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  • OAC Therapy
  • OAC in Special Population and Conditions

OAC in Special Population and Conditions

Thromboembolic diseases bring about great impact on mortality and are a heavy burden to public health.85 There are certain groups of population at a high risk of thromboembolic disorders and thus need anticoagulation therapy. These patients are also at a high risk of experiencing side-effects (such as teratogenicity and bleeding complications) of anticoagulation therapy. Management of anticoagulant therapy in these patients is thus very crucial. These patient groups include elderly population, pregnant women, cancer patients, and the patients with renal impairment.

Anticoagulant Therapy in Elderly

The main indications of anticoagulation therapy include prophylaxis and treatment of venous thromboembolism (VTE) in medical and surgical settings, atrial fibrillation and valvular heart disease. Elderly population is at high-risk for thromboembolism, as well as hemorrhage. Atrial fibrillation is the most common cardiac arrhythmia observed in elderly population. Anticoagulants are often underutilized in elderly population because of underestimation of the thromboembolic risk, and overestimation of the bleeding risk. Although heparin congeners are effective anticoagulants, vitamin K antagonists (VKAs) are the first choice for long-term anticoagulation therapy.86

There are certain issues with the use of anticoagulants in elderly population, which should be addressed to ensure the safety of anticoagulation therapy. Such issues include86:

  • High risk of bleeding
  • Decreased renal function
  • Comorbidities
  • Risk of falls
  • Altered pharmacodynamics and pharmacokinetics of anticoagulants
  • Concomitant use of antiplatelet agents
Risk of bleeding

Bleeding risk depends largely on the intensity of anticoagulation and patient’s intrinsic characteristics. Patients with international normalized ratio (INR)>3.0 are at a higher risk of major bleeding complications, than those with INR maintained between 2.0 and 3.0. Oral anticoagulation, if well controlled, is safer and does not impose high-risk of major bleeding.86

Decreased renal function

Renal function is known to decrease with age. Heparin congeners and other direct coagulation factor inhibitors (such as fondaparinux, dabigatran, and rivaroxaban) are eliminated largely in urine. Thus, the assessment of renal function before prescribing these anticoagulants is suggested so that accumulation can be avoided. Anti-factor Xa monitoring should be conducted periodically.

Comorbidities

Comorbidities such as hypertension, cerebrovascular diseases, ischemic stroke, serious heart disease, diabetes, alcoholism and liver disease predispose to bleeding complications.86

Risk of falls

Patients with atrial fibrillation (AF), who are at high risk of falls, are at an increased risk of intracranial bleeding. Such patients are at higher risk of ischemic stroke associated with AF, and thus benefit from anticoagulation therapy.86

Altered pharmacokinetics and pharmacodynamics

Drug interactions are often observed in elderly population, because of concomitant medications for comorbidities, and frequent changes due to acute illnesses. An increased pharmacodynamics of VKAs may also be observed in elderly population due to several factors such as decreased synthesis of clotting factors in liver disease, less intake of dietary vitamin K, decreased intestinal production of vitamin K, concomitant use of interacting drugs such as aspirin, and hypermetabolic states such as fever. A low dose regimen of VKAs has been recommended in elderly population.86

Concomitant use of antiplatelet agents: Elderly patients with AF associated with ischemic heart disease are often prescribed antiplatelet agents as well as anticoagulants. The risk of bleeding with such a combination is substantial.86

The extent of renal impairment largely affects the choice of anticoagulants in elderly population. VKAs are metabolized in the liver while other anticoagulants depend on renal excretion. Thus, VKAs do not require dosage adjustments in renal impairment patients, and offer convenience in elderly population.87

In a study conducted in the outpatients in a rural community, patients with VTE were treated with acenocoumarol for more than 6 months. The study noted no thromboembolic event recurrence, of death. However there was about 3% incidence of major bleeding events in a 13-month follow-up. Majority of the included patients were elderly, who are considered to be at high risk of bleeding. The other risk factors that predispose to risk of bleeding, such as cancer, chronic renal failure, were minimal in the study population. Thus, for the treatment of VTE, anticoagulation with acenocoumarol may be safely prolonged for 6 months.88

