Moexipril Hydrochloride and Warfarin Sodium

• Generic Name: moexipril
• Dosage Forms: n.a.
• Other Brand Names: Univasc

Management of hypertension (alone or in combination with other classes of antihypertensive agents).

ACE inhibitors are recommended as one of several preferred drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potentials harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to ACE inhibitors. However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.

ACE inhibitors may be preferred in hypertensive patients with heart failure, ischemic heart disease, diabetes mellitus, CKD, or cerebrovascular disease or post-MI.

Heart Failure

Management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers).

Some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.

• Generic Name: warfarin
• Dosage Forms: n.a.
• Other Brand Names: Coumadin, Jantoven

Treatment and secondary prevention of venous thromboembolism (DVT and/or PE).

Initiate concomitantly with a parenteral anticoagulant (e.g., a low molecular weight heparin [LMWH], heparin [referring throughout this monograph to unfractionated heparin], fondaparinux). Overlap parenteral and oral anticoagulant therapy for ≥5 days and until a stable INR of ≥2 has been maintained for ≥24 hours, then discontinue parenteral anticoagulant.

Anticoagulant therapy generally not recommended for treatment of isolated distal DVT unless symptoms are severe and there is a risk for thrombus extension.

The American College of Chest Physicians (ACCP) recommends a moderate intensity of anticoagulation (target INR 2.5, range 2–3) for most patients with DVT or PE.

Appropriate duration of therapy determined by individual factors (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding). For most cases of venous thromboembolism, a minimum of 3 months of anticoagulant therapy is recommended. Long-term anticoagulation (>3 months) may be considered in selected patients (e.g., those with idiopathic [unprovoked] DVT or PE who are at low risk of bleeding, cancer patients with DVT or PE). (See Dosage under Dosage and Administration.)

Warfarin generally is the preferred anticoagulant for long-term treatment of venous thromboembolism in patients without cancer; however, in patients with cancer, ACCP suggests use of an LMWH over warfarin because of certain factors in such patients that may affect warfarin therapy (e.g., possible reduced response to warfarin, drug interactions, need for invasive procedures that require reversal of anticoagulation).

Used in select pediatric patients with DVT or PE. LMWHs or heparin generally recommended for both initial and ongoing treatment of venous thromboembolism in children; however, warfarin may be indicated in some situations (e.g., recurrent idiopathic venous thromboembolism).

Treatment and secondary prevention of venous thromboembolic events secondary to use of central venous access devices (CVAD) in children. Remove affected CVAD if no longer functioning or required; however, if CVAD required, ACCP suggests giving anticoagulants until catheter is removed. After initial 3 months of therapy, may consider use of prophylactic-dose warfarin (target INR 1.5–1.9); however, therapeutic dosages may be required if recurrent thromboembolism occurs.

Prevention of postoperative venous thromboembolism in patients undergoing hip- or knee-replacement surgery or hip-fracture surgery.

ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method) in all patients undergoing major orthopedic surgery (hip- or knee-replacement surgery, hip-fracture surgery). Continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery. Although LMWHs generally preferred, alternative agents (e.g., warfarin) may be considered if an LMWH is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia [HIT] or in those who refuse or are uncooperative with sub-Q injections).

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.

Prevention of stroke and systemic embolism in patients with atrial fibrillation. ACCP, ACC, AHA, the American Stroke Association (ASA), and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated.

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Patients considered to be at increased risk of stroke generally include those with advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.

AHA and ASA state that oral anticoagulation is not recommended in women ≤65 years of age with atrial fibrillation and no other risk factors; instead, antiplatelet therapy is a reasonable option in selected low-risk women.

In patients with atrial fibrillation at increased risk of stroke who cannot take or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), combination therapy with clopidogrel and aspirin rather than aspirin alone is recommended.

Antiplatelet agents may be used in combination with warfarin therapy in selected patients who have coexisting conditions that warrant use of antiplatelet therapy (e.g., those with recent placement of an intracoronary stent, those with acute coronary syndrome).

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance <15 mL/minute), lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function). Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in such patients.

Experts suggest managing antithrombotic therapy in patients with atrial flutter in the same manner as in patients with atrial fibrillation.

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.

ACCP and other experts recommend that patients with atrial fibrillation lasting >48 hours or of unknown duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., usually with warfarin) for ≥3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach may be used. After successful cardioversion, all patients should receive therapeutic anticoagulation for ≥4 weeks.

Experts suggest the same approach to thromboprophylaxis in patients undergoing cardioversion for atrial flutter as that used in patients with atrial fibrillation.

Prevention of thromboembolism associated with various types of valvular heart disease, in combination with or as an alternative to low-dose aspirin; assess risk of thromboembolism versus risk of bleeding when determining choice of antithrombotic therapy.

Warfarin anticoagulation (INR 2–3) is recommended in patients with rheumatic mitral valve disease and concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism.

