Cardiovascular

A review of agents in late-stage development for the treatment of atherosclerosis and thrombosis (June 2006).

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) play a role in the treatment of hypertension (HTN) and heart failure (HF). The literature shows that in patients with HTN with comorbidities, such as HF, myocardial infarction (MI), diabetes mellitus, chronic kidney disease, and stroke, ACE inhibitors and ARBs appear to provide added benefit beyond solely lowering blood pressure. In addition, clinical trials have also demonstrated that ACE inhibitors and ARBs may be beneficial in the prevention of diabetes, atrial fibrillation (AF), and recurrent stroke. This review evaluates the practice guidelines and current literature to assess the implications for the use of ACE inhibitors or ARBs in HTN and HF.

The 55th Annual Scientific Session of the American College of Cardiology (ACC) assembled from March 11 to March 14, 2006, in Atlanta, Ga, to exchange new and continuing research in cardiovascular disease. The program featured more than 1,600 oral and poster presentations of original research and hundreds of invited lectures and interactive sessions, with many offering the opportunity to update attendees' knowledge of available and investigational pharmaceuticals.

Aspirin is the cornerstone of therapy in the treatment and prevention of cardiovascular disease. The potential benefit of aspirin therapy may be significantly reduced in patients with aspirin resistance, creating a clinical and economic burden on the healthcare system. The purpose of this article is to clarify the term "aspirin resistance," describe the proposed mechanisms, review the clinical outcome studies with associated resistance testing, and discuss the potential pharmacologic management of this problem. Literature searches were performed using MEDLINE (January 1966 to January 2006) for review articles on aspirin resistance and antiplatelet activity. Aspirin's primary mechanism of action is to irreversibly inhibit cyclooxygenase-1 (COX-1); however, there are reports of alternative biochemical pathways producing platelet aggregation. The addition of thienopyridines to aspirin should be considered for the management of aspirin-resistant patients. (Formulary. 2006;41:192–201.)

Topiramate safely decreases body mass, hypertension. Topiramate reduces body weight and blood pressure with generally mild-to-moderate adverse effects, according to a randomized, placebo-controlled trial involving obese subjects with hypertension.

A recent meta-analysis published in the Journal of the American Medical Association (JAMA) found that statins have no effect on cancer risk. The finding is in contrast with at least 7 retrospective analyses that suggest that statins reduce the risk of developing cancer.

The serine protease inhibitor aprotinin (Trasylol, Bayer) may increase the risk of renal failure, myocardial infarction, heart failure, stroke, and encephalopathy among patients undergoing coronary artery bypass graft (CABG) surgery, according to an observational study in the New England Journal of Medicine (NEJM).

Beta blockers, touted for 3 decades as first-line drugs in the treatment of hypertension, are less than optimum in comparison to other antihypertensive drugs and raise the risk of stroke, according to a meta-analysis published online by The Lancet.

Early invasive strategy, recommended by the current guidelines in the treatment of patients with acute coronary syndromes (ACS), did not excel when compared with its more conservative alternative in a randomized study published in the New England Journal of Medicine.

Utilizing statin therapy, researchers have provided further evidence that absolute reductions in LDL-C reduce the incidence of coronary heart disease (CHD) and other major vascular events.

Dronedarone, a class III multichannel blocker developed for maintenance of sinus rhythm and ventricular rate control, reduces the risk of all-cause hospitalizations and death in patients with atrial fibrillation/flutter (AF/AFl), according to a post-hoc analysis of 2 randomized, placebo-controlled clinical trials.

The calcium sensitizer levosimendan was associated with an improvement in the clinical course of patients compared with placebo when used for the treatment of acute decompensated heart failure (ADHF), but the drug failed to reduce 6-month mortality when compared with dobutamine in a similar set of patients.

Drugs that reduce brachial blood pressure similarly can have different effects on central blood pressure. This finding may explain differences in clinical end points between antihypertensive drugs that lower blood pressure similarly, said Bryan Williams, MD, lead investigator of the Conduit Artery Function Evaluation (CAF?) trial, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

In a trial comparing high-dose atorvastatin with moderate-dose simvastatin in patients with stable coronary heart disease (CHD), the aggressive LDL-lowering strategy offered no significant advantage over the less aggressive strategy in reducing the number of coronary events, said Terje R. Pedersen, MD.

A nicotinic acetylcholine receptor partial agonist is an effective smoking cessation aid, said Serena Tonstad, MD, PhD, professor of nutrition at the Ulleval University Hospital, Oslo, Norway.

The anti-anginal agent ranolazine, in phase 3 clinical trials, reduced anginal frequency in patients experiencing 3 or more anginal attacks per week despite daily treatment with amlodipine 10 mg/d said Peter Stone, MD, lead investigator of the Evaluation of Ranolazine in Chronic Angina (ERICA) trial.