Anticoagulant Therapy in Pregnancy

Hemostatic changes during pregnancy, along with increased concentration of coagulation factors, coupled with decreased fibrinolysis, result in hypercoagulability, and hence increased risk of thromboembolic disorders. Anticoagulation is recommended in patients with paroxysmal, or permanent atrial fibrillation (AF), left atrial thrombosis, or prior embolism. Women with moderate-to-severe mitral stenosis and spontaneous echocardiographic contrast in the left atrium, large left atrium, or congestive heart failure should also be prescribed anticoagulation therapy.89

Congenital heart disease, pulmonary hypertension and other disorders predispose to maternal, and the offspring risk. Anticoagulation treatment should be considered in such patients.89

The management of valvular heart disease is quite challenging during pregnancy due to adverse maternal and fetal outcomes. Some of the key factors which can optimize the pregnancy outcomes include accurate diagnosis of the severity and etiology of valve disease and preconception evaluation and counseling. Also, patients who are at the highest risk should be referred to the centers expertise in the management of such conditions.90

Recommendations congenital heart disease89
Recommendations Classa Levelb
Pre-pregnancy relief of stenosis (usually by balloon valvulotomy) should be performed in severe pulmonary valve stenosis (peak Doppler gradient >64 mmHg).
Classa:
I
Levelb:
B68,105
Individual follow-up schedules should be arranged; ranging from twice during pregnancy to monthly.
Classa:
I
Levelb:
C
Symptomatic patients with Ebstein's anomaly with cyanosis and/or heart faliure should be treated before pregnancy or advised against pregnancy.
Classa:
I
Levelb:
C
In symptomatic women with marked dilatation of the right ventricle due to severe pulmonary regurgitation, pre-pregnancy pulmonary valve replacement (bioprosthesis) should be performed.
Classa:
I
Levelb:
C
In asymptomatic women with a severely dilated right ventricle due to severe pulmonary regurgitation, pre-pregnancy pulmonary valve replacement (bioprosthesis) should be considered.
Classa:
IIa
Levelb:
C
All women with a bicuspid aortic valve should undergo imaging of the ascending aorta before pregnancy, and surgery should be considered when the aortic diameter is >50 mm.
Classa:
IIa
Levelb:
C
Anticoagulation treatment should be considered during pregnancy in Fontan patients.
Classa:
IIa
Levelb:
C
In PAH, associated anticoagulant treatment should be considered in patients with suspicion of pulmonary embolism as the cause (or partly the cause) of the pulmonary hypertension.
Classa:
IIa
Levelb:
C
In patients who are already taking drug therapy for PAH before becoming pregnant, continuation should be considered after information about the teratogenic effects.
Classa:
IIa
Levelb:
C
Women with pulmonary hypertension should be advised against pregnancy.
Classa:
III
Levelb:
C
Women with an oxygen saturation below 85% at rest should be advised against pregnancy.
Classa:
III
Levelb:
C
Patients with TGA and a systemic right ventricle with more than moderate impairment of RV function and/or severe TR should be advised against pregnancy.
Classa:
III
Levelb:
C
Fontan patients with depressed ventricular function and/or moderate to severe atrioventricular valvular regurgitation or with cyanosis or with protein-losing enteropathy should be advised against pregnancy.
Classa:
III
Levelb:
C

aClass of recommendation.

bLevel of evidence.

cSee the text for detailed description and exceptions.

PAH, pulmonary arterial hypertension; RV, right ventricular; TGA, complete transposition of the great arteries; TR, tricuspid regurgitation.

