Anticoagulation Management in Patients with Valve Replacement · involved valve type is aortic with degenerative etiology.6,7 Surgical repair using either a mechanical or bioprosthetic

Journal of The Association of Physicians of India ■ Vol. 66 ■ January 2018 59

Anticoagulation Management in Patients with Valve ReplacementDevendra Saksena1, S Muralidharan2, Yugal K Mishra3, Vivek Kanhere4, Bipin Bihari Mohanty5, CP Srivastava6, Jagdish Mange7, Manish Puranik8, Manoj P Nair9, Pankaj Goel10, Pankaj Srivastava11, RM Krishnan12, Sathyaki Nambala13, Vikrama Raja14

R e v i e w A R t i c l e

1Professor & Head, Dept. of Cardiac Surgery, Bombay Hospital, Mumbai, Maharashtra; 2Chief Cardiothoracic Surgeon, GKNM Hospital, Coimbatore, Tamil Nadu; 3Director, Department of Cardiovascular Surgery, Fortis Escorts Heart Centre, New Delhi; 4Consultant Cardiothoracic & Vascular Surgeon, Chirayu Health Centre, Bhopal, Madhya Pradesh; 5Chief Consultant Cardiothoracic Surgeon, CARE Hospitals, Bhubaneshwar, Orissa; 6Chief Consultant Cardiac Surgeon, Narayana Hrudayalaya, Jaipur, Rajasthan; 7Chief Cardiothoracic Surgeon, Shree Mahavir Health and Medical Relief Society, Surat, Gujarat; 8Consultant Minimally Invasive Cardiac Surgeon, Seth Nandlal Dhoot Hospital, Aurangabad, Maharashtra; 9Senior Consultant, Cardio Vascular Thoracic Surgery, Aster Medcity, Kochi, Kerala; 10Director, Cardiothoracic & Vascular Surgery, Ivy Healthcare, Amritsar, Punjab; 11Medical Director & Senior Consultant Cardiac Surgeon, Divine Heart & Multi-speciality Hospital, Lucknow, Uttar Pradesh; 12Chief Cardiothoracic Surgeon, Meenakshi Mission Hospital, Madurai, Tamil Nadu; 13Chief Heart Surgeon, Apollo Hospitals, Bangalore, Karnataka; 14Abbott Healthcare Pvt. Ltd.Received: 24.10.2017; Accepted: 25.11.2017

AbstractBackground: Prosthetic valve implantation requires postoperative prophylactic anticoagulation to preclude thrombotic events. The aim of this review is to assess the role of anticoagulation therapy in the management of valve replacement patients.

Methodology: Literature from PubMed, Embase, Medline and Google Scholar were searched using the terms “valvular heart disease”, “anticoagulant”, “mechanical heart valve”, “bioprosthesis”, “bridging”, “Vitamin K antagonist ( VKA)”, and “acenocoumarol”. A committee comprising leading cardiothoracic surgeons from India was convened to review the literature and suggest key practice points.

Results : Prosthetic valve implantation requires postoperative prophylactic anticoagulation to preclude thrombotic events. A paramount risk of thromboembolic events is observed during the first three months after surgery for both mechanical and bioprosthetic devices. The VKA therapy with individualized target international normalized ratio (INR) is recommended in patients after prosthetic valve replacement. Therapies for the management of prosthetic valve complications should be based on the type of complications. Special care is mandated in distinguished individuals and those with various co-morbidities.

Conclusion: In patients with prosthetic valve replacement, anticoagulant therapy with VKA seems to be an effective option. The role for non-VKA oral anticoagulants in the setting of prosthetic valve replacement has yet to be established. Furthermore, whether the novel oral anticoagulants are safe and efficacious in patients after placement of a bioprosthetic valve remains unanswered.

Introduction

Valvular heart disease (VHD) is one of the common causes of

cardiac morbidity and mortality.1 The burden of VHD is growing worldwide due to the high incidence of rheumatic heart disease (RHD), especially in developing countries and the increase in degenerative e t i o l o g i e s i n i n d u s t r i a l i z e d

n a t i o n s . 2 , 3 I n i n d u s t r i a l i z e d countries, the prevalence of VHD is est imated at 2 .5% (2) . Data on the burden of RHD in India comes from hospital data (20-50%), population based studies (2.2-1.6%) and school surveys (0.67-4.54%).4 The pattern of valve involvement is mitral (54.4%), aortic (11.1%), mitral and aortic (18.0%), tricuspid (10.7%) or pulmonary (0.04%). Overall, RHD contributed 63.4% to the prevalence of VHD.5 This pattern of VHD in India is in contrast to the developed countries, w h e r e t h e m o s t f r e q u e n t l y involved valve type is aortic with degenerative etiology.6,7 Surgical repair using either a mechanical or bioprosthetic valve is a common solution practiced globally. The worldwide annual rate of valve replacement is projected around 275,000 to 370,000; of which 55% are mechanical heart valves (MHVs) and 45% are bioprostheses heart valves. In India this number is estimated to be in excess of 10000.8 Global ly , the prosthet ic valve implantations are increasing at a rate of 5-7% per year.9-12 An ideal prosthetic valve with excellent

Journal of The Association of Physicians of India ■ Vol. 66 ■ January 201860

hemodynamic performance and long- term durab i l i ty wi thout enhanced thromboembolic risk or the requirement for long-term anticoagulation therapy does not exist. Choice of operation and the prosthesis used for those patients undergoing valve replacement is important for each individual pat ient and ideal ly should be made together by the patient , cardiologist, and surgeon.

Prosthetic valve implantation requires postoperative prophylactic a n t i c o a g u l a t i o n t o p r e c l u d e thrombotic events; which are the common cause of morbidity and mortality after surgery for VHD. A paramount risk of thromboembolic events is observed during the first three months after surgery for both mechanical and bioprosthetic devices. Nevertheless, mechanical valves exhibit life time thrombotic r i s k . At r i a l f i b r i l l a t i o n ( A F ) , which is a common arrhythmia in VHD, necess i ta tes l i fe long anticoagulation in the majority of patients; especially if it involves mitral valve. Therefore, patients on ant icoagulants are a t r i sk of thrombosis and bleeding, if the target INR leve ls are not m a i n t a i n e d . R e s t r i c t i o n s o n certain physical act ivi t ies are advised subsequently after surgery to reduce chances of bleeding accidents and these compromises the lifestyle of the young patients. These considerations emphasize the importance of addressing proper ant icoagulat ion techniques to minimize postoperative thrombotic

complications, while maintaining acceptable levels of risk related to bleeding.

Anticoagulation in ProsthesisAnticoagulants in mechanical prosthesis

Apart from the thrombogenicity of the intravascular prosthetic m a t e r i a l , m e c h a n i c a l va l v e s cause abnormal flow conditions wi th f low zones wi th in the i r components and areas of high shear stress. This could stimulate platelet activation leading to valve thrombosis and embolic events. A line of evidence shows marked benefits with vitamin K antagonist (VKA) therapy after mechanical valve placement. A meta-analysis inc luding 13 ,088 pat ients for 53,647 patient-years compared no antithrombotic therapy with VKA therapy. The study resulted in statistically significant reductions in the ra te of major systemic embol izat ion ( f rom 4 .0 to 1 .0 events per 100 pat ient-years) , total thromboembolism risk (from 8.6 to 1.8 events per 100 patient-years), and risk of valve thrombosis (from 1.8 to 0.2 events per 100 patient-years).13 Numerous studies have investigated the impact of lower and higher INR targets.14-

18 However, a meta-analysis by ACCP demonstrated an increased risk of major hemorrhage for those targeted for a higher international normalized ratio (INR) and vice

versa. However, the higher targets vary from 3.0 to 9.0 and also no evidence exists demonstrating that higher INR targets have additional benefits over harm.19 Moreover, a study has evaluated the pattern of oral anticoagulant use, achievement of target INR and the complications outside the therapeutic range in India. The study included 70.9% of mitral valve patients of which 58.2% patients were using warfarin and acenocoumarol by 44.8% patients. Thromboembolic complications were reported in 3.6% patients only when the mean INR is <1.6. Hence the study concluded to broaden the INR range from 1.6-4.20

Based on the current evidence, the American College of Chest P h y s i c i a n s ( A C C P ) a n d t h e American College of Cardiology ( A C C ) / A m e r i c a n H e a r t Associat ion (AHA) 19,21 provide recommendations regarding the use of anticoagulation and target INR in patients with mechanical prosthesis, which are comparable in both guidelines and summary of which is presented in Table 1.

