk of gastrointestinal bleeding. As such, the risk of thromboembolism should be balanced against the risk of bleeding.[55] As patient preferences regarding the relative importance of preventing strokes and avoiding bleeding vary widely, alternative approaches to long-term anticoagulation can to be considered.[56]

Concerns regarding the use of NOAC

Based on data from large Phase 3 trials, patients using NOAC experience an incidence of bleeding, even though it is less severe as compared to warfarin. The number of bleeding-related events is expected to increase with rise in use of NOAC.[57] This bleeding is associated with an increased risk of death particularly when immediate surgical intervention is required. Increased incidence of major bleed is also a concern especially when these agents are coprescribed with antiplatelet agents. Recently, antidotes to dabigatran and factor Xa inhibitors have been approved by the FDA. They are available in the market in cases of major bleeding episodes or suspected overdosing. However, the costs of these antidotes is a major limitation. [Table 8] shows the currently available antidotes to these new blood thinning agents along with their present status. It is also recommended to discontinue dabigatran and apixaban prior to an invasive or surgical procedure due to the increased risk of bleeding.
Table 8: Antidotes available for NOAC's

Click here to view


Drug–drug interactions can occur since all the NOAC's serve as a substrate for the efflux transporter P-gp. Therefore reduction in dose by 50% with strong P-gp inhibitors like verapamil is needed.[57] Many drugs used in patients with AF are P-gp substrates, such as amiodarone, dronedarone, which may result in alteration in plasma concentration.[57] Other drugs like macrolides and naproxen inhibit P-gp and therefore increase bioavailability of NOACs. These interactions are particularly important in geriatric age group where use of NOACs seems inappropriate if the patient is having CKD chronic kidney disease. Moreover, in Beers criteria NOACs are considered as potentially inappropriate medications in patients with age >75 years.[58]

The assessment of kidney profile both at the baseline and during follow-up is important with use of NOAC considering their renal route of elimination. The European Society of Hematology 2012 guidelines recommend the assessment of renal function (CrCl) prior to initiation of all the NOACs not only dabigatran.[1] Various advantages and disadvantages, indications, and contraindications are mentioned in [Table 9] and [Table 10]. The clinician should individualize the therapy based on the patient profile.
Table 9: Advantages and disadvantages of NOAC

Click here to view
Table 10: Indications and limitations of NOAC

Click here to view


Another important issue which can affect patient's choice and compliance toward use of NOAC in routine practice is cost of the therapy when compared to standard VKA. Being new drugs, as well as considering the “out-of pocket” expense, the patient might be skeptical to switch to NOAC.

In clinical practice, use of combination therapy of anticoagulant and antiplatelet drugs like aspirin is generally avoided but few exceptions exists such as:

  1. For secondary prophylaxis of ischemic heart disease in patients with CAD who are under the age of 75
  2. Antiplatelet agents including aspirin or clopidogrel or both that are used postpercutaneous intervention (PCI)
  3. Patients with mechanical valves who are deemed high risk for cerebrovascular events as defined by one of the following factors:


    1. Systemic embolism despite adequate anticoagulation with warfarin,
    2. Left ventricular dysfunction,
    3. Concomitant atrial fibrillation,
    4. Left atrial enlargement,
    5. Caged ball or caged disk valves.


Contraindications for NOAC therapy*

  1. Known hypersensitivity
  2. Renal impairment:


  3. Dabigatran (Pradaxa): CrCl <30 mL/min

    Apixaban (Eliquis): CrCl <25 mL/min

    Rivaroxaban (Xarelto): CrCl <30 mL/min (rivaroxaban may be used in patients with CrCl 15-30 mL in prevention of VTE after elective Total hip replacement (THR) or

    Total knee replacement (TKR)

  4. Clinically significant active bleeding
  5. Significant inherited or acquired bleeding disorder
  6. Hepatic disease with coagulopathy
  7. Organ lesions at risk of bleeding including intracranial hemorrhage in previous 6 months
  8. Indwelling spinal or epidural catheter and during the first 6 h after removal
  9. Mechanical heart valve
  10. Pregnancy or breastfeeding mother.


* Adapted form Clinical Excellence Commission, 2017, NOAC Guidelines are available at: http://www.cec.health.nsw.gov.au


 » Conclusion Top


The new oral anticoagulants or non vitamin K oral anticoagulants (NOACs) have ushered a new era in anticoagulation. Recent research and publication of results of various landmark trials have led to the approval of these agents, resulting in their use by clinicians. They appear as a good alternative to VKAs for stroke prophylaxis in patients with AF, VTE, and in patients planning to undergo cardioversion. Their rapid onset of action offers a potential benefit for initiating therapy in the outpatient setting and can potentially decrease the rate of hospitalization and associated costs. Individually speaking, apixaban appears superior because of better PK and PD properties. Its renal excretion is minimal when compared to other NOACs which is a big benefit in patients with progressive renal insufficiency. Edoxaban has been additionally approved for patients of cancer associated venous thromboembolism. Betrixaban, a recently approved drug, claims to be a better alternative in prophylaxis of VTE patients with a peculiar feature of lower hERG affinity thereby reducing the risk of sudden death.