Recommendations valvular heart disease89
Recommendations Classa Levelb
Mitral stenosis
In patients with symptoms or pulmonary hypertension, restricted activities and βI-selective blockers are recommended.
Classa:
I
Levelb:
B7,64
Diuretics are recommended when congestive symptoms persist despite β-blockers.
Classa:
I
Levelb:
B64
Patients with severe MS should undergo intervention before pregnancy.
Classa:
I
Levelb:
C
Therapeutic anticoagulation is recommended in the case of atrial fibrillation, left atrial thrombosis, or prior embolism.
Classa:
I
Levelb:
C
Percutaneous mitral commissurotomy should be considered in pregnant patients with severe symptoms or systolic pulmonary artery pressure >50 mmHg despite medical therapy.
Classa:
IIa
Levelb:
C
Aortic stenosis
Patients with severe AS should undergo intervention pre-pregnancy if:
  • they are symptomatic
Classa:
I
Levelb:
B7
  • or LV dysfunction (LVEF <50%) is present
Classa:
I
Levelb:
C
Asymptomatic patients with severe AS should undergo intervention pre-pregnancy when they develop symptoms during exercise testing.
Classa:
I
Levelb:
C
Asymptomatic patients with severe AS should be considered for intervention pre-pregnancy when a fall in blood pressure below baseline during exercise testing occurs.
Classa:
IIa
Levelb:
C
Regurgitant lesions
Patients with severe aortic or mitral regurgiation and symptoms or impaired ventricular function or ventricular dilatation should be treated surgically pre-pregnancy.
Classa:
I
Levelb:
C
Medical therapy is recommended in pregnant woman with regurgitant lesions when symptoms occur.
Classa:
I
Levelb:
C
Mechanical valves
OACs are recommended during the second and third trimesters until the 36th week.
Classa:
I
Levelb:
C
Change of anticoagulation regimen during pregnancy should be implemented in hospital.
Classa:
I
Levelb:
C
If delivery starts while on OACs, caesarean delivery is indicated.
Classa:
I
Levelb:
C
OAC should be discontinued and dose-adjusted UFH (a PTT ≥2x control) or adjusted-dose LMWH (target anti-Xa level 4–6 hours post-dose 0.8–1.2 U/mL) started at the 36th week of gestation.
Classa:
I
Levelb:
C
In pregnant women managed with LMWH, the post-dose anti-Xa level should be assessed weekly.
Classa:
I
Levelb:
C
LMWH should be replaced by intravenous UFH at least 36 hours before planned delivery. UFH should be continued until 4–6 hours before planned delivery and restarted 4–6 hours after delivery if there are no bleeding complications.
Classa:
I
Levelb:
C
Immediate echocardiography is indicated in women with mechanical valves presenting with dyspnoea and/or an embolic event.
Classa:
I
Levelb:
C
Continuation of OACs should be considered during the first trimester if the warfarin dose required for therapeutic anticoagulation is <5 mg/day (or phenprocoumon <3 mg/day or acenocoumarol <2 mg/day), after patient information and consent.
Classa:
IIa
Levelb:
C
Discontinuation of OAC between weeks 6 and 12 and replacement by adjusted-dose UFH (a PTT ≥2x control; in high risk patients applied as intravenous infusion) or LMWH twice daily (with dose adjustment according to weight and target anti-Xa level 4–6 hours post-dose 0.8–1.2 U/mL) should be considered in patients with a warfarin dose required of >5 mg/day (or phenprocoumon >3 mg/day or acenocoumarol >2mg/day).
Classa:
IIa
Levelb:
C
Discontinuation of OACs between weeks 6 and 12 and replacement by UFH or LMWH under strict dose control (as described above) may be considered on an individual basis in patients with warfarin dose required for therapeutic anticoagulation <5 mg/day (or phenprocoumon <3 mg/day or acenocoumarol <2 mg/day).
Classa:
IIb
Levelb:
C
Continuation of OACs may be considered between weeks 6 and 12 in patients with a warfarin dose required for therapeutic anticoagulation >5 mg/day (or phenprocoumon >3 mg/day or acenocoumarol >2 mg/day).
Classa:
IIb
Levelb:
C
LMWH should be avoided, unless anti-Xa levels are monitored.
Classa:
III
Levelb:
C

aClass of recommendation.

bLevel of evidence.

aPTT, activated partial thromboplastin time; AS, aortic stenosis; LMWH, low-molecular-weight heparin; LVEF, left ventricular ejection fraction; MS, mitral stenosis; OACs, oral anticoagulants; UFH, unfractionated heparin.

