Judy W.M. Cheng

Azilsartan Medoxomil: A New Angiotensin Receptor Blocker

BACKGROUND Azilsartan medoxomil is an angiotensin receptor blocker, approved on February 25, 2011 by the US Food and Drug Administration (FDA) for hypertension management. OBJECTIVE The purpose of this study was to review the pharmacology, pharmacokinetics, efficacy, safety profile, and role of azilsartan for hypertension management. METHODS Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Contents (both 1966 to August 31, 2011) using the search terms azilsartan, TAK-491, TAK-536, pharmacology, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. The FDA Web site and manufacturer prescribing information were also reviewed to identify other relevant information. RESULTS Compared with olmesartan 40 mg daily, azilsartan 80 mg reduced mean systolic blood pressure (SBP) by an additional 2.1 mm Hg (P = 0.038), whereas azilsartan 40 mg was noninferior to olmesartan 40 mg. Azilsartan 40 mg or 80 mg added to chlorthalidone 25 mg daily significantly reduced SBP to a greater extent than did chlorthalidone alone (P < 0.05), but there was no difference between azilsartan 40 mg and 80 mg (40 mg: -31.72 mm Hg; 80 mg: -31.3 mm Hg [P > 0.05]). When coadministered with amlodipine 5 mg daily, both azilsartan 40 mg and 80 mg + amlodipine decreased SBP significantly more than amlodipine alone (amlodipine: -13.6 mm Hg; with azilsartan 40 mg: -24.79 mm Hg; with azilsartan 80 mg: -24.51 mm Hg [P < 0.05]). Compared with ramipril 10 mg daily, both azilsartan 40 mg and 80 mg resulted in significantly (P < 0.001) greater reductions in mean SBP (-20.63 and -21.24 mm Hg, respectively; ramipril: -12.22 mm Hg). The most common adverse events reported were dizziness (4%), dyslipidemia (3.3%), and diarrhea (2%). CONCLUSIONS At the recommended dose of 80 mg once daily, azilsartan is reported to be an efficacious BP-lowering agent. With once-daily dosing and a favorable side-effect profile, azilsartan is an attractive option for the treatment of hypertension. There is a lack of data supporting the use of azilsartan for improvement in cardiovascular outcomes; therefore, azilsartan is not approved for indications other than the treatment of hypertension.

Aliskiren: Renin inhibitor for hypertension management

BACKGROUND The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Aliskiren is the first of a new class of antihypertensive agents known as renin inhibitors. OBJECTIVE The goal of this article was to discuss the clinical pharmacology of aliskiren and its use in the management of hypertension, as well as potential uses in other cardiovascular disorders. METHODS Peer-reviewed articles and abstracts were identified from the MEDLINE and Current Contents databases (both 1966-October 1, 2007) using the search terms aliskiren, drug interaction, pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Abstracts presented at recent professional meetings were also examined. RESULTS Nine published clinical studies have evaluated the effect of aliskiren in lowering blood pressure in hypertensive patients, either alone or in combination with other antihypertensive agents. This review summarizes those studies. Patients treated with aliskiren had significantly lower blood pressure compared with patients with mild to moderate hypertension (systolic blood pressure [SBP] 140-180 mm Hg and diastolic blood pressure [DBP] 95-110 mm Hg) who received placebo. Aliskiren in doses of 75 to 300 mg daily produced reductions of SBP (-5.3 to -15.8 mm Hg) and DBP (-5.8 to -12.3 mm Hg); placebo produced reductions of SBP that ranged from -2.85 to -10.0 mm Hg and DBP reductions from -3.26 to -8.6 mm Hg (P < 0.05 in all studies between aliskiren and placebo). Aliskirens blood pressure-lowering effect at doses of 75 to 300 mg daily was comparable to irbesartan 150 mg daily and valsartan 80 to 360 mg daily alone. When aliskiren was added to ramipril, hydrochlorothiazide, amlodipine, irbesartan, or valsartan, significant additive blood pressure-lowering effects were reported (P < 0.05 in all clinical trials). The total incidence of adverse events was similar to placebo and other comparative agents, including irbesartan, valsartan, losartan, ramipril, and hydrochlorothiazide. The overall adverse-event rates were 22%, 35% to 52%, 25% to 52%, 34% to 55%, and 33% to 52% for aliskiren 37.5, 75, 150, 300, and 600 mg, respectively. The most commonly reported adverse events included headache, dizziness, and fatigue. Studies with cardiovascular outcomes as end points have not been performed with aliskiren. CONCLUSIONS Aliskiren is an effective alternative agent for blood pressure management. Before aliskiren can be recommended as a routine first-line agent, however, clinical studies must explore if the blood pressure-lowering effect will translate into improvement in cardiovascular outcomes.

