Prasugrel: a novel antiplatelet agent.

PURPOSE: The pharmacology, pharmacokinetics, safety, and adverse effects of prasugrel, a novel antiplatelet agent, are described. SUMMARY: Prasugrel is a third-generation thienopyridine. Like clopidogrel, prasugrel is a prodrug requiring hepatic metabolism to its active form to bind irreversibly to the P2Y(12) adenosine diphosphate receptor and inhibits platelet aggregation for the life of the platelet. Prasugrel's pharmacokinetic profile has not been clearly defined. Several preclinical and early-phase clinical trials of prasugrel have been completed. Five trials have assessed the platelet aggregation of prasugrel alone or compared with placebo or clopidogrel. Certain populations with acute coronary syndrome (ACS) may be at higher risk for major bleeding episodes leading to fatal events when using prasugrel with other antithrombotic agents and antiplatelet agents. Information on drug or food interactions with prasugrel is limited. Since prasugrel is still under investigation, an official recommended dosage regimen has yet to be determined. Clinical trials are still being conducted to determine prasugrel's exact place in therapy. In early trials, prasugrel has demonstrated a faster onset of action, higher rate of platelet inhibition, and lower rate of response variability compared with clopidogrel. CONCLUSION: Prasugrel has demonstrated a greater platelet inhibition and a decreased incidence of ischemic events compared with clopidogrel, but with an increased incidence of bleeding events. Future studies with prasugrel should determine its optimal dosage regimen to minimize bleeding risks and evaluate its outcomes in ACS and safety profile in special patient populations.

A review of the investigational antiarrhythmic agent dronedarone.

Arrhythmias are a major cause of morbidity and mortality, and atrial fibrillation is the most widespread disorder of cardiac rhythm. Amiodarone is an effective antiarrhythmic agent that has been in clinical use for about 20 years. It is effective for multiple types of arrhythmias, including atrial fibrillation, and has a low incidence of cardiac adverse events, including Torsade de Pointes. It has many noncardiac adverse effects that are serious and limit its long-term use. Dronedarone is an investigational antiarrhythmic agent that is designed to have similar cardiac effects to amiodarone but with fewer adverse effects. This review presents some of the animal and human studies that evaluate the effects of dronedarone.

Clopidogrel-induced hepatotoxicity and fever.

A 59-year-old woman developed fever and elevated hepatic enzyme levels within days of starting clopidogrel, which had been prescribed in conjunction with a percutaneous coronary intervention. When she discontinued the clopidogrel, her liver enzyme levels returned to baseline and her fever disappeared. These signs and symptoms returned after rechallenge with clopidogrel. Monitoring for fever and elevation of liver enzyme levels in patients taking clopidogrel may be warranted. If a patient has signs of hepatotoxicity with or without fever, discontinuation of clopidogrel should be considered, along with substitution with ticlopidine if clinically warranted.

Ranolazine: a new approach to management of patients with angina.

OBJECTIVE: To review the pharmacology, pharmacokinetics, and clinical efficacy of ranolazine for the treatment of chronic stable angina. DATA SOURCES: MEDLINE was searched (1966-February 2006) using the English-language key terms ranolazine and chronic stable angina. Additional studies were identified from the bibliographies of the reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating ranolazine, alone or in combination with other agents, were incorporated in this review. DATA SYNTHESIS: Ranolazine is a metabolic modulator designed to improve cardiac energy availability and cardiac metabolism. It is believed to be a partial fatty acid oxidation inhibitor. Ranolazine has been shown to improve exercise duration and time to anginal attacks without significantly affecting heart rate or blood pressure. Adverse effects of ranolazine are reported to be dose related. The elimination half-life of ranolazine is estimated to be between 1.4 and 1.9 hours for the immediate-release and 7 hours for sustained-release preparations. CONCLUSIONS: Ranolazine has a unique mechanism of action that is different from that of conventional agents. It has been studied as monotherapy or in combination with other commonly prescribed agents. It appears that ranolazine has a promising safety data profile and does not affect hemodynamic parameters. At this point, although ranolazine should not be used in place of conventional therapy, it appears that ranolazine may be considered in the management of symptomatic patients when standard antianginal medications are not tolerated or are ineffective.