Patients with valvular AF are at a high-risk of thromboembolic disease. Use of oral anticoagulants throughout pregnancy is reported to be beneficial.91 Immediate anticoagulation with unfractionated heparin (UFH), followed by low-molecular-weight heparin (LMWH) in the first and last trimester, and oral anticoagulants or LMWH during the second trimester is recommended.88 In mothers with a lower incidence of valve thrombosis, coumarin derivatives are reported to be relatively safer than UFH and LMWH.92

Although teratogenic, the risk of embryopathy is probably lower with vitamin K antagonists (VKAs) when used at a dose <5 mg (for warfarin) daily. However, no definite conclusions can be drawn. Similarly, acenocoumarol at a dose <2.0 mg may be considered safe in such population.90 The risk of embryopathy with coumarin derivatives can be eliminated by substituting coumarin derivatives with UFH or LMWH from the 6th to the 12th week of pregnancy.92

A case study reported that use of acenocoumarol throughout the second and third trimester in a pregnant woman with a mechanical heart valve caused no embryopathy in the newborn.93 Use of VKAs, such as acenocoumarol, is considered to be safe in breastfeeding mothers, as it is not secreted in the milk in active form. Postpartum anticoagulation with VKAs (for 4–6 weeks; with a target international normalized ratio of 2.0–3.0) is recommended by some of the treatment guidelines.94

Cancer

Malignancy is a major predisposing factor for the development and recurrence of venous thromboembolism (VTE).95 Clinically manifested VTE has been reported in approximately 15% of cancer patients. The risk varies with the type of cancer, stage of cancer, chemotherapy, surgical intervention and generalized debility. In addition to the altered coagulation mechanisms, two extrinsic causes of hypercoagulability are cancer surgery and chemotherapy.96 Approximately 60% of cancer patients undergo surgery for one or another purpose.97

The risk of VTE increases to about 6.7-fold in patients receiving chemotherapy, such as cisplatin, etoposide, medroxyprogesterone and tamoxifen. While on anticoagulant therapy, cancer patients with VTE are at 2-fold higher risk of recurrence than noncancer patients. Longer hospitalization, difficulty in maintenance of anticoagulation and poor prognosis intensify the challenge. For these reasons, cancer patients are considered to be at high-risk for VTE complications and need more intense anticoagulation monitoring.97

It had been postulated earlier that long-term vitamin K antagonist (VKA) therapy may be associated with a lower incidence of cancer, particularly prostate cancer. A population-based observational cohort study was conducted to assess the impact of long-term VKA use on the development of newly-diagnosed malignancies, and on cancer-related and overall mortality. The study included 89,787 individuals; VKA exposure was assessed on the basis of Anatomical Therapeutic Chemical (ATC) codes on the drug prescription.98

It was noted that the patients in the VKA-exposed group were significantly older (76.4±6.8 years vs. 74.8±7.2 years) and followed up for a longer duration (9.1±2.4 years vs. 8.8±2.6 years). Further, the number of females was higher than males in both the groups (VKA-exposed: 50.4% and control group: 59.9%). After adjustments were done for age and sex, it was noted that patients exposed to VKA had lower incidence of cancer (hazard ratio 0.88, p<0.015). Further, the incidence of prostate cancer was significantly reduced (hazard ratio 0.69, p=0.008) among the specific tumors.98

The study results support the hypothesis that long-term treatment with VKAs has a protective effect on the development of cancer, especially prostate cancer in elderly patients. The mechanism of this anticancer effect is proposed to involve thrombin in relation to protease-activated receptors GAS6 and AXL. This GAS6/AXL axis is believed to regulate the invasion, proliferation and survival of prostate cancer. Animal studies supporting this hypothesis have been conducted. The hypothesis has been positively demonstrated in human studies though less number of events raises a concern about the validity of such studies.98