Ambrisentan for the management of pulmonary arterial hypertension.

BACKGROUND Approved by the US Food and Drug Administration in 2007, ambrisentan is the second oral endothelin A-receptor antagonist available for the management of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms. OBJECTIVE This article examines the clinical pharmacology of ambrisentan, its efficacy and adverse effects, and future directions for research. METHODS Pertinent articles and abstracts were identified through searches of MEDLINE and Current Contents from 1966 to January 15, 2008, using the term ambrisentan. The reference lists of identified articles were searched for additional publications. Abstracts presented at professional meetings from 2005 through 2007 were also reviewed. RESULTS The literature review identified 3 studies of ambrisentan in PAH: 1 dose-ranging study; 2 randomized, double-blind, placebo-controlled studies; and 1 drug-conversion study. In the dose-ranging study, ambrisentan at doses of 1 to 10 mg was associated with significant improvements from baseline in the 6-minute walk distance at 12 weeks that ranged from 33.9 m with ambrisentan 1 mg (P = 0.003) to 38.1 m with ambrisentan 5 mg (P = 0.001). In the placebo-controlled studies, ambrisentan at doses of 2.5 to 10 mg/d was associated with significant improvements versus placebo in the 6-minute walk distance at 12 weeks that ranged from 22 m with ambrisentan 2.5 mg (P = 0.022) to 59 m with ambrisentan 5 mg (P <or= 0.001). Improvements were sustained for up to 1 year. Patients who had elevations in serum aminotransferases during previous therapy with bosentan or sitaxsentan therapy were able to make a successful transition to ambrisentan without further abnormalities in liver function. Ambrisentan was generally well tolerated. The most common adverse effects associated with ambrisentan in clinical trials were peripheral edema (17%), nasal congestion (6%), palpitation (5%), constipation (4%), flushing (4%), abdominal pain (3%), nasopharyngitis (3%), and sinusitis (3%). In the placebo-controlled studies, the incidence of liver aminotransferase and bilirubin abnormalities at 12 weeks was lower with ambrisentan than with placebo (0.8% vs 2.3%, respectively). CONCLUSIONS The available evidence suggests that ambrisentan is effective and well tolerated in the management of PAH. Areas for future research include the long-term safety of ambrisentan, its potential for drug interactions with other agents commonly used by patients with PAH, and its efficacy relative to other agents used to manage PAH.

Vernakalant in the Management of Atrial Fibrillation

OBJECTIVE: To review the pharmacology and clinical evidence of the use of vernakalant in the management of atrial fibrillation (AF). DATA SOURCES: Peer-reviewed articles published in the English language were identified from MEDLINE and Current Contents databases (both 1966–March 5, 2008) using the search terms RSD 1235 and vernakalant. Citations from available articles and recent meeting abstracts were reviewed for additional references. During the preparation of this article, vernakalant was being reviewed by the Food and Drug Administration (FDA). Therefore, information posted on the FDA Web site was also evaluated. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and Phase 3 clinical studies of both intravenous and oral vernakalant were reviewed. The design and results of the studies were critically evaluated. DATA SYNTHESIS: Vernakalant is a sodium and ultra-rapid potassium channel blocker with atrial selective effects. In 2 clinical studies evaluating use of intravenous vernakalant in cardioversion of patients with recent-onset AF, vernakalant improved the chance of restoration of normal sinus rhythm (combined results 51% vs 3.8% with placebo; p < 0.001). In postoperative AF, intravenous vernakalant also improved the chance of restoration of normal sinus rhythm (45% vs 15% with placebo; p = 0.0002). Early Phase 2 studies demonstrated that oral vernakalant 300 mg or 600 mg twice daily successfully maintained sinus rhythm compared with placebo. No proarrhythmias relating to vernakalant have been reported to date. Common adverse effects include dysgeusia, sneezing, and paresthesia. CONCLUSIONS: Vernakalant is a new atrial-selective antiarrhythmic agent. Phase 3 clinical trials of the intravenous formulation and early Phase 2 studies of the oral formulation demonstrated vernakalant to be efficacious and safe in converting recent-onset AF to sinus rhythm. Further studies are needed to explore the efficacy and safety of vernakalant use in patients with severe heart failure and AF, as well as its relative efficacy and safety compared with other antiarrhythmic agents, especially with long-term use.