Additionally, NOACs have been tried in patients of CAD undergoing PCI in combination with antiplatelet agents. Several ongoing trials are being done in patients of heart failure and MI in order to refine the indications further. The results of these trials are awaited and may prove to be an important landmark in the use of these newer agents. Appropriate use of these medications can prove to be immensely fruitful and an outstanding alternative to warfarin in anticoagulation therapy. They have a potential and promising role of replacing warfarin. The cost of therapy is the only concern in the developing world.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Maan A, Heist EK, Ruskin JN, Mansour M. Practical issues in the management of novel oral anticoagulants—,cardioversion and ablation. J Thorac Dis 2015;7:115.  Back to cited text no. 1
    
2.
Parakh R, Krishna PR, Amin P, Bedi VS, Desai S, Dumra HS, et al. Consensus on Management of Deep Vein Thrombosis with Emphasis on NOACs (Non-Vitamin K Antagonist Oral Anticoagulants): Recommendations from Inter-Disciplinary Group of Indian Experts. J Assoc Physicians India 2016;64:7-26.  Back to cited text no. 2
    
3.
Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: Their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015;11:967.  Back to cited text no. 3
    
4.
How CH. Novel oral anticoagulants for atrial fibrillation. Singapore Med J 2015;56:6578; quiz 659.  Back to cited text no. 4
    
5.
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.  Back to cited text no. 5
    
6.
Barnes GD, Ageno W, Ansell J, Kaatz S; Subcommittee on the Control of Anticoagulation of the International Society on Thrombosis and Haemostasis. Recommendation on the nomenclature for oral anticoagulants: Communication from the SSC of the ISTH. J Thromb Haemost 2015;13:1154-6.  Back to cited text no. 6
    
7.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.  Back to cited text no. 7
    
8.
da Silva RM. Novel oral anticoagulants in non-valvular atrial fibrillation. Cardiovasc Hematol Agents Med Chem 2014;12:3-8.  Back to cited text no. 8
    
9.
Martins RP, Galand V, Colette E, Behar N, Pavin D, Leclercq C, et al. Defining nonvalvular atrial fibrillation: A quest for clarification. Am Heart J 2016;178:161-7.  Back to cited text no. 9
    
10.
Fauchier L, Philippart R, Clementy N, Bourguignon T, Angoulvant D, Ivanes F, et al. How to define valvular atrial fibrillation?. Arch Cardiovasc Dis 2015;108:530-9.  Back to cited text no. 10
    
11.
Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of subgroups. Thrombosis 2013;2013:640723  Back to cited text no. 11
    
12.
Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386-99.  Back to cited text no. 12
    
13.
Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, et al. Cardiovascular, bleeding, and mortality risk in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131:157-64.  Back to cited text no. 13
    
14.
Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.  Back to cited text no. 14
    
15.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.  Back to cited text no. 15
    
16.
Little JW. New oral anticoagulants: Will they replace warfarin? Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:570-80.  Back to cited text no. 16
    
17.
Hoffman R, Brenner B. The promise of novel direct oral anticoagulants. Best Pract Res Clin Haematol 2012;25:351-60.  Back to cited text no. 17
    
18.
Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-3939 – An oral, direct Factor Xa inhibitor – After multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873-80.  Back to cited text no. 18
    
19.
Weinz C, Radke M, Sshmreer R. In vitro metabolisem of BAY 5979-39 and oral, direct factor Xa inhibitor. Drug Metab Rev 2004;36(Supp 1):98.  Back to cited text no. 19
    
20.
EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510.  Back to cited text no. 20
    
21.
Einstein–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.  Back to cited text no. 21
    
22.
Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous thromboembolism – A systematic review with indirect comparisons. Vasa 2014;43:535-64.  Back to cited text no. 22
    
23.
Gallego P, Roldán V, Lip GY. Novel oral anticoagulants in cardiovascular disease. J Cardiovasc Pharmacol Ther 2014;19:34-44.  Back to cited text no. 23
    
24.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.  Back to cited text no. 24
    
25.
Shantsila E, Lip GY. Apixaban, an oral, direct inhibitor of activated factor Xa. Curr Opin Investig Drugs 2008;9:1020-33.  Back to cited text no. 25
    
26.
Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 2016;5:e003725.  Back to cited text no. 26
    
27.
Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, et al. DU-176b, a potent and orally active factor Xa inhibitor: In vitro and in vivo pharmacological profiles. J Thromb Haemost 2008;6:1542-9.  Back to cited text no. 27
    
28.
O'Riordan M (9 January 2015). FDA Approves Edoxaban for Stroke Prevention in AF and DVT/PE Prevention. Medscape. Available from: http://www.medscape.com/viewarticle/837837. [Last accessed on 2015 Jan 10].  Back to cited text no. 28
    