With the finding that VKAs exhibit reduced risk of cancer after years of exposure, it has been suggested that the protective effect of VKAs is exhibited at the stage of tumor initiation or promotion rather than an effect on established tumor.98

A study conducted in cancer patients analyzed the efficacy and safety of early and short-term thromboprophylaxis with acenocoumarol and dalteparin in the prevention of nonocclusive and occlusive central vein catheter-related thrombosis (CVCRT). The study reported that acenocoumarol was better than dalteparin in the prevention of CVCRT.99

It has been recommended that in cancer patients, low-molecular-weight heparin (LMWH) should be initiated and continued for the first 3–6 months, followed by either LMWH or VKA up to indefinite duration or until the cancer is treated.100

Renal Impairment

Dosing and monitoring of anticoagulants are especially important considerations in patients with renal insufficiency.96 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/min). Drug clearance may be reduced by about 40% in patients with severe renal impairment. Clinicians have raised concerns about bleeding complications in patients with kidney failure.101

The prevalence of atrial fibrillation (AF) is reported to be higher in patients with renal impairment. Also, the risk of AF development increases with worsening of renal function. In patients with mild-to-moderate chronic kidney disease and AF, use of vitamin K antagonist (VKA) is shown to reduce ischemic complications without significant bleeding risk.102

As VKAs are metabolized in the liver, no dosage adjustments are required in patients with chronic renal impairment. However, a careful monitoring of therapy is recommended. Contrary to VKAs, heparin congeners as well as newer anticoagulants depend largely on renal excretion. Thus, the patients with renal impairment are at risk of accumulation and hence over anticoagulation.103

While no dosage adjustments are required with VKAs, the doses of newer anticoagulants need to be reduced to prevent their accumulation and hence adverse events. VKAs thus offer convenience in patients with renal impairment.

Minor Surgeries

Minor surgical procedures can be performed with international normalized ratio (INR) <2 and oral anticoagulation can be resumed on the day of surgery. Studies have reported that discontinuing oral anticoagulation before cataract extractions and other oculoplastic surgical procedures is not necessary, provided the INR is not above the therapeutic range.104

Major Surgeries

Major surgical procedures require lowering of the international normalized ratio (INR) to < 1.5. In such cases anticoagulation needs to be maintained with heparin. Heparin should be started when the INR is <2.5 in high risk patients (such as those with mitral mechanical valves) and < 2.0 in patients with aortic mechanical valves. Heparin should be continued until six hours before surgery and resumed 6–12 hours after surgery, when surgically feasible. It should be continued until INR is > 2. Oral anticoagulation can be resumed 1–2 days after surgery.104

Protocol

Usage Protocol of Anticoagulation in Patients Undergoing Major and Minor Surgeries

Very often, the patients presenting for elective surgical procedures have comorbid conditions for which anticoagulants have been prescribed. The risk of procedure-associated bleeding depends on the organ, pathology and surgical methodology. Antithrombotic medications may affect the risk of bleeding, where generally minor procedures (associated with minimal bleeding rates), such as bowel polypectomy or pacemaker insertion, may induce significant bleeding.105

Patients undergoing various dental, ophthalmic, and other major/minor, cardiac/non-cardiac surgeries need adjustments in their anticoagulation regimens, according to the risk of thromboembolism and the risk of bleeding.104 A risk-benefit evaluation of antithrombotic drugs to assess the likelihood of operation-associated bleeding with or without antithrombotic use, and morbidity or mortality linked with this complication is suggested.105

Risk assessment of non-cardiac surgical procedures104
According to risk factors related to: Low risk High risk
Patients
Atrial fibrillation +
Previous thromboembolism +
Hypercoagulable congenital or acquired conditions +
Left ventricular dysfunction +
Heart failure +
Prostheses design
Ball valve +
Tilting disk +
Bileaflet +
Prostheses position
Aortic +
Mitral +
Procedures
Dental, ophthalmic +
Skin +
Gastrointestinal +
Pathology
Tumour +
Infection +

Different strategies for management of anticoagulation have been suggested, including104:

  • discontinuation of oral anticoagulation until international normalized ratio (INR) is normal, without heparin replacement;
  • discontinuation of oral anticoagulation until INR is normal, with heparin replacement as soon as the INR is <2.0;
  • lowering the intensity of anticoagulation while oral anticoagulation is maintained;
  • continuing a therapeutic level of anticoagulation.