Is the Volume of Distribution of Digoxin Reduced in Patients with Renal Dysfunction? Determining Digoxin Pharmacokinetics by Fluorescence Polarization Immunoassay

Study Objective. To determine digoxin pharmacokinetics in subjects with different degrees of renal function using fluorescence polarization immunoassay (FPIA), which is associated with less interference from digoxin‐like immunoreactive substances (DLIS) than radioimmunoassay.

Antiplatelet Therapy After Placement of a Drug-Eluting Stent: A Review of Efficacy and Safety Studies

BACKGROUND Dual antiplatelet therapy with a thienopyridine (ticlopidine or clopidogrel) and aspirin is used to reduce the risk of late stent thrombosis and complications (myocardial infarction [MI] and death) after placement of a drug-eluting stent (DES). OBJECTIVE This article reviews available clinical efficacy and safety data on antiplatelet therapies for the prevention of stent thrombosis and cardiac events after DES placement. METHODS MEDLINE, EMBASE, and International Pharmaceutical Abstracts (1966-June 2010) were searched for studies relating to the clinical efficacy and safety of antiplatelet therapy after DES placement using the terms antiplatelet therapy, thienopyridine, aspirin, clopidogrel, cilostazol, prasugrel, ticlopidine, paclitaxel-eluting stent, sirolimus-eluting stent, and drug-eluting stent. The reference lists of the identified articles were reviewed for additional relevant publications. RESULTS Ten studies were identified that evaluated the efficacy of antiplatelet therapies after DES placement; of these, 5 also assessed safety. In a prospective, observational cohort study, early discontinuation of clopidogrel (within the first 6 months after DES placement) was a major predictor of stent thrombosis (hazard ratio [HR] = 13.74; 95% CI, 4.04-46.68; P < 0.001). In an observational cohort study, early discontinuation of clopidogrel was associated with significantly higher rates of long-term clinical events (death and death or MI) (discontinuation at 6 months: P = 0.004; discontinuation at 12 months: P < 0.001). A multicenter, randomized, double-blind, prospective study found a reduction in the composite end point of death, MI, and target-vessel revascularization within 30 days after DES placement in patients who received a high loading dose of clopidogrel (600 mg) compared with the conventional loading dose (300 mg) (4% vs 12%, respectively; P = 0.041). In a multicenter, randomized, prospective study in patients with long coronary lesions undergoing DES placement, triple antiplatelet therapy (clopidogrel, cilostazol, and aspirin) was associated with significant reductions at 6 months compared with dual antiplatelet therapy (clopidogrel and aspirin) in in-stent late loss (mean [SD], 0.22 [0.48] vs 0.32 [0.51] mm, respectively; P = 0.03) and in-segment late loss (0.34 [0.49] vs 0.51 [0.49] mm; P = 0.001). In a similar study in patients with diabetes mellitus, triple therapy was associated with significant reductions at 6 months in rates of in-segment restenosis (8.0% vs 15.6%; RR = 0.51; 95% CI, 0.27-0.96; P = 0.033), target-lesion revascularization (2.5% vs 7.0%; RR = 0.36; 95% CI, 0.13-0.97; P = 0.034), and major adverse cardiac events (2.8% vs 7.6%; P = 0.016). In a multicenter, retrospective study comparing triple and dual antiplatelet therapy in patients with ST-segment elevation MI undergoing DES placement, triple therapy was associated with significant reductions at 8 months compared with dual therapy in rates of cardiac deaths (2.0% vs 3.2%; P = 0.019), total deaths (3.1% vs 4.9%; P = 0.006), and total major adverse cardiac events (7.6% vs 9.3%; P = 0.049). Overall, use of triple therapy was not associated with an increased risk of major or minor bleeding events compared with dual therapy. In a multicenter, randomized, double-blind, prospective study in patients with acute coronary syndrome (ACS) who underwent DES placement and received the combination of prasugrel or clopidogrel and aspirin, the prasugrel regimen was associated with significant reductions in rates of the composite end point of cardiovascular death, nonfatal MI, and nonfatal stroke (HR = 0.82; 95% CI, 0.69-0.97; P = 0.019) and late stent thrombosis (0.42% vs 0.91%, respectively; P = 0.04). However, the combination of prasugrel and aspirin was associated with significant increases compared with clopidogrel and aspirin in rates of total bleeding events (5.0% vs 3.8%; P = 0.002), major bleeding events (2.4% vs 1.8%; P = 0.03), and life-threatening bleeding events (1.4% vs 0.9%; P = 0.01). CONCLUSIONS The combination of clopidogrel (loading dose, 300-600 mg; maintenance dose, 75 mg/d) and low-dose aspirin (75-162 mg/d) for 12 months is the preferred regimen for the prevention of stent thrombosis and cardiac complications after DES placement. The combination of prasugrel and aspirin may be appropriate in patients with ACS, although it was associated with a significantly increased risk for bleeding. Triple antiplatelet therapy may be beneficial in certain high-risk patients.