Studies revealed, VKA therapy being superior to aspirin therapy alone for total thromboembolism risk and currently there is no evidence to support its replacement by antiplatelet agents (APA) as demonstrated in CAPTA trial.22

The pat ients with mechanical aortic valve were randomized to Coumadin vs aspirin/clopidogrel in this trial. The trial was stopped after valve thrombosis events reported in 22 patients in the APA group.22 Succeeding studies have shown that the addition of aspirin to VKA therapy in patients with mechanical valves leads to reduction in risk of thromboembolism and mortality when compared to VKA therapy alone (65% observed risk reduction in major systemic embolism or death in the aspirin plus VKA group) . 23,24 The addit ion of a t least 50 to 75 mg/day of aspirin is , therefore, recommended in the current ACC/AHA and ACCP guidelines in all patients with mechanical valves, though care must be taken to an individual patient’s bleeding risk.19,21

Anticoagulants in bioprosthesis

Thromboembolic events with

Table 1: The target INR values for prosthetic valve patients on VKA19, 21

Type of valve Target INRAortic position Mitral position

Uncomplicated/without risk

factors

With risk factors$

Uncomplicated/ without risk

factors

With riskfactors$

Mechanical Valve*Bileaflet 2.0-3.0 2.5-3.5 2.5-3.5 2.5-3.5Tilting disc 2.0-3.0 2.5-3.5 2.5-3.5 2.5-3.5Caged ball 2.5-3.5 2.5-3.5 2.5-3.5 2.5-3.5Caged disc valve 2.5-3.5 2.5-3.5 2.5-3.5 2.5-3.5

Bioprosthetic**Xenografts 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0

$AF, previous thromboembolism, LV dysfunction, or hypercoagulable conditions; *VKA plus aspirin, class I indication by ACC (75-100 mg o.d.), ACCP (50-100mg o.d.) recommends aspirin only in high risk patients; **VKA for 3 months in all except uncomplicated aortic valve replacement where ACCP recommends aspirin over VKA and it should be continued if there is no other indication of anticoagulation. Postoperative aspirin (80-100mg o.d.) is recommended for all by ACC, while ACCP recommend aspirin 3 months after replacement.


bioprosthetic valves have been reported to range from 0.2% to 3.3% per year.19,25,26 The risk is higher in the mitral position compared to valves in the aortic position. Studies have demonstrated that bioprosthet ic devices have an increased risk for thromboembolic events during the first three months after the procedure but less than that associated with mechanical valves.27,28

Several large cohort studies h a v e a d d r e s s e d t h e n e e d o f VKA anticoagulation with and without APA after bioprosthetic valve replacement29-32 Numerous Indian studies have demonstrated the benefits of adding APA to anticoagulants.33-35 The optimal antithrombotic regimen and its durat ion af ter placement of a bioprosthetic device are less clear across these studies. The optimal antithrombotic regimen and its durat ion af ter placement of a bioprosthetic device are less clear across these studies.

The variat ion in an optimal

antithrombotic regimen and its duration after valve replacement in the literature have made the r e c o m m e n d a t i o n s g i v e n b y guidelines for bioprostheses to be d i s s imi la r compared wi th the mechanical prosthesis. The ACCP current ly recommends VKA therapy with target INR 2.5 (range 2.0 to 3.0) for the first three months after bioprosthetic mitral valve replacement . For aortic valve replacement with a bioprosthetic device, the ACCP recommends aspirin (50 to 100 mg/day) over VKA therapy for the first three months after surgery, for patients in whom there is no other indication for anticoagulation (i.e., atrial dysrhythmias, history of thromboembolism, etc.). If the patient remains without a definitive indication for anticoagulation, the ACCP recommends the continuation of aspirin therapy without VKA therapy beyond the initial three-month postoperative period in all patients with a bioprosthesis. In the 2014 ACC/AHA guidelines, class I recommendations supporting the

use of VKA therapy in patients wi th b ioprosthet ic va lves are not ava i lab le . The ACC/AHA does, however, offer a class IIa r e c o m m e n d a t i o n s u p p o r t i n g VKA therapy for the first three months after bioprosthetic valve replacement at the mitral position and a class IIb recommendation s u p p o r t i n g V K A t h e r a p y f o r t h e f i r s t t h r e e m o n t h s a f t e r bioprosthetic valve replacement at the aortic position. Aspirin therapy at a dose of 75 to 100 mg/day is recommended in patients regardless of whether ant icoagulat ion is employed in a l l b ioprosthet ic valve patients. Moreover, there are no specific recommendations offered in regards to duration of aspirin therapy in this population. Recommendations from the ACC/AHA largely leave the choice of the antithrombotic regimen in the setting of bioprosthetic valve replacement up to individual clinicians. Several factors that may influence a clinician’s decision include institutionally-specific o u t c o m e s , t h e l i k e l i h o o d f o r patient adherence to medication regimen, prior personal experience, regional convention, and personal preference . The durat ion and i n t e n s i t y o f t r e a t m e n t w i t h aspirin are also left up to the individual clinician’s discretion. These recommendations have been summarized in Table 1.Anticoagulants in TAVR

T r a n s c a t h e t e r a o r t i c va l ve replacement (TAVR) has become established as a treatment option for patients with symptomatic aortic stenosis. In comparison with surgical aortic valve replacement, TAVR offers superior quality of life with similar mortality rates among pat ients at very high surgical risk.36 However, thromboembolic complicat ions f rom TAVR are significant, and stroke, in particular is a concern.37 While the immediate procedural risk relates to valvular debris embolization, 50% of strokes develop after the first day and may re late to non-procedural e v e n t s . 3 6 - 3 8 T h e i n c i d e n c e o f cerebrovascular events after TAVR remains raised for ≤60 days. This implies that the prothrombotic environment of the bioprosthesis

Fig. 1: Post-procedural antithrombotic recommendations in patients undergoing transcatheter aortic valve implantation (TAVI)


itself may be implicated in distal thromboembolism, and therefore ant iplatelet or ant i thrombotic treatment should play an important role in stroke prevention.39

Va r i o u s c o m b i n a t i o n s o f antithrombotic regimens (single-antiplatelet , dual-antiplatelet , or VKAs) have been used, but evidence-based guidance remains lacking. A number of randomized a n d n o n - r a n d o m i z e d s t u d i e s evaluated the risk of embolization, optimal antithrombotic regimen and duration thereof after TAVI.36-

41 The evidence on anticoagulation after TAVI from India is limited t o o n l y f e w c a s e r e p o r t s . 4 2 - 4 3 Antithrombotic recommendations for TAVI from various guidelines are illustrated in Figure 1.

Key pointsAnticoagulants in mechanical prosthesis • VKA therapy with a target INR

range of 2.0 to 3.0 is recommended in patients with mechanical aortic valve replacement without risk factors.

• VKA therapy with a target INR range of 2.5 to 3.5 is recommended in patients with mechanical aortic valve replacement with risk factors- AF, previous thromboembolism,

LV dysfunction, or hypercoagulable conditions.

• In mechanical mitral valve replacement, VKA therapy with a target INR range of 2.5 to 3.5 is recommended in patients with and without additional thromboembolic risk factors.

• With mechanical valves in both the aortic and mitral position, a target INR range of 2.5 to 3.5 is recommended.

• VKA therapy in combination with antiplatelet therapy (aspirin 75- 100mg) is recommended for long-term management over no antiplatelet therapy with mechanical valve prosthesis.

Anticoagulants in bioprosthesis• VKA therapy is recommended in

bioprosthetic aortic valve and mitral valve replacement, with a target INR range of 2.0 to 3.0 over no VKA therapy for 3 months

• In patients with dual valve replacement (aortic, mitral) VKA therapy is recommended with a target INR range of 2.5 to 3.5

• After bioprosthetic aortic or mitral valve replacement, antiplatelet therapy at a dose of 75 to 100 mg/day is recommended

Anticoagulants in TAVR• Anticoagulants are recommended

pretreatment and during treatment.• Life-long aspirin 75-100 mg/day

along with clopidogrel 75 mg daily is recommended for 3- 6 months.

Bridging AnticoagulationThe perioperative management

of patients who are receiving VKAs or antiplatelet drugs and require a surgical or invasive procedure presents a dilemma for practicing clinicians. Several factors such as type, location and number of heart valve prosthesis and type of procedure and r isk factors should be taken into account while managing patients with mechanical heart valves in whom interruption of anticoagulation therapy is needed for diagnostic or surgical procedures. To minimize the delay in achieving therapeutic ant icoagulat ion, a “br idging” a n t i c o a g u l a n t i s p r e s c r i b e d . The “br idge” i s adminis tered p a r e n t e r a l l y ( s h o r t a c t i n g anticoagulant as UFH or LMWH), thereby providing an immediate anticoagulant effect. However, the use of low molecular weight heparin (LMWH) or unfractionated heparin (UFH) as perioperative bridging is an off-label use because their use is not approved by regulatory authorities or drug manufacturers in this clinical setting as a bridging agent. There is a relative paucity of well-designed clinical trials to enlighten best practices. There are a disproportionately large number of methodologically weak observational studies.

Large number of studies have e va l u a t e d , a n d p r o p o s e d a n interval of 1-3 days preoperatively and 7 days postoperatively for VKA interruption. 44 However , VKA interruption may not be required in minor procedures like dental procedures,45-50 minor dermatological procedures51-53 and cataract surgery.54 Furthermore, no wel l s tandardized s tudies were performed regarding the use of LMWH and UFH. However, a study showed no significant difference in thromboembolic and major bleeding between patients bridged with LMWH and those

bridged with UFH.55 Most studies assessing the use of LMWH as bridging anticoagulation have used therapeutic dose regimens; for detailed information refer Douketis et al.56 Two studies have used low dose LMWH (including patients with mitral valve prosthesis),57,58 however, whether the dose utilized is sufficient is not known clearly as it can be argued that higher doses of LMWH are needed for the prevention of arterial thrombosis. The latter, however, is also not established.

O n a c c o u n t o f t h e c u r r e n t e v i d e n c e , A C C a n d A C C P recommend uninterrupted VKA with local hemostasis optimizing agents in procedures with minimal bleeding, such as surgeries on the skin (excision of basal and squamous cell skin cancers, actinic keratosis, and premalignant or cancerous skin nevi), cataracts, glaucoma and dental c leaning or simple treatment for dental caries. For tooth extractions and endodontic procedures, ACCP recommend uninterrupted VKA with co-administration of an oral prohemostatic agent or stopping VKAs for 2 to 3 days (part ia l reversal). However, both guidelines recommend interruption of VKA with bridging anticoagulation in patients with any mitral valve prosthesis, caged-ball, tilting disc aortic valve prosthesis, bileaflet AVR with additional risk factors such as the recent (within 6 months) stroke or transient ischemic attack, prior thromboembolism during the temporary interruption of VKAs. In such cases when the interruption is required, ACC recommends s topping for 2 -4 days while ACCP recommends not less than 5 days before the p r o c e d u r e . B o t h r e c o m m e n d restarting approximately 12 to 24 h after surgery when there is adequate hemostasis instead of la ter resumption of VKAs. Moreover, the reversal of VKA required during emergency surgery or invasive procedures can be achieved by administration of fresh frozen plasma (FFP) or intravenous prothrombin complex concentrate (PCC).


Key points• It is not recommended to interrupt

VKA therapy during minor dental procedures (cleaning), dermatological procedures and cataract surgery due to minimal bleeding.

• In patients with low thrombotic risk (bileaflet AVR without any risk factors) it is recommended to interrupt VKA without bridging.

• Bridging anticoagulation is recommended in patients with any mitral valve prosthesis, any caged-ball or tilting disc aortic valve prosthesis, bileaflet AVR with additional risk factors, patients with recent (within 6 months) stroke or transient ischemic attack, patients with prior thromboembolism during temporary interruption of VKAs.

• When interruption of VKA therapy is required, it is recommended to stop 2-4 or not more than 5 days before the procedure. The VKA should be restarted after 12-24 hours after surgery.

• The reversal of VKA therapy during emergency surgeries can be achieved by administration of FFP or PCC. Low dose vitamin K may be administrated with caution to sustain effects with FFP as rebound is known with vitamin K.

• Interruption of VKA therapy with bridging anticoagulants is recommended for not more than 2 days in case of major surgeries.

Point of Care INR TestingT h e s u b t h e r a p e u t i c t a r g e t

I N R i n c r e a s e s t h e r i s k o f thromboembolic events, on the other side, above the therapeutic INR presents the patient to bleeding risk. Apart from the assistance i n d e c i d i n g t h e a p p r o p r i a t e dosage regimen, monitoring helps in avoiding over coagulat ion. Routine monitoring can help detect dangerous situations well in time, allowing dose adjustment, as well as actions can be taken to prevent recurrence of such situations. The prothrombin time (PT) test is the most common test used to monitor anticoagulation therapy that is expressed as the INR. Further, the time in therapeutic range (TTR) is a good overall measure of the quality of antithrombotic treatment with VKAs in patients with valvular heart disease.59-62

The gold standard for monitoring INR is the lab testing of blood obtained by venipuncture, in the

hospital. The point of care (POC) INR systems can be an alternative to older laboratory test ing of INR. POC testing involves putting a single drop of blood from a f inger st ick, onto a test s tr ip. POC is aimed at convenience for the patient , faster test results to a healthcare provider, faster decision making, improved clinical outcome and reduced healthcare resources. However, these devices are economical as they reduce the cost of visiting the healthcare facility. This is of great importance in India, as most of INR facilities are available far from the urban or semi urban area. These POC devices have shown to be cost-effective for patients on long term anticoagulants.63,64 Studies have found a statistically significant advantage of self-management methods for achieving better INR control in patients with mechanical valves. 65,66 Nevertheless , ACC/AHA recommends the practice of self-management of patients over outdoor INR monitoring for VKA anticoagulation, in patients who are motivated, and can demonstrate competency in self-management strategies.

Key points• Practice of self-management is

recommended in patients who are living in urban and semi-urban areas, who are competent of doing the same.

• Use of POC devices can be alternated with the conventional laboratory testing to reduce hospital visits and the cost of the treatment.

Management of Prosthetic Valve ComplicationsThromboembolic events

T h e a n n u a l r i s k o f thromboembolic events in patients with a mechanical heart valve is 1% to 2% versus 0.7% with a bioprosthetic valve, even with a p p r o p r i a t e a n t i t h r o m b o t i c t h e r a p y . 1 3 , 1 7 T r a n s t h o r a c i c echocardiogram (TTE) is the first step in the evaluation of suspected prosthetic valve thromboembolism to evaluate valve hemodynamics. H o w e v e r , t r a n s e s o p h a g e a l echocardiography (TEE) is needed o f ten , par t i cu lar ly for mi t ra l prosthetic valves.21,67 However, if

the echocardiography findings are unchanged the prosthetic valve should be considered the source of thromboembolism in suspected cases. 68

T h e p a t i e n t s w i t h t h e thromboembol ic event should be evaluated for the adequacy of anticoagulation and any issues related to compliance with medical therapy. Screening questions about symptoms that may be related to embolic events are especially important if anticoagulation has been suboptimal.69 Measures to improve patient compliance and more frequent monitoring should be instituted.70,71 Patients’ education about symptoms related to embolic events and instructing them to promptly report to a healthcare provider immediately after onset of an event should be in routine.72-75

Thrombosis of prosthetic valves

The prevalence of mechanical valve thrombosis is 0.3-1.3% per patient-year in developed countries and 6 .1% per pat ient -year in developing countries.76-78 Type of valve and location also affect the risk of thrombosis. Thrombosis is 20 times more likely to occur in the tricuspid position; mitral prosthetic valve thrombosis is 2-3 times more common than aortic prosthetic thrombosis.

It is suggested to perform TTE in suspected cases of thrombosis. This will allow evaluation of valve hemodynamics and detection of valve stenosis or regurgitation, measurement of left ventricular (LV) size and systolic function, left atrial size, right heart function, and an estimation of pulmonary pressures . 78,79 The TEE a l lows direc t imaging of mechanica l valve thrombosis particularly for thrombi on the left atrial side of the mitral valve.78,80 In addition to TTE and TEE, f luoroscopy can be used to assess annular or valvular calcification, as it enables calcification to be distinguished f r o m f i b r o s i s w i t h a h i g h e r specificity than echocardiography. I t i s a lso useful to assess the kinetics of the mobile part of a mechanical prosthesis. However, ACC recommends TTE in patients with suspected prosthetic valve


thrombosis to assess hemodynamic severity and resolution of valve dysfunction, and if the thrombus is detected, TEE to assess thrombus size and valve motion. The left s i d e d p r o s t h e t i c h e a r t va l ve thrombosis can be treated either wi th f ibr inolyt ics or surgica l intervention. When treating left-sided PVT, the risks associated with re-operative surgery must be weighed aga ins t the r i sks of embol ic complicat ions and bleeding associated with the use of fibrinolytic therapy. Factors that identify patients at risk for adverse outcomes of fibrinolytic therapy include active internal bleeding, history of hemorrhagic stroke, recent cranial trauma or neoplasm, diabetic hemorrhagic retinopathy, large thrombi, mobile thrombi, systemic hypertension (>200 mm Hg/120 mm Hg) , hypotension or shock, and New York Heart Association (NYHA) class III to IV symptoms. The degree of risk is directly related to thrombus size. Thrombus area (2D TEE) >0.8 cm2 and thrombus diameter 1.0 cm is associated with increased embolic risk. Rate of complications increases 2.4–fold, per 1.0 cm2 increase in s ize , which makes surgery better option.80 In patients with recent hemorrhagic stroke, surgery is a better choice because of the bleeding risks associated with fibrinolysis.80 Although RCTs have not been performed, the weight of the evidence favors surgical intervention for left-sided prosthetic valve thrombosis unless the patient is asymptomatic and the thrombus burden is small.81,

82 However, fibrinolysis of right-

sided valve thrombosis appears better option with the resulting small pulmonary emboli seem to be well tolerated and systemic emboli are uncommon.83,84

ACC and ACCP recommend fibrinolytics or surgical intervention for management of PVT; the clinical judgment should be based on the position of the valve (left or right) and thrombus burden as assessed by echocardiography.19,21

Bleeding complications

The incidence of major bleeding complications in patients with a mechanical valve and taking oral anticoagulants varies from 0.34% to 1.32% per patient-year.85 The prominent feature of anticoagulant overdose is bleeding, which may be manifested as nasal bleeds, h a e m a t e m e s i s , h a e m o p t y s i s , gastrointestinal bleeding, vaginal bleeding, haematuria, cutaneous haemorrhages, gingival bleeding, haematomata, and bleeding into joints or menorrhagia. Numerous risk scores have been developed to help predict bleeding events, considering the other comorbidities such as previous gastrointestinal bleeding, chronic kidney disease, previous stroke or myocardial infarct ion, and anemia (Table 2 ) . F u r t h e r m o r e , e x c e s s i v e anticoagulation (INR ≥ 5) greatly increases the risk of hemorrhage. Discontinuation of anticoagulation for 1-2 weeks had a low probability o f t hr omb oe mb ol i c even t s i n patients with high embolic risk.86

I n t h e p r e s e n c e o f m a j o r bleeding (active bleeding) with VKA, four factor prothrombin complex concentrate (FFPCC) or

FFP should be given for reversal of anticoagulation.21,56 However, ACCP recommends additional use of Vitamin K (5-10 mg IV inj.) along with coagulation factors and shows a preference for FFPCC over FFP. In the absence of active bleeding, but INR>10, withholding VKA and administrating oral Vitamin K (1-2.5mg) is recommended.21,56 In the cases of no active bleeding and INR between 4.5-10, withholding VKA with the serial determination of INR, and resuming the same, once the therapeutic INR is achieved is suggested.21,56

Key pointsThromboembolic events• TTE is recommended for diagnosis of

thromboembolic events.• Treatment with tPA and heparin is

recommended to patients with stroke; other vascular occlusions should be managed by surgery.

• Daily aspirin (75-80 mg) is recommended in anticoagulated patients with thromboembolic events with increase in the target INR range (mechanical AVR: 2.5-3, mechanical MVR: 3-4).

• In patients with bioprosthetic valve, who are already on aspirin, addition of VKA can be considered.

• Measures to increase patient compliance (patient education) are recommended in all patients with thromboembolic events.

Thrombosis of prosthetic valves• It is recommended to address adequacy

of anticoagulation (low INR), and exclusion of other causes of high gradients like anemia, tachycardia, fever.

• TTE is recommended in patients with suspected prosthetic valve thrombosis to assess hemodynamic severity and resolution of valve dysfunction.

Table 2: Bleeding risk prediction scores

Risk score Bleeding risk factors Risk classification points

Annual rate of major bleeding

Outpatient bleeding risk index169

Age ≥ 65 years, history of stroke, history of gastrointestinal bleeding, recent MI or, Hct<30% or SCr> 1.5 mg/dl or diabetes; 1 point each

Low: 0Intermediate: 1-2High: ≥3

Low: 3Intermediate: 12High: 30

Contemporary bleeding risk model170

(0.49 x age ≥70 years) + (0.32 x female sex) + (0.58 x remote bleed) + (0.62 x recent bleed) + ( 0.71 x alcohol/drug abuse) + (0.27 x diabetes) + (0.82 x anemia) + (0.32 x antiplatelet therapy)

Low: ≤1.07Intermediate: 1.07-2.18High: > 2.19

Low: 0.9Intermediate: 2.0High: 5.4

HAS-BLED171 Hypertension (SBP>160mmHg), abnormal renal/liver function, stroke, history of bleeding, labile INR, age >65 years), drugs (antiplatelet/NSAIDs/alcohol); 1 point each

Low: 0-1Intermediate: 2High: ≥3

Low: 1.1Intermediate: 1.9High: 4.9

HEMORR2HAGES172 Hepatic or renal disease, ethanol abuse, malignancy, older age (>75 years) reduced platelet function, re-bleeding, uncontrolled hypertension, anemia, genetic factors (CYP2C9 SNP), excessive fall risk, stroke; 1 point each

Low: 0-1Intermediate: 2-3High: ≥4

Low: 2.1Intermediate: 5High: 8.8

MI= myocardial infraction; SBP= systolic blood pressure; NSAIDs= non-steroidal anti-inflammatory drugs


• TEE is recommended to assess thrombus size and valve motion

• UFH is recommended in a very small thrombus burden of left sided PVT, if not treated fibrinolytics are recommended.

• In patients with left PVT, with thrombus burden ≤ 0.8 cm2, fibrinolytics are recommended over surgery.

• Emergency surgery is recommended in case of Left sided PVT with a mobile or large thrombus >0.8 cm2. Fibrinolytics can be considered in patients with contra-indications to surgery.

• The right sided thrombosis can be treated by fibrinolytics if no contraindications to fibrinolytics are present. If fibrinolytic therapy is successful, IV UFH is recommended until the patient achieves an INR of 3.0 to 4.0 for aortic prosthetic and 3.5 to 4.5 for mitral prosthetic valves.

• Patients with protein C and S deficiency are recommended for a change of mechanical to bioprosthetic valves as they are unsuited for Coumadin therapy

Bleeding complications• For patients with VKA associated active

bleeding, withhold VKA, administer FFP or PCC. Vitamin K may also be used with caution.

• In absence of active bleeding, and INR in range of 4.5-10, it is recommended withholding VKA with serial INR determination, and resuming when INR is therapeutic.

• In absence of active bleeding, and INR >10, it is recommended withholding VKA and administering FFP or PCC. Oral Vit.k1 (1-2.5 mg) can also be administered with caution.

Factors Affecting VKA TherapyPharmacogenetics

Growing evidence indicates that up to 60% of the individual p h a r m a c o l o g i c a l r e s p o n s e t o wa r f a r i n m i g h t b e d u e t o genetic variables and affected by polymorphisms in the genes mainly, v i tamin K epox ide reductase complex subunit 1 (VKORC1), the target enzyme of warfarin and cytochrome P450 2C9 (CYP2C9), the main enzyme involved in warfarin metabolism.87 Similarly, many Indian studies have earlier shown that around 75-80% of the Indian population carries VKORC1-1639GG (rs9923231) genotype, which is associated with the high dose requirement.88-92

Recently, FDA has recommended pharmacogenetics testing before in i t ia t ing warfar in . However , ACCP remains against the routine use of pharmacogenetics testing for guiding doses of VKA in patients initiating VKA therapy.93,94

Anticoagulant interactionsDrug-drug interaction

As VKAs are metabolized mainly by cytochrome P-450 (CYP) 2C9, the inhibition of CYP 2C9 results in a decreased catabolism of VKAs and a stronger anticoagulant effect, whereas its induction enhances their catabolism and leads to a lower anticoagulant effect. Drugs such as amiodarone, fluconazole, f l u v a s t a t i n , f l u v o x a m i n e , isoniazid, lovastatin, miconazole, metronidazole , t r imethoprim-sulfamethoxazole, phenylbutazone are known inhibitors of CYP 2C9, thus potentiating VKAs effect.95 Antibiotics, which cause decreased production of vitamin K by the intestinal microbiota result in an increased sensitivity to VKAs. Barb i tura tes ( carbamazepine , rifampicin) are inducers of CYP 2C9.95 Over the counter medications, i . e . p a r a c e t a m o l a n d o t h e r nonsteroidal anti-inflammatory drugs (NSAIDS) were shown to enhance the anticoagulant effect of warfarin, thus patients receiving warfarin must monitor their INR more f requent ly when taking these medicat ions espec ia l ly , paracetamol at doses exceeding 2g/day.96-98 However, acenocoumarol compared to warfarin may elicit lower drug interactions due to less sensitive to metabolic enzymes (CYP2C9) and easy clearance from the body.99 In line with this, ACCP suggests avoiding concomitant treatment with NSAIDs, including COX-2-se lect ive NSAIDs, and certain antibiotics for patients taking VKAs.93 For a more detailed list of drugs interacting with VKA, refer Bungard et al.95

Drug-Herbs interaction

The interaction of VKAs with herbs is well reported in literature. These includes the interaction with Panax ginseng, Hypericumper-foratum, Salvia milthiorizza, Gingko b i l oba , Serenoarepens , Ange l i ca sinensis, Vaccinium species, Allium

sativum, Zingiberofficinale, Tanac-etumparthenium, Luciumbarbarum, Matricariachamomilla, Boswelliaser-rata and Camellia sinensis have been estimated.100,101

Drug -food interaction

Indians with their different d i e t a r y h a b i t s c o m p a r e d t o their western counterparts are m o r e p r o n e f o r V K A s - f o o d interactions. An average Indian consumes more of dietary green leafy vegetables, which would prevent the achievement of target INR in patients with warfarin/a c e n o c o u m a r o l a n d c a u s e variabil i ty in INR values. The interaction between the dietary vitamin K and VKAs is well known. Evidence has demonstrated that anti-coagulated patients should maintain a steady intake of vitamin K once INR stabil i ty has been a c h i e ve d . Pa t i e n t s s h o u l d b e educated not to avoid Vitamin K rich foods; however, they should be advised to maintain the vitamin K content of diet constant. The best way to achieve this is by avoiding changes to normal eating pa t te rns . 102 ,103 ACCP sugges t s against routine use of vitamin K supplementation for patients on VKA.93

Key pointsDrug-drug interaction• It is recommended to avoid drugs

metabolized by cytochrome P450 enhancing or inhibiting VKAs effect during the therapy.

• It is recommended to educate patients on drug interaction with over the counter drugs and antibiotics; and need for frequent monitoring INR when they are used.

Drug-food interaction• Patients are advised to maintain

constant Vit K composition in the diet to avoid fluctuation of VKA therapy.

• Food inhibiting (Cabbage, spinach, brussels, sprouts) and potentiating (Mango, grapefruit, cranberry) the efficacy of VKAs should be taken in moderation while maintaining regularity

Anticoagulation in Special Patient PopulationsPregnancy

Pregnancy is a hypercoagulable state, due to increase in fibrinogen,


f a c t o r s V I I , V I I I a n d X , v o n Willebrand factor, and a relative decrease in protein S activity, stasis, and venous hypertension.104 T h e i n c r e a s e i n t o t a l b l o o d volume affects the distribution of anticoagulants during pregnancy contr ibut ing to unpredictable c h a n g e s i n t h e a m o u n t o f medication required. 105,106 This state of hypercoagulability extends into the postpartum period too, and requires a persistently higher maintenance dose of warfarin.105 Thus, optimal anticoagulat ion therapy is considered essential, but the appropriate choice of agent among the options available (VKAs, hepar in or LMWH) is highly debatable.107

T h e l o w m o l e c u l a r we i g h t of warfarin enables it to cross the placental barrier and cause embryopathy. The embryopathy actions are dose dependent; reduced adverse events are seen with dose <5mg.108-110 However, warfarin can be replaced with LMWH since they do not cross the placenta. The use of heparin is associated with reported incidence of 12-24% of the increased risk of maternal thromboembolic events.111 Henceforth, women of childbearing age should be warned about the teratogenic and harmful ef fects of VKAs, especial ly in early pregnancy. They should be advised to use secure methods of contraception while on VKAs. If pregnancy is suspected, early pregnancy test 5 weeks from last menstrual period must be offered. Hence, if patients are not prior educated about the teratogenic effects, the risk of embryopathy increases with continuous use of VKAs in the 1st trimester.112

T h e c u r r e n t A C C , A C C P guidelines recommend warfarin in first trimester if dose required for target INR is <5mg (or equivalent acenocoumarol dose). VKAs should be replaced with heparin at 36th week of gestation before delivery. T h e r e c o m m e n d a t i o n s f r o m ACC, ACCP and ESC have been summarized in Table 3.21,113,114

Elderly population

Management of anticoagulation in elderly patients represents a particularly challenging issue.

Indeed, this patient population is at high thromboembolic and hemorrhagic r isk . Assessment o f t h e b e n e f i t - r i s k b a l a n c e o f a n t i c o a g u l a t i o n i s t h e key point when decis ions are made about introducing and/or continuing such treatments in the individual elderly patient. In order to maximize the safety of anticoagulation in the elderly, factors like comorbidities and co-medication, pharmacokinetic and pharmacodynamics alteration due to the renal and hepatic function associated with aging, consequences due to insuff ic ient educat ion, need to be considered.115-117 The European society of cardiology- working group on thrombosis recommend considering all of the above factors for antithrombotic therapy in elderly.94,118

Renal impairment

As VKAs are metabolized in the liver, no dosage adjustments are required in patients with chronic renal impairment. Pharmacokinetic studies have shown that anti-Xa activity is prolonged in patients with severe renal impairment (creatinine clearance <30 mL/ min) and, to a lesser extent, in patients with moderate dysfunction (30-50 mL/minute) . 119 The prevalence of AF is reported to be higher in patients with renal impairment. Also, the risk of AF development increases with worsening of renal function.120 Heparin derivatives depend largely on renal excretion; dosage adjustment is necessary in order to avoid accumulation and hence over-anticoagulation.115 Dosage adjustment for factor Xa inhibitors in patients with renal insufficiency is recommended by ACCP.121

Key pointsPregnancy• Women of childbearing age who have

undergone valve replacement should be educated about the importance of early detection of pregnancy and informing the healthcare provider (cardiologist and gynecologist) immediately, which can help to avoid the potential teratogenic and harmful effects associated with higher dose VKAs

Before 36 weeks of gestation• Oral VKA therapy is recommended

throughout pregnancy in patients with daily warfarin dose requirement of ≤5mg (or equivalent acenocoumarol dose) with target INR of 3.

• It is recommended to replace VKAs by LMWH and UFH if warfarin dose>5mg (or equivalent acenocoumarol dose) is required for achieving therapeutic INR.

• Low dose (75-100 mg) aspirin is recommended in second and third trimester (only in high risk patients or all patients or in stable to reduce INR by 0.5 and reduce dose of VKAs).

At 36 weeks of gestation• At 36 weeks of gestation, VKA should

be discontinued and iv UFH or LMWH should be initiated and continued till 36 hours before delivery.

• If vaginal delivery is expected VKA should be discontinued at 34 weeks and LMWH should be administered with monitoring of factor X assays.

• If labor starts unexpectedly, 2-4 mg IV vitamin K and FFP should be administered to reduce risk of fetal injury.

• When hemostasis is adequate, VKA therapy should be restarted on day 1-2 as maintenance dose.

Elderly population• Frequent renal tests and observation

for adverse effects with concomitant medications, are recommended in elderly patients considering them as high risk patients for developing hemorrhagic complications.

Renal impairment• Monitoring of anticoagulation therapy

in renal insufficiency patients is recommended to avoid the risk of over anticoagulation

Concomitant Cardiac DiseaseHeart failure

Prosthetic valve patients are at high risk of congestive cardiac failure due to significant cardiac compromise. Cardiac medicines l i k e a n g i o t e n s i n c o n v e r t i n g enzyme inhibitors, diuretics, and digoxin should be given as per the standard heart failure management guidelines.122 CAD

The concurrent use of dual antiplatelet agents with VKAs has been a major issue in percutaneous c o r o n a r y i n t e r v e n t i o n ( P C I ) patients in an era of widespread use of drug-eluting stents (DES).


Table 3: Recommendations on management of anticoagulation in pregnancy

ACC/AHA21 ACCP113 ESC114

Before 36 gestational weeksOral (VKA) • Can be used throughout pregnancy (class IIa) with

substitution by UFH/LMWH during weeks 6-12 of gestation if

- preferred by the patient - dose of warfarin required to achieve target INR >5mg

(class IIa) - just before planned delivery has to be replaced by

UFH or LMWH (class I) - Strongly recommended in MPV in 2nd and 3rd

trimesters

• Can be used throughout pregnancy in high risk* patients with UFH or LMWH before delivery (grade 1A)

• If warfarin daily dose is <5mg, oral anticoagulation is the safest regimen with 3% embryopathy throughout the pregnancy

Heparin derivatives

• Recommendations on 1) s.c use of LMWH and UFH throughout pregnancy2) s.c UFH in the 1st trimester completely removed in current 2014 guidelines.

• The patients who prefer: **LMWH administered twice daily and the dose should be adjusted to attain peak anti-factor Xa levels: 0.8–1.2 U/mL approx. 4–6 hours after the injection.

• Alternatively, continuous IV UFH (with aPTT at least twice that of the control) during the 1st trimester is permissible if the dose of warfarin >is 5 mg/day

• IV UFH in the first trimester is difficult from a practical standpoint, as a three-month hospital admission is required.

• Monitored UFH or LMWH can be option throughout gestation Or during 6-12 weeks of gestation (grade 1A)

• In low risk patients LMWH should be given twice daily with anti-factor Xa levels of 0.35–0.70 U/mL 4 h after sc injection

• The starting dose should be 100 U/kg of dalteparin and 1 mg/kg of enoxaparin.

• LMWH and UFH considered if warfarin dose>5mg

• LMWH adjusted to achieve anti factor Xa activity of 0.8-1.2 U/ml 4-6 h after administration, monitored on a weekly basis

All of the above guidelines agree that LMWH should be given twice daily and that it is harmful to administer LMWH without regularly monitoring the patient’s anti-factor Xa levels

Aspirin • Low dose (75-100mg/day) given in second and third trimesters (Class I)

• Low dose given in addition to anticoagulation in high risk patients (grade 2C)

• Not recommended

Target INR • 3 for all prosthetic valve patients • 2-3 for patients with bileaflet aortic valves w/o high risk factors*

• No target recommendation

After 36 gestational weeks• The ACC/AHA guidelines suggest stopping warfarin

at 36 weeks and starting continuous IV UFH with aPTT monitoring, which should be continued until approximately 2–3 weeks before the planned delivery.

• Additionally, they recommend that UFH be discontinued 4–6 hours before the planned delivery and restarted 4–6 hours after delivery.

• In the absence of significant bleeding, oral warfarin should then be initiated 24 hours after the birth.

• ESC guidelines suggest stopping warfarin at 36 weeks and starting dose-adjusted IV UFH or LMWH.

• This treatment should continue until 36 hours before delivery, when LMWH should be replaced by IV UFH

• Continuing VKA until the patient is close to term$ (At this point, warfarin should be replaced by IV UFH or LMWH.

• If spontaneous labour occurs on oral anticoagulation, a caesarean section is indicated due to obstetric-related causes.

*First generation prosthesis, mitral valve prosthesis, history of thromboembolism, atrial fibrillation, left ventricular dysfunction; ACC/AHA: American college of cardiology/American heart institute; ACCP: American college of chest physician; ESC: European society of cardiology; INR: international normalized ratio; LMWH: low molecular weight heparin, UFH: unfractionated heparin; **ACC/AHA recommend to discuss the preferred option of anticoagulation in pregnant patients; $although the word term is not specified, it is generally accepted to signify 48 hours before delivery).

Approximately 5% of patients requiring PCI also present with an indication for oral anticoagulation therapy. In such cases, the type of stent selected; the use of oral anticoagulants, antiplatelet, or their combinations; the target INR; and the duration of treatment i s essent ia l cons iderat ions in relation to the risk of thrombosis/t h r o m b o e m b o l i c e v e n t s a n d bleeding risk. Whenever possible, shorter durations of triple therapy are favored in preference to longer durations of triple therapy.123 The

WOEST (What i s the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial is the first published study to address the question of optimal antiplatelet therapy in patients taking oral anticoagulant medication. Patients randomized to single antiplatelet treatment with clopidogrel had significantly fewer b leeding compl icat ions and no increase in thrombotic e ve n t s c o m p a r e d w i t h t h o s e randomized to DAPT with aspirin

and clopidogrel.124

The ACC/AHA recommends in patients with non ST segment elevation acute coronary syndrome (NSTE-ACS) who require oral anticoagulation for AF, mechanical h e a r t v a l v e , d e e p v e n o u s thrombosis, or other conditions, a bare-metal stent may offer the advantages of lower bleeding risk over a DES because of the potentially shorter duration of triple antithrombotic therapy.125 However, these recommendations do not specify the optimal treatment


according to the various indications for anticoagulation or the duration of treatment, nor do they take into account the estimated thrombosis and bleeding risks.Atrial Fibrillation

Overall , i t is estimated that the incidence of post-operative atrial fibrillation is approximately 30% after pure coronary artery bypass grafting (CABG) surgery, 40% following valve replacements o r r e p a i r , a n d i n c r e a s e s t o approximately 50% after combined CABG / valvular procedures.126,127 In a large prospective trial, the Prophylactic Oral Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement , or Repair (PAPABEAR), amiodarone was compared wi th p lacebo . Ora l amiodarone prophylaxis of atrial tachyarrhythmia af ter cardiac surgery was effective and safe.128 Furthermore, a meta-analysis of 19 trials comparing amiodarone with placebo has demonstrated a significant reduction in AF (reduced by 50% in the amiodarone group), ve n t r i c u l a r t a c h ya r r h y t h m i a , s t r o k e s , a n d h o s p i t a l s t a y . Prophylactic amiodarone should be implemented as a routine therapy for high-risk patients undergoing cardiac surgery.129 The addition of beta-blockers can also help in reducing sympathetic triggers of AF post-operatively.130 The European Society of Cardiothoracic Surgery recommends the perioperative use of beta blockers as the first choice in all patients undergoing cardiac surgery, unless otherwise contraindicated.131

Cardiac catheterization in patients with prosthetic valves

B R U I S E C O N T R O L t r i a l , COMPARE trial and some similar t r i a l s e va l u a t e d wa r f a r i n i n patients undergoing implantation of a pacemaker or implantable c a r d i o v e r t e r – d e f i b r i l l a t o r . A s c o m p a r e d t o h e p a r i n o r d i s c o n t i n u a t i o n o f wa r f a r i n w i t h b r i d g i n g , a s t r a t e g y o f cont inued warfar in t reatment markedly reduced the incidence of clinically significant device-pocket hematoma, risk of the stroke and bleeding, and reduction of in-

hospital stay.132,133

The European Heart Rhythm A s s o c i a t i o n ( E H R A) p o s i t i o n d o c u m e n t o n a n t i t h r o m b o t i c management in patients undergoing electrophysiological procedures, recommends un-interrupted VKA in patients undergoing ablation procedures like pulmonary vein isolation ablation (PVI).134 Patients on VKS requiring implantation of cardiac implantable electronic devices should be operated on VKA unless they are a t very low risk for a thromboembolic event. In this particular case, it recommends interrupting VKA without bridging with heparin. The ACC recommends only slight modification in VKA dosing for procedures with a low bleeding risk, such as coronary angiography from the radial approach. With interventional procedures at higher risk, stopping VKA anticoagulation and using bridging therapy as is done for other surgical procedures has been recommended.21 Follow up cardiac evaluation

Doppler echocardiography at baseline (before discharge) serves as a reference for subsequent examinations. The measurements should include regional and global left and right ventricular systolic function and size, diastolic LV function (not assessable with mitral valve prosthesis) , atr ial s ize , funct ion of the nat ive valves , estimates of pulmonary artery pressure, pressure gradient across the newly implanted prosthesis, e f f e c t i ve va l va r o r i f i c e a r e a , presence of paravalvular leaks.135 The first postoperative workup should include echocardiography a long with a l l o ther physica l and blood tests.135,136 Ideally, all pat ients who have undergone valve surgery should continue to be followed-up at a cardiac center in order to detect deterioration in prosthetic function, recurrence of regurgitation following valve repair, or progression of disease at another valve site at an early stage.136 The frequency of future follow-up should be determined by the pat ient ’s progress and availability of local facilities. The frequency of echocardiography d u r i n g f o l l o w - u p s h o u l d b e

de termined by the resu l t s o f p r e v i o u s e c h o c a r d i o g r a p h y , symptomat ic s ta tus , the type of surgery , and the ex is tence of other pathology. However , ESC recommends the first post-operative visit to a hospital or a cardiac specialist within 6 weeks of discharge if there has been no period of inpatient rehabilitation or within 12 weeks if a rehabilitation program has been completed. The current 2014 ACC VHD guideline recommends annual follow up for cardiac history and physical examination in an asymptomatic uncomplicated patient . I t also recommends an echocardiographic examination at 6 weeks to 3 months after valve implantation, while AS-Echo guideline recommends a baseline TTE at discharge or 2-4 weeks after hospital discharge; as an essential component of the first post-operative visit . Both guidelines recommend further fol low up by TTE and/or TEE i f c l in ica l symptoms or s igns suggestive of prosthetic valve d y s f u n c t i o n o r o t h e r c a r d i a c pathology persist; with preference to TTE for initial examination. ACC and As-Echo recommend no further echocardiographic testing af ter the ini t ia l postoperat ive evaluation in stable mechanical valve patients and who have no symptoms or cl inical evidence of prosthetic valve or ventricular dysfunction or dysfunction of other heart valves. ACC recommend TTE after the first 10 years, while AS-Echo recommends annua l echocardiography after the first 5 years in bioprosthet ic valve patients; even in the absence of a change in clinical status.21,67

CT and MRI scan-Post valve implantation

Prosthetic cardiac valves are general ly made up of metals , polymers, and carbons. However, there is a hypothetical probability of e lectromagnetic interact ion with metal in valves that may cause interruption of opening and closing of valves (referred to as the Lenz effect). Nevertheless, no such cases have been reported in clinical practice.137 Consequently, these patients are unlikely to be at risk for valve dehiscence and the


heating due to MR was reported to be minor.138-141 Consequently, prosthetic heart valves, as well a s m e t a l s t e r n a l s u t u r e s a n d mediastinal clips, should not be considered as contraindications for an MRI at 3 T or less any time after implantation.142,143

According to AHA scientific s t a t e m e n t , t h e p r e s e n c e of a prosthet ic heart valve or annuloplasty ring that has been f o r m e r l y e v a l u a t e d f o r M R safety should not be considered a c o n t r a i n d i c a t i o n t o a n M R examination at 3 T or less (and possibly even 4.7 T in some cases) any time after implantation. MR examination of patients with sternal wires is generally considered to be safe and patients with endocarditis and risk of valve dehiscence cannot undergo MRI.144