Several factors influence the time interval before surgery for which anticoagulants need to be discontinued, such as half-life of the oral anticoagulant used, the actual INR, the desired INR for the specific procedure, and the individual vitamin K pool. The American College of Cardiologists (ACC)/American Heart Association (AHA) and the British Society of Hematology suggest discontinuing vitamin K antagonists 72 hours before routine non-cardiac surgical procedures. Close monitoring of INR is suggested since the INR levels may vary greatly among different patients.104

Dental Surgery

Dental surgery is one of the procedures with the lowest risk for thromboembolic complications. As such, dental surgical procedures do not require major changes in the anticoagulation intensity. The safest approach in dental surgery is to continue anticoagulation to maintain international normalized ratio in the range of 2.0–2.5.104

Interventional Cardiac Procedures

For left heart catheterization by the brachial route, the international normalized ratio should be < 2.5, and by the femoral route it should be < 1.8.104

Postprocedural Anticoagulation

Patients with coronary artery bypass grafting (CABG) are at associated with high risk of atrial fibrillation (AF) and postoperative stroke. Thus, anticoagulation with vitamin K antagonists (VKA) is indicated for 4 weeks. Among the patients who had a recent myocardial infarction , left ventricle mural thrombus and are at risk of stroke after CABG, long‐term (3–6 months) anticoagulation is probably indicated for the patient with recent anteroapical infarct and persistent wall‐motion abnormality.104

Optimal thromboprophylaxis following bioprosthetic aortic valve replacement (AVR) remains controversial. Despite the overall lower thrombogenic state of bioprostheses, there remains an increased risk of thromboembolic events in the first 3 months following surgery. The American College of Cardiologists (ACC)/American Heart Association (AHA), the European Society of Cardiology (ESC) and the American College of Chest Physicians (ACCP) advocate anticoagulation therapy during the first 3 months following bioprosthetic AVR. In patients with additional risk factors, such as AF, history of previous thromboembolism, poor left ventricular function and hypercoagulability states, VKAs are indicated for indefinite duration.106

Summary

Elderly population is at high risk of thromboembolism as well as risk of bleeding. Comorbidities and concomitant medications make the use of anticoagulants difficult. Vitamin K antagonists (VKAs) play an important role in oral anticoagulation, as no dosage adjustment is required in renal impairment, which is common in elderly.

Pregnancy predisposes to the risk of developing thromboembolism with the raised concentration of clotting factors and other stimuli. Anticoagulants are required in valvular heart disease, congenital heart disease, atrial fibrillation and certain other disorders. VKAs at low dose are considered safe during first trimester of pregnancy. Use of VKA such as acenocoumarol is considered to be safe in breastfeeding mothers, as it is minimally secreted into the breast milk.

The risk of thromboembolism is higher in cancer patients. In addition to malignancy, the chemotherapy and surgery further increase the risk of venous thrmboembolism. Long-term VKA use has a protective role towards the development of cancer, particularly prostate cancer. In cancer patients, low-molecular-weight heparin (LMWH) should be initiated and continued for the first 3–6 months, followed by either LMWH or VKA up to indefinite duration or until the cancer is treated.

Patients with renal impairment tend to accumulate the anticoagulants excreted through kidneys. Such patients are thus at an increased risk of bleeding. Dosage adjustment of novel anticoagulants is necessary in such conditions. As VKAs are metabolized in the liver and do not depend on renal excretion, these can be used conveniently in patients with renal impairment, without any dosage modifications. VKAs are shown to reduce ischemic complications in chronic kidney disease patients without significant bleeding risk.