Intravenous Diuretic Therapy for the Management of Heart Failure and Volume Overload in a Multidisciplinary Outpatient Unit

OBJECTIVES This study sought to evaluate the effectiveness of intravenous (IV) diuretic treatment for volume management in heart failure (HF). BACKGROUND Limited data exist regarding IV diuretics for the outpatient treatment of volume overload in HF patients. METHODS We analyzed 60 consecutive patients with chronic HF and clinical evidence of worsening congestion who received a bolus and 3-h IV infusion of furosemide at an outpatient HF clinic. Diuretic dosing was derived from the maintenance oral loop diuretic dose with a standardized conversion algorithm. Outcomes included urine output during the visit, weight loss at 24 h, and hospitalization and mortality at 30 days. Safety outcomes included hypokalemia and worsening of renal function. Outcomes were analyzed across subgroups defined by maintenance diuretic dose and ejection fraction (EF). RESULTS The median age of the cohort was 70 years (interquartile range [IQR]: 58 to 80 years), and the median daily loop diuretic dose was 240 mg (IQR: 80 to 800 mg) oral furosemide or equivalent. Twenty-six patients (43.3%) were women, and 36 (60%) had an EF ≤45%. For the entire cohort, the median urine output and 24-h weight loss were 1.1 l (IQR: 0.6 to 1.4 l) and 1.1 kg (IQR: 0.2 to 1.9 kg), respectively. Outcomes were similar across patients with varying maintenance diuretic doses (<40 mg, 40 to 160 mg, 160 to 300 mg, or >300 mg of furosemide or equivalent) and in patients with reduced or preserved EF. Transient worsening of renal function and hypokalemia occurred in 10 patients (8.9%) and 4 patients (3.5%). Although hospitalization was reported as imminent for 28 patients (52.8%), the observed rate of all-cause hospitalization was 31.7% at 30 days with no deaths. CONCLUSIONS Short courses of IV diuretics for volume management in patients with HF were safe and associated with significant urine output and weight loss across a wide range of maintenance diuretic doses and EF. This strategy may provide an alternative to hospitalization for the management of selected HF patients.

Dabigatran etexilate: an oral direct thrombin inhibitor for the management of thromboembolic disorders.