An exploratory analysis of PROactive (Prospective Pioglitazone Clinical Trial In Macrovascular Events Study) demonstrated a significant reduction in the risk of a second coronary event in patients with type 2 diabetes who took pioglitazone.

Oral anticoagulant therapy proved superior to the combination of clopidogrel and aspirin in preventing adverse vascular outcomes in patients with atrial fibrillation (AF). This outcome was observed in a large, multicenter trial at the 2005 AHA meeting in Dallas, comparing warfarin therapy with combination antiplatelet therapy in patients with AF.

The American Heart Association (AHA) Scientific Sessions comprise the world's largest conference for scientists and healthcare professionals focusing on cardiovascular disease.

Short-term treatment with the macrolide clarithromycin may cause significantly higher cardiovascular mortality in patients with stable coronary heart disease, according to a randomized, placebo-controlled multicenter study that took place in Denmark and was published in the British Medical Journal (BMJ).

Men who have used 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors to reduce their cholesterol levels may be at less risk of developing prostate cancer, according to a case-control study published in the American Journal of Epidemiology.

ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) possess a similar and significant ability to reduce the development of new-onset type 2 diabetes among patients with hypertension, coronary artery disease, and heart failure, according to a meta-analysis study published in Diabetes Care.

Acetaminophen at doses of more than 500 mg/d and nonsteroidal anti-inflammatory drugs (NSAIDs) at doses of more than 400 mg/d increase the risk of incident hypertension in younger and older women, according to cohort studies published in Hypertension.

Ranolazine (Ranexa, CV Therapeutics) is a partial fatty acid oxidase inhibitor that increases the amount of ATP produced from glucose and increases the ability of the myocardium to retain functionality despite a reduced oxygen supply. Ranolazine is under FDA review for the treatment of chronic stable angina (CSA). Ranolazine was first reviewed in the August 2003 issue of Formulary. Since the initial review of ranolazine by FDA, additional data have emerged that merit an update in this journal. Clinical trials have demonstrated the efficacy of ranolazine as both monotherapy and combination therapy in patients with CSA. Recently published clinical trials (MARISA and CARISA) have shown an improvement in symptom-limited exercise duration. The results of the ERICA trial demonstrated a reduction in weekly anginal attacks when ranolazine was added to maximum-dose amlodipine therapy. Headache and generalized weakness were the most commonly reported adverse events in clinical trials. Prolongation of the QT interval has raised concerns; however, a lack of development of ventricular tachyarrhythmias-specifically Torsade de Pointes-remains an important safety finding. (Formulary. 2005;40:323–328.)

Early use of clopidogrel, started prior to rather than at the time of angioplasty, reduces the risk of death, MI, or stroke by nearly half, reported Marc S. Sabatine, MD, MPH, lead investigator of PCI-CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy).

The factor Xa inhibitor fondaparinux prevents death, MI, and refractory ischemia at 9 days as well as the low-molecular-weight heparin enoxaparin in patients with acute coronary syndromes (ACS), while reducing the incidence of bleeding.

Following the voluntary withdrawal of rofecoxib in September 2004 and the subsequent FDA-requested withdrawal of valdecoxib in April 2005, formulary decision-makers are considering options in navigating the changing pain management landscape. With one remaining COX-2 inhibitor available on the market (celecoxib [Celebrex, Pfizer]) and more cardiovascular (CV) risk data available for the class, the efficacy, adverse events, risk/benefit profiles, and costs of both COX-2-selective and nonselective NSAIDs are receiving more attention than ever.

Analyses of 3 retrospective databases found that warfarin is much less effective at preventing strokes in the real world in patients with chronic atrial fibrillation (AF) than it is in clinical trials. The retrospective data were reported at the ASA's International Stroke Conference 2005.

Clopidogrel reduces 28-day mortality in the treatment of patients with acute myocardial infarction (MI) when given on top of standard therapies, but metoprolol has no effect on in-hospital mortality when given during the acute phase of MI.

The American Heart Association (AHA) Scientific Sessions comprise the largest meeting of its kind held in the cardiovascular field, with several thousand presentations given each year. The recently concluded 2004 AHA Scientific Sessions, which took place in New Orleans, included presentations of trials that evaluated potential therapeutic compounds, as well as widely used and accepted compounds in new dosages or combinations, for the treatment of cardiovascular disorders. The compilation of clinical news that follows focuses on the cardiovascular pharmacotherapy trials of greatest interest to formulary decision-makers, including: CREATE, PEACE, A-HeFT, PROTECT, CLEAR Platelets, DIPOM, GEMINI, SHIELD, and RIO-NA.