29.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.  Back to cited text no. 29
    
30.
Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15.  Back to cited text no. 30
    
31.
Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010;121:1523-32.  Back to cited text no. 31
    
32.
Holy EW, Beer JH. Update on the status of new oral anticoagulants for stroke prevention in patients with atrial fibrillation. Cardiovasc Med 2013;16:103-14.  Back to cited text no. 32
    
33.
Rognoni C, Marchetti M, Quaglini S, Liberato NL. Edoxaban versus warfarin for stroke prevention in non-valvular trial fibrillation: A cost effectiveness analysis. J Thromb Thrombolysis 2015;39:149-54.  Back to cited text no. 33
    
34.
Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-24.  Back to cited text no. 34
    
35.
Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016;375:534-44.  Back to cited text no. 35
    
36.
Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manage 2015;11:343.  Back to cited text no. 36
    
37.
Connolly SJ, Eikelboom J, Dorian P, Hohnloser SH, Gretler DD, Sinha U, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: Results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013;34:1498-505.  Back to cited text no. 37
    
38.
Authors/Task Force Members:, Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. EP Europace 2016;18:1609-78.  Back to cited text no. 38
    
39.
Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423-34.  Back to cited text no. 39
    
40.
Cannon CP, Bhatt DL, Oldgren J, Lip GY, Ellis SG, Kimura T, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513-24.  Back to cited text no. 40
    
41.
Pascal Vranckxa, Thorsten Lewater, Marco Valgimigli, Jan G. Tijssend, Paul-Egbert Reimitz, Lars Eckardt et al. Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial. American Heart Journal 2018;196:105-12.  Back to cited text no. 41
    
42.
Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.  Back to cited text no. 42
    
43.
Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.  Back to cited text no. 43
    
44.
Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH, et al. Dabigatran versus warfarin in patients with atrial fibrillation: An analysis of patients undergoing cardioversion. Circulation 2011;123:131-6.  Back to cited text no. 44
    
45.
Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013;61:1998-2006.  Back to cited text no. 45
    
46.
Flaker G, Lopes RD, Al-Khatib SM, Hermosillo AG, Hohnloser SH, Tinga B, et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: Insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014;63:1082-7.  Back to cited text no. 46
    
47.
Cappato R, Marchlinski FE, Hohnloser SH, Naccarelli GV, Xiang J, Wilber DJ, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015;36:1805-11.  Back to cited text no. 47
    
48.
Calkins H, Willems S, Gerstenfeld EP, Verma A, Schilling R, Hohnloser SH, et al. Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017;376:1627-36.  Back to cited text no. 48
    
49.
Clemens A, Fraessdorf M, Friedman J. Cardiovascular outcomes during treatment with dabigatran: Comprehensive analysis of individual subject data by treatment. Vasc Health Risk Manag 2013;9:599.  Back to cited text no. 49
    
50.
Huisman MV, Rothman KJ, Paquette M, Teutsch C, Diener HC, Dubner SJ, et al. Two-year follow-up of patients treated with dabigatran for stroke prevention in atrial fibrillation: Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry. Am Heart J 2018;198:55-63.  Back to cited text no. 50
    
51.
ThomasI, EncisoSilva J, Schlueter M, Greenberg B. Anticoagulation Therapy and NOACs in Heart Failure. Handb Exp Pharmacol 2017;243:515-35.  Back to cited text no. 51
    
52.
Lopes RD, Vora AN, Liaw D, Granger CB, Darius H, Goodman SG, et al. An Open-label, 2×2 Factorial, Randomized Controlled Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention: Rationale and Design of the AUGUSTUS Trial. Am Heart J 2018;200:17-23.  Back to cited text no. 52
    
53.
Zannad F, Greenberg B, Cleland JG, Gheorghiade M, Van Veldhuisen DJ, Mehra MR, et al. Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: The COMMANDER HF trial. Eur J Heart Fail 2015;17:735-42.  Back to cited text no. 53
    
54.
Duceppe E, Yusuf S, Tandon V, Rodseth R, Biccard BM, Xavier D, et al. Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE). Can J Cardiol 2018;34:295-302.  Back to cited text no. 54
    
55.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.  Back to cited text no. 55
    
56.
Stavrakis S, Stoner JA, Kardokus J, Garabelli PJ, Po SS, Lazzara R. Intermittent vs. Continuous Anticoagulation theRapy in patiEnts with Atrial Fibrillation (iCARE-AF): A randomized pilot study. J Interv Card Electrophysiol 2017;48:51-60.  Back to cited text no. 56
    
57.
Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al., Advisors:. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. EP Europace. 2015;17:1467-507.  Back to cited text no. 57
    
58.
Sehgal V, Bajwa SJ, Bajaj A. New orally active anticoagulants in critical care and anesthesia practice: The good, the bad and the ugly. Ann Card Anaesth 2013;16:193-200.  Back to cited text no. 58
[PUBMED]  [Full text]  


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow