CHAPTER 53: ANTITHROMBOTIC THERAPY FOR VALVULAR HEART DISEASE

The worldwide burden of valvular heart disease (VHD) continues to grow as a result of increases in life expectancy combined with the high incidence of rheumatic heart disease in developing nations.¹ Patients with VHD and certain comorbid conditions or prosthetic heart valves (PHVs) are at high risk for thromboembolic complications and often require antithrombotic therapy (Table 53–1). Although bleeding is a risk with all antithrombotic agents, the frequency and consequences of a stroke make drug therapy appropriate in many patients with VHD.²

Antithrombotic therapy among individuals with native valve disease (defined as VHD in absence of PHV or mitral stenosis [MS]) is based on the presence of concomitant risk factors (Fig. 53–1). The most common risk factors for thromboembolism include atrial fibrillation (AF) and left ventricular (LV) systolic dysfunction.

Atrial Fibrillation

Nonvalvular AF has been defined as AF in the absence of rheumatic MS, a mechanical or bioprosthetic heart valve, or mitral valve repair.³ Multiple randomized controlled trials have demonstrated the clinical benefits of antithrombotic therapy with either warfarin or aspirin compared with placebo or no treatment in reducing ischemic events among individuals with “nonvalvular” AF. Based on a meta-analysis of over 28,000 patients comprising 29 trials, adjusted-dose warfarin therapy was associated with a 60% and 40% reduction in ischemic stroke compared with placebo and antiplatelet therapy, respectively.⁴ Antiplatelet therapy alone reduced the risk by 20%.⁴ The addition of clopidogrel to aspirin further reduced ischemic events, including stroke, among patients with AF who were unsuitable for vitamin K antagonist therapy,⁵ but was inferior to warfarin in warfarin-eligible patients.⁶ Data from contemporary trials have shown that there has been a significant reduction in stroke event rate over the past two decades as a result of greater time spent in therapeutic anticoagulation (stroke or systemic embolism rate of 1.66% per year).⁷ The benefits of anticoagulation are graded, increasing as the risk for ischemic stroke increases. Multiple risk stratification schemes exist for guiding clinicians in assessing stroke risk among individuals with nonvalvular AF, but currently the CHA2DS2-VASc is preferred as it has a broader range and includes a larger number of risk factors.³ In summary, warfarin is recommended in any AF patient who has had a stroke/transient ischemic attack/systemic embolus. It is also recommended in those with a CHA2DS2-VASc score ≥ 2. For patients with a CHA2DS2-VASc of 0, no antithrombotic therapy is needed; for those with a score of 1, either aspirin or an oral anticoagulant may be considered.³ The newer oral anticoagulants (dabigatran, apixaban, rivaroxaban) are not indicated for AF associated with rheumatic MS, mechanical or bioprosthetic heart valve, or after mitral valve repair.^2,3 Post-hoc analysis of the ARISTOTLE trial found that one-fourth of the study population had at least moderate valvular disease (excluding more than mild MS)⁸ whereas 14% of the patients in the ROCKET-AF trial had significant valvular disease (without hemodynamically significant MS).⁹ In both of these analyses, the efficacy of apixaban and rivaroxaban was similar to that of warfarin in reducing stroke and systemic embolism among patients with VHD. As such, the newer oral anticoagulants may be considered as an alternative to warfarin in patients with VHD (mild to moderate severity) with AF without MS/PHV/mitral valve repair, with consideration given to the cost, tolerability, and patient preference and the fact that definitive trials in this subset are awaited.¹⁰

Patients with MS (of any severity) with AF increase the risk of stroke 17-fold (as compared to nonvalvular AF, which increases the risk five-fold).¹⁰ Anticoagulation with warfarin is indicated in patients with MS with AF irrespective of the severity.²

Left Ventricular Dysfunction

Among clinically stable individuals with left ventricular dysfunction, the rate of thromboembolism ranges from 1% to 3% per year.¹¹ This risk may be partially attributable to blood stasis and hypercoagulability. The WARCEF trial found no significant overall difference between warfarin and aspirin among patients with LV dysfunction in sinus rhythm.¹³ Although ischemic stroke was reduced with warfarin therapy, this was offset by increased risk of major hemorrhage. Given the sufficiently low rates of thromboembolism, there is no compelling indication for the use of warfarin or aspirin in patients with LV dysfunction without a specific indication (eg, AF, thromboembolism, or CHADS2 score ≥ 2).¹²

Previous Thromboemboli

A thromboembolic event defines patients who are at high risk for having a recurrent event in clinical situations unrelated to valve disease (eg, in patients with AF, MS, or a PHV). It is unclear whether this is true in patients with native valve disease, but lifelong warfarin therapy should be considered if there are no contraindications to its use.

Hypercoagulable Conditions

Hypercoagulable states clearly increase the risk of venous thrombosis. The most common are the factor V Leiden and prothrombin gene mutations, defects in protein C, protein S, or antithrombin, and many malignancies. Less is known about their effect on the incidence of thromboemboli related to valve disease, but their presence is a reason to more strongly consider anticoagulation.

Other Potential Thromboembolic Risk Factors

Beyond an assessment of LV systolic dysfunction, the use of transthoracic and transesophageal echocardiography to determine which patients are at risk of thromboemboli is not yet well defined. Left atrial enlargement or thrombi, a patent foramen ovale, an atrial septal aneurysm, or spontaneous echocardiographic contrast are occasional findings of concern. The value of treatment based on these findings remains unproven.

Both mitral and aortic valve calcifications are associated with an increased risk of stroke, coronary events, and cardiovascular mortality.^{14,15,16,17,18} Further, mitral annular calcification is associated with increased risk for the development of conduction system disease, AF, and mitral valve disease.¹⁸ To date, however, there have been no formal trials to assess the efficacy of antithrombotic therapy in reducing stroke risk among patients with calcified valvular lesions in the absence of other known indications for oral anticoagulation. Based on the increased embolic risk among such individuals, however, low-dose aspirin (75-100 mg/d) or clopidogrel (75 mg/d) is reasonable in the presence of calcific mitral or aortic valve disease that is complicated by systemic embolism, stroke, or transient ischemic attack.^{19, 20}

Thromboembolic risk and antithrombotic therapy for PHV vary based on type of valve (bioprosthetic or mechanical), valve position (aortic or mitral), time from surgery, and other stroke risk factors. In general, embolic risk is greater for mitral compared with aortic PHVs^2,19,21 and is also higher in the first few days and months after surgery prior to full endothelialization of the sewing ring.

Mechanical Valves

Observational data from patients with mechanical PHV in the aortic or mitral position, or both, suggest that the incidence of valve thrombosis, major embolism, and total embolism in the absence of anticoagulation approaches 1.4, 4.0, and 8.6 per 100 patient-years, respectively, with an approximate doubling of embolic risk associated with mitral versus aortic prosthetic valves.²² With warfarin, this risk is reduced to 0.2 (odds ratio [OR]: 0.11; 95% confidence interval [CI]: 0.07 to 0.2), 1.0, and 1.8 (OR: 0.21; 95% CI: 0.16 to 0.27) per 100 patient-years respectively. With aspirin alone, these figures are 1, 1.4, and 7.5 events per 100 patient-years, respectively, indicating inadequate protection. Thrombogenicity of mechanical valves is greatest for caged-ball valves, followed by tilting-disk valves and bileaflet valves.²¹ To date, no randomized trials have compared initial bridging with unfractionated heparin (UFH) versus low molecular weight heparin (LMWH) after surgery for mechanical PHV replacement.¹⁹ The use of LMWH is off-label in patients with mechanical prosthetic valves. Based on nonrandomized and observational data, LMWH may be a efficacious alternative to bridging with UFH in the immediate postoperative period,²³ but a meta-analysis of 23 studies including 9534 patients noted higher bleeding rates with early bridging therapy with LMWH.²⁴ A reasonable approach is to initiate bridging therapy with UFH after surgery, once hemostasis is secure (usually within 24-48 hours). The activated partial thromboplastin time (aPTT) should be maintained at a “therapeutic effect” level (Table 53–2) until warfarin therapy has achieved the recommended international normalized ratio (INR) level.²

Anticoagulation with vitamin K antagonist (VKA) with INR monitoring is recommended for all patients with a mechanical heart valve.² For patients with mechanical aortic valve replacement (AVR) (bileaflet or current-generation single tilting disc) and no risk factors for thromboembolism, the recommended target INR is 2.5 (range 2-3).² A target INR of 3 (range 2.5-3.5) is recommended for patients with mechanical mitral valve replacement (MVR), combined AVR and MVR, older-generation mechanical AVR (ball-in-cage), and those with mechanical AVR with additional risk factors for thromboembolic events (AF, previous thromboembolism, LV dysfunction, or hypercoagulable conditions).²

A systematic review found that adjunctive therapy with aspirin in addition to oral anticoagulation was associated with a reduction in overall mortality and thromboembolic events among patients with mechanical PHV at the cost of increased bleeding.²⁵ This increased risk of bleeding was not seen among low-dose aspirin trials (aspirin 100 mg/d) (OR: 0.96, 95% CI: 0.60 to 1.55, P = 0.87). On the other hand, the effectiveness of low-dose aspirin (100 mg/d) was similar to that of higher-dose aspirin. Accordingly, the addition of low-dose aspirin (< 100 mg) is recommended by the American College of Cardiology (ACC) and American Heart Association (AHA) for all patients with mechanical valves.² The European Society of Cardiology (ESC) 2012²⁶ guidelines are more selective and recommend the addition of low-dose aspirin in mechanical valve patients with concomitant atherosclerotic disease or after thromboembolism despite adequate INR. The American College of Chest Physicians guidelines¹⁹ recommend low-dose aspirin only if the risk of bleeding is low. Clopidogrel may be considered if aspirin cannot be taken.

The importance of anticoagulation variability on long-term outcomes was demonstrated by Butchart and colleagues²⁷ in a prospective study involving more than 1400 patients who underwent single-valve replacement with a tilting disk (Medtronic Hall, Minneapolis, MN) prosthesis. Anticoagulation variability emerged as the strongest independent predictor of survival; patients whose INR levels were therapeutic < 70% of the time experienced a 32% reduction in survival compared with those whose levels were therapeutic at least 80% of the time. One method to improve the quality of oral anticoagulation control is INR self-monitoring and adjustment.²⁸ Meta-analysis have shown a significant reduction in the rate of thromboembolic complications, but not in major bleeding or overall mortality.^29,30 Advantages of this strategy over conventional laboratory-based methods include improved patient compliance, convenience, and greater frequency of monitoring. However, as compared to the routine laboratory-based monitoring, self-testing was associated with only a modest increase in the time in therapeutic range.³⁰ There was a significant improvement in patient satisfaction and quality of life.³¹ Despite the clear benefits of INR self-management, barriers to widespread implementation of such programs include increased cost and patient training and education. More than one half of the patients in various randomized controlled trials had to be to excluded from self-management because of physical limitations, lack of competence with the device, or patient refusal.²⁸

The use of newer anticoagulants that are direct inhibitors of factor II or factor X (dabigatran, rivaroxaban, apixaban) is contraindicated in patients with mechanical prosthetic valve.^2,26 The RE-ALIGN trial³² evaluated three doses of dabigatran (150, 220, or 300 mg twice daily based on kidney function) versus warfarin (INR 2-3 or 2.5-3.5 as per thromboembolic risk) among 252 patients who had undergone mechanical AVR or MVR. The trial was terminated prematurely because of excess thromboembolic (9% vs 5%) and bleeding events (27% vs 12%) among patients in the dabigatran group.

Bioprosthetic Valves

Thromboembolic risk associated with bioprosthetic valves appears to be greatest in the first 3 months after implantation.³³ The risk is greater after mitral valve surgery. Based on this risk, antithrombotic therapy with a VKA is recommended for the first 3 months after bioprosthetic MVR or mitral valve repair to achieve an INR of 2.5 (range 2.0 to 3.0).^2,26 After 3 months, the tissue valve and the repaired valve can be treated as native valve and anticoagulation discontinued. Anticoagulation needs to be continued in those with associated risk factors for thromboembolism: AF, previous thromboembolism, hypercoagulable condition, or severe LV dysfunction (ejection fraction < 0.3). For bioprosthetic AVR, the need for anticoagulation for the first 3 months has been challenged because of the low risk of thromboembolism in these patients (albeit greater than in the normal population). Most centers use low-dose aspirin 75-100 mg/day (class IIA).²⁶ However, one large observational registry of 4075 patients undergoing isolated bioprosthetic AVR demonstrated significant reduction in the risk of stroke and cardiovascular death without a significant increase in the risk of bleeding among patients treated with VKA versus those without.³⁴ Anticoagulation with VKA (to achieve an INR of 2.5) may still be reasonable for the first 3 months after bioprosthetic AVR² (class IIb). After the first 3 months, low-dose aspirin (75-100 mg/d), should be continued indefinitely for bioprosthetic AVR or MVR and mitral valve repair patients² because this is associated with a reduction in thromboembolic events compared with no antithrombotic treatment.³⁵

For patients undergoing transcatheter aortic valve replacement, clopidogrel 75 mg daily is recommended for the first 6 months after the procedure along with lifelong low-dose aspirin (75-100 mg daily).² For patients with AF, the use of VKA with a single antiplatelet agent (low-dose aspirin) is recommended.³⁶ Development of transcatheter valve thrombosis (clinical or subclinical) should lead to initiation of anticoagulation therapy.^37,38

Altered Native Valves

Valve disease is treated increasingly by interventional catheter techniques or surgical valve repair. The recommendations given for treatment of native valve disease would seem most applicable in such patients; that is, antithrombotic treatment depends on associated stroke risk factors. Data on thrombotic complications after the Ross procedure are limited, but the risk seems low, and the recommendations for a biologic valve seem reasonable.³⁹

Following percutaneous edge-to-edge repair for mitral regurgitation using the Mitra-Clip device, aspirin (325 mg/d) is recommended for 6 months along with clopidogrel (75 mg/d) for 30 days after the procedure.⁴⁰ After percutaneous balloon mitral/aortic valvuloplasty, no specific antithrombotic therapy is recommended unless it is needed for another indication (eg, left atrial thrombus, atrial fibrillation).

Noncardiac Surgery

The risk of bleeding during surgery for a patient while on antithrombotic therapy has to be weighed against the thromboembolic risk caused by stopping the therapy. This should take into account the type of surgical procedure; risk factors for thromboembolism; and the type, location, and number of mechanical valves.² In a worst-case scenario (mechanical valve with previous thromboembolism), the risk of embolus is 0.08-0.16% if VKA therapy is stopped for 3 days,⁴¹ Although antithrombotic therapy must be individualized, some generalizations apply. For procedures where bleeding is unlikely or would be inconsequential if it occurred, antithrombotic therapy should not be stopped. This can apply to surgery on the skin, dental prophylaxis, or simple treatment for dental caries.² Eye surgery, in particular surgery for cataracts or glaucoma, is usually associated with very little bleeding; many ophthalmologists do not alter antithrombotic therapy.

For patients with bileaflet aortic valve and no risk factors for thromboembolism, the risk of stopping VKA for a few days is small and these patients do not need bridging therapy. VKA is stopped 2-4 days before surgery, to allow the INR to fall < 1.5 when surgery can be safely performed. Once bleeding risk allows (usually 12-24 hours after surgery) VKA is restarted.²

For patients with mechanical MVR, older-generation AVR (ball-in-cage valve, eg Starr Edwards valve), and mechanical AVR with other risk factors for thromboembolism (AF, previous thromboembolism, hypercoagulable condition, LV systolic dysfunction (LV ejection fraction < 30%), or > 1 mechanical valve), bridging anticoagulation with intravenous UFH or subcutaneous LMWH is recommended to reduce the risk of adverse effects.² VKA is stopped 2-4 days before surgery. When the INR falls to < 2.0, intravenous heparin infusion or weight-adjusted LMWH (twice daily) is initiated. This is stopped 4-6 hours (for intravenous UFH) or 12 hours (for LMWH) before surgery. Once bleeding risk allows (usually 12-24 hours after surgery), a VKA is restarted. Bridging heparin after surgery needs to be individualized depending on the bleeding risk and risk of thrombosis. The use of LMWH allows outpatient bridging but has the disadvantage of partial anticoagulation reversal with protamine, a long half-life, and is contraindicated in those with severe renal failure.

If a patient is taking aspirin, it should be discontinued 7 days before the procedure and restarted as soon as it is considered safe by the surgeon. Clopidogrel and ticagrelor should be stopped 5 days before the procedure, whereas prasugrel should be stopped 7 days in advance.

Cardiac Catheterization and Angiography

Urgent cardiac catheterization procedures can be performed in patients taking warfarin. For nonurgent cases, warfarin should be stopped 72 hours before cardiac catheterization so that the INR is < 1.8 (for femoral access) or < 2.2 (for radial access) at the time of the procedure,⁴² and restarted the same day after the procedure for patients who are at low risk for thromboembolism. For patients at high thromboembolic risk, heparin should be started 48 hours before the procedure and continued until warfarin is resumed and the desired INR is achieved. Of note, the European guidelines advocate avoidance of interruption of VKAs (but not non-VKA oral anticoagulants) in elective percutaneous coronary intervention (PCI) (with radial access as the preferred option) in order to avoid the bleeding or ischemic complications associated with bridging therapy.⁴³ A post hoc analysis of the WOEST trial⁴⁴ found that uninterrupted oral anticoagulation (periprocedural INR 2.5) was not associated with excess bleeding complications and tended to have reduced major adverse cardiac events as compared to bridging therapy. In patients who are scheduled to undergo transseptal puncture, all antithrombotic therapy should be discontinued, and the INR should be < 1.2 prior to the procedure.⁴¹

Coronary Artery Stents in Patients With Valve Disease

Dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine (eg, clopidogrel, prasugrel) is superior to oral anticoagulation for preventing stent thrombosis in patients following PCI with stent implantation.⁴⁵ On the other hand, oral anticoagulation is superior to DAPT for the prevention of thromboembolic events in patients with AF and mechanical valves.^46,47 Hence, patients with a compelling indication for anticoagulation (eg, mechanical valves, MS with AF, CHA2DS2-VASc score ≥ 2), undergoing PCI require triple therapy with aspirin, clopidogrel, and an oral anticoagulant (VKA in case of mechanical valve and MS with AF).^43,48 Triple antithrombotic therapy with aspirin, clopidogrel, and warfarin increases the bleeding risk with increasing duration.⁴⁹ In order to balance the ischemic and bleeding complications, certain recommendations with general consensus have been made^43,48: (1) the duration of triple therapy must be kept as short as possible; (2) low-dose aspirin (< 100 mg) should be used; (3) the use of prasugrel or ticagrelor as part of triple therapy should be avoided; (4) prophylactic proton pump inhibitor use is recommended to reduce gastrointestinal bleeding; (5) a lower target INR of 2-2.5 is recommended; and (6) for patients with a low risk of bleeding (HAS BLED score ≤ 2), the newer generation drug-eluting stents (DES) are recommended in preference to bare metal stent (BMS), given that the former are associated a lower risk of restenosis and stent thrombosis. For patients with a high risk of bleeding (HAS BLED score > 2), the choice of stent between a BMS and DES should be individualized. A BMS is preferred if the risk of bleeding is very high and the risk of restenosis low.

The optimal duration of triple therapy depends on the clinical setting (stable coronary artery disease or acute coronary syndrome), the risk of stent thrombosis, and the risk of bleeding.^38,43 For stable coronary artery disease, patients undergoing PCI with a high bleeding risk (HAS BLED score > 2), triple therapy (oral anticoagulants, aspirin 75-100 mg daily, and clopidogrel 75 mg daily) is recommended for 4 weeks followed by dual therapy with an oral anticoagulant and clopidogrel 75 mg/d (or alternatively, aspirin 75-100 mg/d) up to 12 months.⁵⁰ For patients at low bleeding risk (HAS BLED score ≤ 2), the minimum duration of triple therapy is 4 weeks (not to exceed 6 months depending on risk of stent thrombosis with 6 months recommended for acute coronary syndrome)⁵¹ followed by dual therapy with oral anticoagulant and clopidogrel 75 mg/d (or alternatively, aspirin 75-100 mg/d) up to 12 months. The WOEST trial⁵⁰ compared dual therapy (VKA plus clopidogrel alone) to triple therapy (VKA plus aspirin and clopidogrel) in 573 patients taking long-term oral anticoagulation who received a coronary stent. The primary outcome of any bleeding was significantly reduced in the dual therapy arm without any increase in the rate of thrombotic events (stent thrombosis). Further, there was a significant reduction in the all-cause mortality (secondary end point) at 12 months in the dual therapy arm. On the other hand, the ISAR TRIPLE trial,⁵¹ which randomized 614 patients with an indication for oral anticoagulation to either 6 weeks or 6 months of triple therapy with aspirin, clopidogrel, and warfarin, followed by double therapy with aspirin and warfarin thereafter, found no difference in the primary end points of death, myocardial infarction, definite stent thrombosis, stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding at 9 months. There was no difference in the individual end points either. However, Bleeding Academic Research Consortium (BARC) type ≥ 2 bleeding was reduced in the dual therapy arm.⁵¹

After 12 months, stable coronary artery disease patients may be managed with oral anticoagulants alone. But in the case of mechanical valves, the addition of low-dose aspirin to anticoagulant therapy has been shown to be beneficial in the long term and is recommended. In select cases such as left main stenting, proximal bifurcation stenting, or proximal left anterior descending coronary artery stenting, clopidogrel 75 mg/d may be preferred over low-dose aspirin for the long-term treatment.

Pregnancy

Pregnancy with a mechanical heart valve constitutes the World Health Organization (WHO) risk class III (significantly increased risk of maternal mortality or severe morbidity).⁵² Pregnancy is associated with alterations in hemostasis and coagulability that increase the risk of thromboembolic events among women with mechanical PHVs.⁵³ Estimates of maternal mortality range from 1%⁵³ in developed countries to 3% in emerging countries,⁵⁴ with most deaths attributable to thrombotic complications. The possibility of fetal toxicity and changes in dose requirements of antithrombotic agents during pregnancy further complicate management decisions in this high-risk population. The primary objective should be to prevent the occurrence of valve thrombosis and its lethal consequences for both the mother and the fetus.⁵² There is no ideal anticoagulation regimen. Anticoagulation options are (1) use of VKA (warfarin) throughout pregnancy with switch to UFH at 36 weeks; (2) use of UFH/LMWH restricted to the first 6-12 weeks, followed by warfarin up to 36 weeks with a switch to heparin; and (3) use of UFH/LMWH throughout pregnancy.^2,52,55,56 The last regimen is usually not favored, as continuous use of UFH/LMWH throughout pregnancy markedly increases the risk of prosthetic heart valve thrombosis (PHVT).

Warfarin crosses the placenta and is associated with teratogenicity, increased incidence of spontaneous abortion, prematurity, stillbirth, and fetal bleeding (including cerebral hemorrhage).⁵⁷ Embryopathy resulting from in utero exposure to warfarin appears to be greatest during the first trimester, particularly between weeks 6 and 12 of gestation. The risk of warfarin-associated embryopathy appears to be dose-related. The incidence is < 3% with a daily dose of ≤ 5 mg but increases to > 8% with a warfarin dose of > 5 mg/d.^58,59 Some centers have used acenocoumarol (a coumarin derivative) with a very low incidence of warfarin-related embryopathy.⁶⁰ With respect to valve thrombosis and thromboembolism, warfarin given throughout pregnancy is the safest option.⁶¹ UFH does not cross the placenta and is considered a safer alternative to warfarin in terms of fetal adverse effects (no teratogenicity or fetal bleeding), but it may be less efficacious in reducing maternal thromboembolic risk compared with warfarin.⁶¹ Heparin is preferably given as an intravenous infusion rather than subcutaneous injections. Prolonged exposure to heparin is associated with thrombocytopenia and osteoporosis. Given the short half-life of heparin and the change in its volume of distribution during pregnancy, frequent dose adjustments and higher doses may be needed. There is also the added risk of intravenous line infection, which may rarely lead to prosthetic valve infective endocarditis.

In the absence of controlled clinical trials, current recommendations are based on limited, observational data. In a systematic review comprising 24 studies of over 900 pregnant women with mechanical PHVs, Chan and colleagues⁶¹ evaluated maternal and fetal outcomes according to the type of antithrombotic regimen used during pregnancy: oral anticoagulants alone, oral anticoagulants substituted with heparin during the first trimester, heparin throughout pregnancy, or antiplatelet agents alone. Results from this analysis (Table 53–3) suggested that warfarin is more efficacious than UFH for thromboprophylaxis of pregnant women with mechanical PHVs but is associated with an increased risk of embryopathy. Warfarin therapy throughout pregnancy is recommended for patients with a daily dose requirement of < 5 mg/d and for those who at are at very high risk of thromboembolism (older generation mitral valve prosthesis or those with previous history of thromboembolism).²

LMWHs offer several advantages over UFH with longer half-life, greater bioavailability, and more predictable anticoagulant response. During pregnancy, LWMHs do not cross the placenta and have a lower incidence of osteopenia and thrombocytopenia compared with UFH.⁶² Previously, several authors had reported fatal valve thrombosis in pregnant women receiving weight-adjusted LMWH alone.^63,64 Of late, there have been a number of reports of successful pregnancies using dose-adjusted LMWH (twice daily) according to anti-Xa levels (see Table 53–3).^65,66 Using this approach, the rates of valve thrombosis and spontaneous abortions are lower than with UFH.² The dosage requirement of LMWH may increase by as much as 50% over the course of pregnancy. Hence frequent dose adjustments are needed. There remain some unresolved questions—the optimal anti-Xa levels, the importance of peak vs trough levels, the best time interval for monitoring anti-Xa level, and the optimal timing of dosage (twice a day or three times a day). In the absence of monitoring of anti-Xa levels, LMWH should not be used.^2,62

The decisions on the choice of anticoagulation should be made by both the physicians and patient, who needs to be fully informed of the potential risks and benefits associated with the various therapeutic options.⁵²

Current guidelines recommend frequent monitoring of anticoagulation therapy during pregnancy irrespective of the antithrombotic regimen chosen.^2,52,56 INR should be measured weekly. For mechanical MVR, older-generation AVR, and those with risk factors for thromboembolism, the target INR should be 3 (range 2.5-3.5). For patients with a bileaflet aortic valve and no risk factors for thromboembolism, the recommended target INR is 2.5 (range 2-3). Low-dose aspirin (75-100) is recommended for pregnant patients with either mechanical or bioprosthetic valves in the second and third trimester. The dose of unfractionated heparin should prolong the 6-hour postinjection aPTT to at least twice the control. Recommendations on LMWH suggest twice-daily administration to achieve an anti-factor Xa level of 0.8 to 1.2 U/mL 4 to 6 hours² after injection performed every 1-2 weeks.^52,62

Delivery should be planned so that the mother does not enter labor in a fully anticoagulated state, which would increase the risk of severe maternal hemorrhage and place the neonate at risk of intracranial hemorrhage (in case of VKA).⁵² A switch from VKA to UFH/LMWH is done at 36 weeks. LMWH is switched to UFH 36 hours before planned delivery. UFH is discontinued 4-6 hours before planned delivery and restarted 4-6 hours after delivery if there are no bleeding complications. Vaginal delivery is preferred. Catheter placement for epidural anesthesia is not advisable within 12 hours of the last LMWH dose because of the risk of spinal or epidural hematoma. VKA can be restarted on same day of an uneventful vaginal delivery and after 1-2 days in those with caesarean section. A complete switchover to VKA should be done in-hospital. VKA is safe during breast feeding, as warfarin is highly protein bound and not readily detectable in breast milk.

In case of an emergency delivery with the patient on UFH/LMWH, protamine is used to reverse the effect of heparin although it only partially reverses the anticoagulant effect of LMWH (60%-80%). If emergency delivery occurs with the patient on VKA, the neonate is at risk of intracranial hemorrhage during vaginal delivery. Hence caesarean section is recommended.⁵² Prothrombin complex concentrates or fresh frozen plasm is administered to achieve an INR < 2. A management algorithm for pregnant women with PHV is outlined in Fig. 53–2.⁶⁷

Acute Management

For eligible patients with ischemic stroke (cardioembolic stroke), presenting within 3 hours of stroke onset, administration of intravenous recombinant tissue plasminogen activator (tPA, 0.9 mg/kg) is recommended.⁶⁸ This therapy is not recommended if the INR > 1.7 or prothrombin time > 15 seconds for patients on anticoagulation or for those with current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests.⁶⁸ The therapeutic window has been extended to up to 4.5 hours, but with additional exclusion criteria: patients > 80 years old, those taking oral anticoagulants regardless of INR, those with a baseline National Institutes of Health Stroke Scale (NIHSS) score > 25, those with imaging evidence of ischemic injury involving more than one-third of the middle cerebral artery (MCA) territory, or those with a history of both stroke and diabetes mellitus are excluded.⁶⁸ Intra-arterial fibrinolysis can be administered up to 6 hours after stroke onset, and can be used for those with contraindications for intravenous thrombolysis (eg, oral anticoagulation).⁶⁸ Urokinase has been well studied for this indication. Recently, a number of trials have shown the superiority of mechanical thrombectomy (using stent retrievers) over intravenous thrombolytic therapy.^69,70,71 Mechanical thrombectomy (with stent retrievers) is recommended up to 6 hours after stroke onset.⁷² They have the added advantage that they may be used in those with contraindications for fibrinolytic therapy (eg, oral anticoagulants, newer oral anticoagulants). They had better recanalization rates of up to 58% to 88%^69,70,71 as compared to 30%⁷³ with intravenous tPA (for MCA territory).

There is much debate regarding the optimal timing for initiating or continuing anticoagulants in patients in whom an embolus is the presumed cause of a stroke. The risk of early stroke recurrence has to be balanced against the risk of hemorrhagic transformation following the initiation of anticoagulation. Other potential benefits of early anticoagulation include prevention of deep vein thrombosis and coronary events. The risk of cardioembolic stroke recurrence within 2 weeks is in the range of 0.3-0.5% per day.⁶⁸ The risk of symptomatic hemorrhagic transformation (HTr) ranges from 3% to 5%^74,75 (asymptomatic HTr is more common⁷⁵). This risk is greater with larger infarcts. A meta-analysis of seven randomized controlled trials⁷⁴ (4624 patients) of anticoagulation in acute cardioembolic stroke did not find any reduction in risk of recurrent stroke or mortality but it was associated with excess intracranial bleeds. Current guidelines do not recommend urgent anticoagulation for the prevention of early stroke recurrence or halting neurological worsening (class III recommendation) in view of the risk of HTr.⁶⁸ This was evident in a large prospective study of 1029 consecutive cardioembolic stroke patients, which found that the best time to initiate anticoagulation is 4 to 14 days after stroke onset.⁷⁵ On balance, it seems preferable to withhold therapy for at least 72 hours. If a computed tomography scan at that time reveals little or no hemorrhage, heparin should be administered to maintain an aPTT at the lower end of the therapeutic level until warfarin, started at the same time, results in the desired INR. If the computed tomography scan demonstrates significant hemorrhage, antithrombotic therapy should be withheld until the bleed is treated or has stabilized.

The optimal timing for the resumption of anticoagulation after intracranial hemorrhage is also uncertain.⁷⁶ Previous guidelines indicated that anticoagulation could be restarted after 7-14 days.⁷⁷ A large retrospective study of 234⁷⁸ patients with warfarin-related intracranial hemorrhage found that the risk of rebleeding with early resumption of anticoagulation exceeded the risk of thromboembolism from withholding it, whereas with later resumption, the opposite was true. The authors suggested a delay of at least one month after intracranial hemorrhage, and found that the combined risk of ischemic plus hemorrhagic stroke was minimized when anticoagulation was reinitiated after ≈10 weeks.⁷⁸

Long-Term Management

If the embolic event occurs when a patient is off antithrombotic therapy, long-term warfarin therapy is required. If the embolic event occurs while the patient is on adequate antithrombotic therapy with the following parameters, the therapy should be altered as follows⁴¹:

• If on warfarin with INR of 2.0 to 3.0: increase dose to achieve an INR of 2.5 to 3.5.

• If on warfarin with INR of 2.5 to 3.5: increase dose to achieve an INR of 3.5 to 4.

• Not taking aspirin: initiate aspirin at 75-100 mg/d.

• If on warfarin with INR of 2.5 to 3.5, plus aspirin 75 to 100 mg/d: aspirin dose may also be increased to 325 mg/d.

• If on aspirin alone: aspirin dose may be increased to 325 mg/d and/ or clopidogrel 75 mg/d may be added. Patients with a bioprosthetic valve with embolic events on aspirin (75-100 mg/d) may need consideration for anticoagulation with VKA.

Embolism occurring after this medical approach should lead to consideration of possible valve surgery if the valve is the likely source of the thrombus.

Most patients with an INR above the therapeutic range can be managed by withholding warfarin and following the level of anticoagulation with serial INR determinations. Excessive anticoagulation (INR > 5.0) greatly increases the risk of hemorrhage. However, rapid decrease in INR can lead to the INR falling below the therapeutic level and increase the risk of thromboembolism. For patients with an INR between 5 and 10 who are not bleeding, most patients can be managed by withholding VKA and serial INR monitoring (without administration of vitamin K).^2,28 For patients with an INR > 10 without bleeding, in addition to holding VKA, oral vitamin K (2.5 mg) is recommended.^2,28 Once the INR returns to therapeutic range, warfarin therapy can then be restarted and dose-adjusted appropriately.

For patients who present with serious/life-threatening bleeding (eg, intracranial hemorrhage), irrespective of INR elevation, immediate reversal of anticoagulation using prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) to achieve an INR < 1.5 after 30 minutes is recommended.^2,28,79 In addition, slow infusion of intravenous vitamin K (5-10 mg) is given to sustain the effects of these products because of their relatively short half-lives. Intravenous vitamin K may, very rarely, cause anaphylaxis. Four-factor PCC (II, VII, IX, and X) (25-50 U/kg) is preferred over FFP (15-30 mL/kg).⁷⁹ Four-factor PCC can completely reverse the coagulopathy within 10 minutes, but is expensive. FFP is inexpensive and widely available, but has the disadvantage of transfusion reactions, risk of transmitting infections, preparation times, and the need to administer large volumes. The data for use of recombinant factor VIIa in VKA-associated bleeding are limited and this is currently not recommended.^2,28,79

When bleeding occurs, especially with the INR in the therapeutic range, the presence of an underlying occult lesion needs to be ruled out (gastrointestinal tract, urinary tract).²⁶

PHVT is a potentially life-threatening complication occurring in inadequately anticoagulated mechanical valve patients. This is rare in developed countries (0.3%-1.3% per patient-year), but frequent in developing countries (6.1% per patient-year).^2,80 Patients may be asymptomatic or may present with worsening dyspnea, cardiogenic shock, or thromboembolic events. Clinical examination may reveal muffling of the valve click and appearance of a new regurgitant/obstructive murmur. Differentiation of thrombus versus pannus is required, as thrombolytic therapy is ineffective in the latter. Diagnostic workup for patients with suspected PHV thrombosis begins with a transthoracic echocardiogram.^2,26 Most will also benefit from transesophageal echocardiography, which allows superior visualization of valve and valve motion along with a more precise measurement of thrombus size and differentiation between thrombus and pannus (Fig. 53–3A). Cinefluroscopy is a readily available, noninvasive imaging modality to visualize mechanical valve motion (Fig. 53–3B). It does not enable differentiation between a thrombus and pannus. Computed tomography scan is another promising modality for the three-dimensional visualization of the mechanical valve and also enables differentiation between a thrombus and pannus.²

If a patient has a thrombotic obstruction of a right-sided PHV, fibrinolytics are the first choice of therapy because they are successful in 80% to 100% of treated patients.^2,19,26

The optimal therapy for left-sided PHVT includes surgery (thrombectomy or valve replacement), fibrinolytic therapy, or heparin. There are no randomized trials comparing these modalities and all modalities are associated with a high risk. A meta-analysis⁸⁰ of seven observational studies comparing surgery with thrombolytic therapy that included 690 episodes of left-sided PHVT (73% in NYHA III/IV) found no difference in mortality (13.5% vs 9%), but surgery was associated with greater restoration of normal valve function (90% vs 70%), lower rates of thromboembolism (1.4% vs 16%), lesser major bleeding (1.4% vs 5%), and recurrent PVHT (7% vs 25%) compared to thrombolytic therapy.

Another meta-analyis⁸¹ of 44 studies with 2302 patients found greater mortality with surgery as compared to fibrinolytic therapy (18% vs 6.6%). This meta-analysis included single-arm (fibrinolytic therapy or surgery alone) as well as comparative studies, unlike the previous meta-analysis that included only comparative studies. The stroke rate, success rate, and bleeding rates were similar with both therapies whereas embolic events were greater in the fibrinolytic arm. The lack of randomized trial data has contributed to disagreement among the guidelines issued by various international bodies.^2,19,26,82 The ACC/AHA 2014² valvular heart disease guidelines recommend emergency surgery (class 1 recommendation) for left-sided PHVT with moderate-to-severe (NYHA class III-IV) symptoms. Emergency surgery is also preferred in patients with a mobile or large thrombus (> 0.8 cm²).³⁶ For patients with mild symptoms (NYHA class I-II) of recent onset (< 14 d) and small thrombus burden (< 0.8 cm²), an initial trial with intravenous infusion of UFH may be given.² If this is unsuccessful, fibrinolytic therapy is recommended. Various regimens using tPA, streptokinase, and urokinase have been used.^2,83,84 tPA appears to be superior, although cost remains a concern in developing countries. During thrombolysis, heparin is withheld. tPA is given in a loading dose of 10 mg followed by 90 mg over 2 hours. A lower dose of 20-mg intravenous bolus followed by 10 mg/hour for 3 hours may be given in those at increased risk of bleeding. Streptokinase is given in a loading dose of 250,000 units over 30 minutes followed by an infusion of 100,000 units/hour up to 48-72 hours.⁸³ Another protocol used a loading dose of 500,000 units over 20 minutes with an infusion of 1.5 million units over 10 hours. In case of hemodynamic instability, shorter protocols are recommended (eg, 1.5 million units over 60 minutes).⁸⁴ In the event of a successful outcome, fibrinolytic therapy is followed by intravenous UFH with VKA to achieve an INR of 3-4 for AVR and 3.5-4.5 for MVR. Low-dose aspirin is also recommended. If thrombolysis is unsuccessful, surgery is recommended. One prospective study noted delayed spontaneous normalization of valve motion in almost half the patients with failed thrombolysis over a mean period of 3 months with intensive anticoagulation.⁸⁵ This may be of relevance in low-resource settings in NYHA class I-II patients.

The American College of Chest Physicians 2012¹⁹ guidelines recommend early surgery for large thrombus area (≥ 0.8 cm²) and fibrinolytic therapy for small thrombus area (< 0.8 cm²).

The ESC 2012²⁶ guidelines recommend urgent or emergency surgery for obstructive PHVT in critically ill patients who are not at high risk for surgery. Surgery is also recommended for large nonobstructive thrombi > 10 mm complicated by embolism or which persist despite optimal anticoagulation. Fibrinolysis is recommended by the ESC for critically ill patients with serious comorbidities or with severely impaired heart function or if surgery is not immediately available. The Society of Heart Valve Disease⁸² takes a contrarian approach and recommends fibrinolytic therapy for all patients, with surgery recommended only if lytic therapy has failed or is contraindicated. Finally, it appears that local expertise and resource availability appears to drive the choice of therapy in PHVT.

The risk of thrombosis with bioprosthetic valves after 3 months of implantation is very low. Symptomatic thrombosis after transcatheter aortic valve replacement is also rare (<1%). This has been treated successfully with anticoagulation with heparin followed by VKA.^48,49

With significant bleeding, antithrombotic therapy should be stopped, and if the patient is at risk of further bleeding, drug effects should be reversed.² If possible, the cause of bleeding should be corrected, and antithrombotic therapy should be restarted as soon as possible. If this is not possible, treatment decisions are difficult. In patients with a mechanical prosthesis or multiple risk factors for thromboemboli, acceptance of intermittent bleeding with acute management for the bleeds may be necessary. In valve patients who are at lower risk of emboli or in whom the role of antithrombotic treatments is less clear (eg, those with LV dysfunction), it may be optimal to withhold chronic therapy or, if a patient is on warfarin, to switch to aspirin. With mechanical PHVs, consideration should be given to replacing the mechanical valve with a biologic valve in patients who have had multiple, large, life-threatening or organ-threatening bleeds.

Patients with infective endocarditis are at a high risk of embolic events (up to 40%) with the brain being the most common site.⁸⁶ The routine use of antithrombotic therapy for prevention of thromboembolism is not recommended in patients with infective endocarditis,^2,19 and may in fact be harmful (with more bleeding).⁸⁷ Anticoagulation is recommended for patients with infective endocarditis who have other indications for anticoagulant therapy^2,19 (eg, MS, mitral stenosis with AF, AF with a CHADS2 score ≥ 2). At the time of presentation, VKAs are replaced with UFH or LMWH until it is clear that there is no central nervous system involvement and that invasive procedures will not be required. Once the patient has stabilized without central nervous system involvement, anticoagulation with VKA therapy can be restarted.¹⁹ In the event that a patient with infective endocarditis does develop signs of central nervous system involvement (embolism or stroke), anticoagulation is temporarily discontinued irrespective of other indications of anticoagulation for fear of risk of hemorrhagic transformation of infarct.²

We would like to thank Dr. Usman Baber and Dr. Valentin Fuster, who contributed to the previous version of this chapter in the 13th edition.