Prosthetic Valve -Endocarditis

Prosthetic Valve Endocarditis (PVE) is a serious complication of cardiac valve replacement and is an important cause of morbidity and mortality. Echocardiography should be performed in all cases in which there is a medium or high clinical suspicion or when the patient is severely ill, after excluding other common causes of fever.145 The diagnostic strategy proposed by Durack and colleagues ( t he Duke c r i t e r ia ) comb ines echocardiographic findings with clinical and microbiological data. Three echocardiographic findings were considered to be major criteria for the diagnosis of endocarditis: (1) presence of vegetation defined as mobi le echo dense masses implanted in a valve or mural endocardium in the tra jectory of a regurgitant jet or implanted in prosthetic material with no alternative anatomical explanation; (2) presence of abscesses; or (3) presence of a new dehiscence of a valvular prosthesis.146

The reported sensitivity and specificity for the diagnosis of perivalvular abscesses with TTE are 28% and 98%, respectively, and wi th TEE, 87% and 95%, respectively.147-150 Bioprosthetic valve leaflets may become infected with secondary destruction of leaflet tissue. The distinction between

wear-and-tear degeneration of t issue valves and endocarditis is often difficult. TEE also led to an improved diagnostic accuracy in the diagnosis of endocarditis on bioprosthetic valves.151 TEE is therefore necessary in cases in which infective endocarditis is strongly suspected, even when no significant findings are seen on TTE.152 Further, multiple TEE planes combined with TTE views must be exploited to minimize the risk of missing a significant finding when images are technically difficult to obtain. When both TEE and TTE studies are negative, there is a 95% negative predictive value.153,154

Antimicrobial therapy remains the mainstay of therapy; however, most patients require surgical r e m o va l a n d r e p l a c e m e n t o f infected prosthesis . The delay in embol izat ion prevent ion is associated with stroke within 3 days of diagnosis.155 The risk of embolism is related to the size, and mobility of vegetation, the risk is increased in large (>10 mm) vegetation and particularly high with very mobile and large (>15 mm) vegetation. The risk of new embolism is highest during the first days following initiation of antibiotic therapy and decreases after 2 weeks.68

In a case-control study, Agarwal et al identified the risk factors for prosthetic valve endocarditis in Indian populat ion. 156 These r i s k f a c t o r s we r e f u n c t i o n a l class III or IV (New York Heart Association), alcohol consumption, pr ior h is tory of endocardi t is , fever in the intensive care unit, and gastrointest inal bleeding. Functional c lass I I I or IV and complications of the surgical wound we r e i n d e p e n d e n t p r e d i c t o r s of early infective endocarditis, whereas fever in the intensive care unit and gastrointestinal bleeding were predic tors of prosthet ic valve endocarditis late after the operation.156 However, there are no randomized studies assessing the impact of antithrombotic therapy on PVE. The results of observational s tudies sugges t tha t the r i sk of cont inuing ant icoagulat ion outweighs the benefits.155,157-160

I n p a t i e n t s o n V K A f o r a

prosthetic valve who develop IE, ACCP suggest VKA be discontinued at the time of initial presentation unt i l i t i s c lear that invas ive procedures will not be required and the patient has stabilized without signs of CNS involvement. When the patient is deemed stable without contraindications or neurologic complications, reinstitution of VKA therapy is recommended.19

Key points• Concomitant heart failure should be

managed as per standard heart failure management guidelines.

• In patients with non ST segment elevation acute coronary syndrome (NSTE-ACS) who are on anticoagulation, bare metal stent is preferred over drug eluting stent that offers the advantages of lower bleeding risk because of the potentially shorter duration of triple antithrombotic therapy.

• Beta blockers should be used for management of perioperative atrial fibrillation, unless otherwise contraindicated.

• Un-interrupted VKA can be offered in patients undergoing ablation procedures like PVI.

• Interruption of VKA should not be performed during implantation of cardiac implantable electronical devices unless patients are at very low risk of thromboembolic events. However, if required can be interrupted without bridging.

• Low bleeding risk procedures like coronary angiography by radial approach can be performed with slight modification in VKA dose. However, interventional procedures with high risk of bleeding should be performed with interruption of VKA and bridging as with other surgeries.

Follow up cardiac evaluation• The first postoperative workup should

include echocardiography along with all other physical and blood tests.

• The frequency of future follow-up should be determined by the patient’s progress and availability of local facilities.

CT and MRI scan-Post valve implantation • Patients with prosthetic valve which is

formerly evaluated for MR safety can undergo MR examination at 3T or less any time after implantation. However, patients at risk of valve dehiscence should not undergo MR examination

Prosthetic Valve -Endocarditis Diagnosis• TTE in recommended in suspected IE,

in case of negative TTE in suspected PVE, TEE is recommended. If initial examinations are negative, repetition of TTE/TEE is recommended within 7-10


days in patients with high suspicion of IE. Modified Duke Criteria should be used in evaluating a patient with suspected IE.

Prophylaxis• Antibiotic prophylaxis is recommended

in dental procedures (gingival tissue, perforation of oral mucosa), invasive respiratory tract procedures and skin tissue treatment procedures.

Antithrombotic• It is recommended to discontinue VKA,

in patients on VKA for a prosthetic valve who develop IE, until it is clear that invasive procedures will not be required and the patient has stabilized without signs of CNS involvement. When the patient is deemed stable without contraindications or neurologic complications, reinstitution of VKA therapy is recommended

Future AnticoagulantsIn the current era of expanding

strategies for anticoagulat ion, investigators have yet to establish t h e r o l e f o r n o n - V K A o r a l anticoagulants in the setting of prosthetic valve replacement. To date, there are no large randomized clinical trials enrolling to answer this question. New anticoagulants that are direct thrombin inhibitors or factor Xa inhibitors (dabigatran, apixaban, and rivaroxaban) have b e e n a p p r o ve d b y U . S . F o o d and Drug Adminis t ra t ion for an t i coag ulant prophylax i s in patients with AF not caused by VHD.161 There was no evidence of a differential effect of apixaban over VKAs in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease demonstrated in the ARISTOTLE tr ia l . 162 There a r e r e p o r t s o f t h r o m b o s i s o f valve despite dabigatran use.163-

166 Following this report, Food a n d D r u g A d m i n i s t r a t i o n (FDA) announced a s tatement to contraindicate dabigatran for mechanical heart valves.

A ques t ion i s unanswered , w h e t h e r t h e n o v e l o r a l a n t i c o a g u l a n t s a r e s a f e a n d e f f i c a c i o u s i n t h e p a t i e n t s early following placement of a bioprosthetic valve. Dedicated s t u d i e s i n t h i s s e t t i n g a r e unfortunately likely to be years away, thus leaving some degree of uncertainty regarding optimal

antithrombotic therapy for the near future.Disclaimer

This publication was funded by Abbott Healthcare Pvt Ltd. Dr. Vikrama Raja, Medical Affairs has authored this publication in the capacity of employee of Abbott Healthcare Pvt Ltd., Dr. Devendra Saksena, Dr. S. Muralidharan, Dr. Bipin Bihari Mohanty, Dr. C.P. Srivastava, Dr. Jagdish Mange, Dr. Manish Puranik, Dr. Manoj P Nair, Dr. Pankaj Goel, Dr. Pankaj Sr ivastava , Dr . RM Krishnan, Dr. Sathyaki Nambala, Dr. Vivek Kanhere, Dr.Yugal K Mishra have co-authorized this publication. The authors have declared and confirmed that there is no conflict of interest with respect to this authored publication.

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Anticoagulation Management in Patients with Valve Replacement · involved valve type is aortic with degenerative etiology.6,7 Surgical repair using either a mechanical or bioprosthetic