ACCP suggests warfarin anticoagulation in patients with rheumatic mitral valve disease and normal sinus rhythm who have a left atrial diameter >5.5 cm because of their high risk of developing atrial fibrillation.

Warfarin also recommended by ACC and AHA for prevention of thromboembolic events in selected patients with mitral valve prolapse and a history of stroke who have concomitant atrial fibrillation, mitral valve regurgitation, or left atrial thrombus.

Generally should not initiate antithrombotic therapy in patients with infective endocarditis involving a native valve because of the risk of serious (e.g., intracerebral) hemorrhage and lack of documented efficacy. In patients with a prosthetic valve who are already receiving warfarin, ACCP suggests temporary discontinuance of the drug if infective endocarditis develops and reinitiation of therapy once invasive procedures no longer required and patient is stabilized without signs of neurologic complications.

Used in a limited number of patients undergoing percutaneous balloon mitral valvotomy to prevent left atrial embolism.

Used to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or biological heart valves.

Risk of systemic embolism higher with mechanical versus bioprosthetic valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves versus newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) valves, higher with >1 prosthetic valve, and higher with prosthetic mitral versus aortic valves; risk also increases in the presence of atrial fibrillation.

Long-term warfarin therapy required in all patients with mechanical heart valves because of associated high risk of thromboembolism.

Warfarin anticoagulation also suggested in patients with mitral bioprosthetic valves, at least for the first 3 months after valve insertion. In patients with aortic bioprosthetic valves who are in sinus rhythm and have no other indications for warfarin therapy, aspirin generally suggested for initial (e.g., first 3 months after valve insertion) and long-term antithrombotic therapy. However, long-term warfarin therapy (INR 2.5, range 2–3) may be indicated in some patients with bioprosthetic heart valves who have additional risk factors for thromboembolism (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).

In general, target INR of 2.5 (range 2–3) is suggested in patients with an aortic mechanical valve, while target INR of 3 (range 2.5–3.5) is recommended in those with a mitral mechanical valve. A higher intensity of warfarin anticoagulation also may be considered in patients with both aortic and mitral mechanical valves.

ACCP recommends adding low-dose aspirin (e.g., 50–100 mg daily) to warfarin therapy in all patients with mechanical heart valves who are at low risk of bleeding. Combination therapy also may be warranted in some patients with bioprosthetic valves (e.g., those with additional risk factors for thrombosis).

Used for secondary prevention to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after acute STEMI.

In general, antiplatelet therapy is preferred to anticoagulants for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI; however, warfarin (in combination with low-dose aspirin) may be indicated in selected patients (e.g., those with atrial fibrillation, prosthetic heart valve, left ventricular thrombus, or concomitant venous thromboembolic disease).

The manufacturer and other experts recommend warfarin therapy (target INR 2–3) in conjunction with low-dose aspirin (≤100 mg daily) for ≥3 months following acute STEMI in high-risk patients (e.g., those with large anterior MI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event). Triple therapy with warfarin, low-dose aspirin, and clopidogrel is suggested in some patients (e.g., those with anterior MI and left ventricular thrombus who undergo coronary artery stent placement).

Oral anticoagulation with warfarin or one of the non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban) is recommended for secondary prevention of cerebral embolism in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications exist.

Warfarin anticoagulation also is recommended for the prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., prosthetic mechanical heart valves, anterior MI and left ventricular thrombus).

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.

ACCP, AHA, and ASA generally recommend oral anticoagulation with warfarin following initial therapy with heparin or an LMWH in patients with acute cerebral venous sinus thrombosis. AHA and ASA recommend postpartum anticoagulation with warfarin (target INR of 2–3) as an alternative to LMWH for at least 6 weeks (for a total minimum duration of 6 months of anticoagulant therapy) following LMWH therapy during pregnancy in women with cerebral venous sinus thrombosis. Warfarin is suggested by ACCP as an option for long-term anticoagulation in children with arterial ischemic stroke associated with dissection or a cardioembolic cause. Warfarin also has been used in children with cerebral venous sinus thrombosis who do not have substantial intracranial hemorrhage.

Has been used in certain patients with peripheral arterial occlusive disease. However, ACCP generally recommends use of antiplatelet agents (aspirin or clopidogrel) for primary or secondary prevention of cardiovascular events in patients with peripheral arterial disease.

Indefinite anticoagulation with warfarin recommended by ACCP in all patients with chronic thromboembolic pulmonary hypertension.

May be used as follow-up therapy after initial treatment with a nonheparin anticoagulant (e.g., lepirudin, argatroban) in patients with HIT. Overlap therapy with warfarin and nonheparin anticoagulant for ≥5 days and until desired INR has been achieved.

Do not initiate warfarin in patients with HIT until substantial platelet recovery occurs (e.g., platelet count ≥150,000/mm3); in patients already receiving warfarin at the time of HIT diagnosis, ACCP suggests administration of vitamin K. (See Necrosis under Cautions.)