BACKGROUND Until recently, warfarin was the only oral anticoagulant available in the United States. Its narrow therapeutic index, interpatient variability in dose response, and drug and food interactions make it difficult to use. Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor that was approved in the US and in Canada for the prevention of thromboembolic events in patients with atrial fibrillation (AF), as well as in Europe and Canada for the prevention of venous thromboembolism (VTE). OBJECTIVE To discuss the role of DE for the prevention and treatment of VTE, as well as for the prevention of stroke in patients with AF. METHODS Peer-reviewed clinical trials, review articles, and treatment guidelines were identified from MEDLINE and the Current Contents database (both 1966-February 15, 2012) using the search terms dabigatran, VTE, Afib, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. Citations from available articles were also reviewed for additional references. RESULTS For VTE prophylaxis, DE 150 or 220 mg orally daily has demonstrated either superiority or noninferiority to subcutaneous enoxaparin once daily in most studies. However, one study failed to demonstrate noninferiority to subcutaneous enoxaparin dosed BID in the composite end point of VTE, and all-cause mortality. For VTE treatment, DE 150 mg BID orally was shown to be noninferior to warfarin in preventing recurrent events. For AF, DE 150 mg BID orally is superior to warfarin in the prevention of thromboembolism, whereas 110 mg BID is noninferior to warfarin. Pharmacoeconomic analyses performed in the United Kingdom and Ireland found that DE can be cost-saving compared with enoxaparin in the prevention of VTE. Adverse effects of DE reported in clinical studies include dyspepsia (12%-13%) and bleeding (minor bleeding: 6%-22%). CONCLUSIONS DE exhibited a safety profile and efficacy comparable to enoxaparin for VTE prophylaxis; comparable safety profile and efficacy to warfarin for VTE treatment; and superiority (150 mg BID orally) in the prevention of stroke and systemic embolism compared with warfarin in patients with AF. The relative ease of oral administration, no need for routine monitoring, and lack of significant drug interactions, may favor use of DE over other anticoagulants. However, there is no antidote for DE currently available.

Current Perspective on the Use of Angiotensin-Converting Enzyme Inhibitors in the Management of Coronary (Atherosclerotic) Artery Disease

OBJECTIVE: To review the pathophysiology of atherosclerosis, the role of the renin—angiotensin system in atherogenesis, and studies supporting the potential beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in reducing cardiovascular events with long-term use. BACKGROUND: Through its action in converting angiotensin I to angiotensin II and by degrading bradykinin, local tissue ACE exerts many effects that can contribute to the development of atherosclerosis. Therefore, the use of ACE inhibitors can possibly result in antiatherogenic effects. Possible mechanisms for antiatherogenic effects of ACE inhibitors include: (1) reduction of blood pressure; (2) antiproliferative and antimigratory effects on vascular smooth muscle cells, neutrophils, and monocytes; (3) restoration of endothelial function; (4) stabilization of fatty plaque by preventing vasoconstriction; (5) antiplatelet effects; and (6) enhancement of endogenous fibrinolysis. DATA SOURCES: English-language clinical studies, abstracts, and review articles pertaining to the use of ACE inhibitors and atherosclerosis. STUDY SELECTION AND DATA EXTRACTION: Relevant human studies examining the role of ACE inhibitors and atherosclerosis. DATA SYNTHESIS: Studies evaluating the possible beneficial effects of ACE inhibitors in the development of atherosclerosis are reviewed and critiqued. Design of ongoing studies with clinical and surrogate end points are discussed. CONCLUSIONS: Based on current published studies, recommendations are made regarding the use of ACE inhibitors in atherosclerosis. Therapeutic monitoring parameters for efficacy and adverse effects are also reviewed.

Azilsartan/chlorthalidone combination therapy for blood pressure control

Background Edarbyclor® is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. Objective To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Methods Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms “azilsartan”, “chlorthalidone”, “pharmacology”, “pharmacokinetics”, “pharmacodynamics”, “pharmacoeconomics”, and “cost-effectiveness”. The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Results Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Conclusions Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan/chlorthalidone will be the most appropriate combination therapy for an individual patient.