Combination of clopidogrel and statins: a hypothetical interaction or therapeutic dilemma?

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and clopidogrel are frequently used in the treatment of patients with various cardiovascular disorders. The possibility of a drug-drug interaction between certain statins and clopidogrel has been extensively investigated in the literature recently. Investigators have proposed that the use of statins that are metabolized by the cytochrome P450 (CYP) system may diminish the conversion of clopidogrel to its active form by inhibiting the CYP3A4 isoenzyme. This inhibition could result in a decreased antiplatelet effect of clopidogrel, which could translate into an increased risk of cardiovascular events. METHODS: We performed a MEDLINE search of the literature from 1993-2005 to evaluate and discuss the existing data on a possible interaction between clopidogrel and statins and to provide clinicians with relevant and practical recommendations. Additional studies were identified from the bibliographies of the reviewed literature. RESULTS: Several articles were discovered that discuss this potential drug-drug interaction. Whereas some studies indicated that there was not a relevant interaction between statins and clopidogrel, other studies demonstrated that the concomitant administration of some statins with clopidogrel resulted in diminished platelet inhibition activity of clopidogrel. CONCLUSIONS: Although the interaction between certain statins and clopidogrel seems to be a pharmacologic certainty, the clinical relevance of this interaction needs further clarification. While investigators continue to evaluate the clinical relevance, we provide several recommendations for clinicians responsible for treating patients who require combination therapy with statins and clopidogrel.

Frequency and management of thrombocytopenia with the glycoprotein IIb/IIIa receptor antagonists.

Glycoprotein IIb/IIIa receptor antagonists (GPRAs) are widely used in the management of a variety of patients with acute coronary syndromes. Major adverse reactions to these agents include bleeding and thrombocytopenia. Immune mechanisms responsible for severe thrombocytopenia seen with GPRAs have been hypothesized for all 3 agents currently available in the United States, although specific laboratory tests are not available for use in routine practice. A review of published research for GPRA-induced thrombocytopenia (GIT) is provided. Although the incidence of severe GIT is relatively low, the implications for patients are potentially life threatening. Prompt recognition of severe thrombocytopenia is essential to facilitate the necessary care of patients. Treatment strategies include the modification of drug regimens and other interventions targeting the reduction of immediate bleeding risk and the provision of supportive care measures. A review of published research supporting the conservative use of corticosteroids and intravenous gamma globulin in this syndrome is provided. Clinicians identifying severe thrombocytopenia after GPRA exposure are encouraged to report these events, following national and institutional guidelines.

A protocol for the use of enoxaparin during pregnancy: results from 85 pregnancies including 13 multiple gestation pregnancies.

Many practitioners consider low-molecular-weight heparin (LMWH) an alternative to unfractionated heparin, although there are limited safety data regarding maternal and fetal outcomes in patients using an LMWH during pregnancy. A retrospective chart review was performed on 72 patients with thrombophilia exposed to the LMWH, enoxaparin, during pregnancy. Eighty-five pregnancies resulted in 93 of 99 potential live births. Eleven of 12 twin pregnancies and one triplet pregnancy were successful. One preterm live birth infant of 33 weeks' gestation did not survive. Three patients with thrombophilia spontaneously aborted. A patient receiving injectable fertility treatment had spontaneously aborted one twin at 5 weeks' gestation. One patient terminated the pregnancy after discovering the presence of Down's syndrome. The mean maximum dose required to achieve a therapeutic anti-Xa level of 0.2-0.4 IU/mL at 5 to 6 hours following administration, was 38.1 mg every 12 hours (median 35 mg, range 30-75 mg every 12 hours). The mean anti-Xa level was 0.28 IU/mL (median 0.3, range 0.05-0.8 IU/mL). A total of nine patients experienced bleeding events, two requiring discontinuation of enoxaparin for the remainder of the pregnancy. Two patients experienced injection site reactions requiring discontinuation of enoxaparin. Three patients developed preeclampsia, two placenta abruptio, and one placenta previa. No thromboembolic complications or osteoporotic fractures had occurred. Enoxaparin was safe and effective for preventing thromboembolism and adverse obstetrical complications in our patients, including 12 of 13 multiple gestation pregnancies.