Variability in response to clopidogrel: how important are pharmacogenetics and drug interactions?

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel.

Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data.

For many years, warfarin was the only effective oral anticoagulant to prevent and treat thromboembolism. Nevertheless, its clinical use is limited by a narrow therapeutic window, extensive drug interactions, need of strict dietary control and frequent monitoring. The pharmacological response is also unpredictable and highly variable among patients. Suboptimal anticoagulation can lead to detrimental thromboembolic events or life-threatening bleeding. Direct thrombin inhibitor (DTI) activity represents a new class of anticoagulant activity that was intended to replace warfarin. Ximelagatran was the first DTI shown to have similar efficacy to warfarin, but failed to replace it because of a high incidence of liver toxicity. Dabigatran etexilate is another novel DTI with a more predictable pharmacokinetic profile and fewer drug interactions compared with warfarin. Recent large-scaled, randomized studies have shown that it does not share ximelagatran's hepatotoxicity, and is as effective as conventional anticoagulants for venous thromboembolism (VTE) and prophylaxis in atrial fibrillation (AF). These findings led to the approval of dabigatran etexilate for thromboprophylaxis following hip or knee replacement surgery in Europe, Canada and the United Kingdom. Here we summarize the latest evidence concerning the use of dabigatran etexilate in VTE (BISTRO, RE-MODEL, RE-NOVATE, RE-MOBILIZE and RECOVER) and AF (PETRO and RELY). Potential problems related to dabigatran use are also discussed to examine whether it can truly replace warfarin as the gold standard.

Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation.

Atrial fibrillation (AF) is associated with a fivefold increased risk for stroke due to thromboembolic events. Warfarin remains the standard medical therapy for decades in these patients but is difficult to use safely and conveniently. Chronic warfarin therapy is contraindicated in 14% to 44% of patients with AF who are at risk for stroke. In clinical practice, warfarin is prescribed to only 15% to 60% of patients with AF who are at high risk for thromboembolic events and have no clear contraindication to their use. Alternatives to warfarin include (i) antiplatelet therapy; (ii) new oral anticoagulants; and (iii) exclusion of the left atrial appendage (LAA) as a major embolic source. Dual antiplatelet therapy with aspirin and clopidogrel was superior to aspirin alone in reducing the risk of stroke in patients unsuitable to warfarin. Furthermore, a number of newer oral anticoagulants are currently under investigation for stroke prevention in AF. Oral direct thrombin or factor Xa inhibitors are in the most advanced stages of development. Given that about 90% of the source of thromboembolism occurs in the LAA in patients with non-valvular AF, occlusion of flow into the LAA may prevent thrombus formation in the appendage and hence reduction of stroke. Recently, several devices have been employed percutaneously with encouraging results in selected patients. Current review summarizes the latest clinical trial data pertinent to dual-antiplatelet therapy, several newer antithrombotic agents and LAA occlusion.

Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status.

Activation of the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction, muscular (vascular and cardiac) hypertrophy and fibrosis. Established arterial stiffness and cardiac dysfunction are key factors contributing to subsequent cardiovascular and renal complications. Blockade of RAAS has been shown to be beneficial in patients with hypertension, acute myocardial infarction, chronic systolic heart failure, stroke and diabetic renal disease. An aggressive approach for more extensive RAAS blockade with combination of two commonly used RAAS blockers [ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] yielded conflicting results in different patient populations. Combination therapy is also associated with more side effects, in particular hypotension, hyperkalaemia and renal impairment. Recently published ONTARGET study showed ACEI/ARB combination therapy was associated with more adverse effects without any increase in benefit. The Canadian Hypertension Education Program responded with a new warning: 'Do not use ACEI and ARB in combination'. However, the European Society of Cardiology in their updated heart failure treatment guidelines still recommended ACEI/ARB combo as a viable option. This apparent inconsistency among guidelines generates debate as to which approach of RAAS inhibition is the best. The current paper reviews the latest evidence of isolated ACEI or ARB use and their combination in cardiovascular diseases, and makes recommendations for their prescriptions in specific patient populations.

Impact of genetic and acquired alteration in cytochrome P450 system on pharmacologic and clinical response to clopidogrel.

Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce subsequent cardiac events in patients with acute coronary syndrome or coronary artery stenting. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 (CYP) enzyme system. The genes encoding CYP enzymes are polymorphic. Recent data demonstrated patients carrying a genetic variant of CYP enzymes (e.g. CYP2C19) would have a higher rate of ischemic events than non-carriers due to an attenuation of the pharmacokinetic and pharmacodynamic responses to clopidogrel. Furthermore, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is commonly prescribed to patients because of the increased risk of bleeding with dual antiplatelet therapy. PPIs are extensively metabolized by the cytochrome P450 system and have been associated with decreased antiplatelet activity of clopidogrel. In this review, we will discuss the impact of CYP450 enzymes genetic variation and CYP450 pathway drug-drug interactions in pharmacological and clinical response to clopidogrel.

Causes of mortality in patients with peptic ulcer bleeding: a prospective cohort study of 10,428 cases.

OBJECTIVES: Despite advances in endoscopic and pharmacological treatment for peptic ulcer bleeding (PUB), mortality remains at 5-10% worldwide. Our aim was to investigate the causes of death in a prospective cohort of PUB in a tertiary referral center. METHODS: Between 1993 and 2005, all patients with upper gastrointestinal bleeding (UGIB) admitted to the Prince of Wales Hospital were prospectively registered. Demographic data, characteristics of ulcer, and pharmacological, endoscopic, and surgical therapy, were documented. Mortality cases were classified as (A) bleeding-related death (A1: uncontrolled bleeding, A2: within 48 h after endoscopy, A3: during surgery for uncontrolled bleeding, A4: surgical complications or within 1 month after surgery, and A5: endoscopic related mortality) or (B) non-bleeding-related death (B1: cardiac causes, B2: pulmonary causes, B3: cerebrovascular disease, B4: multiorgan failure, and B5: terminal malignancy). RESULTS: In all, 18,508 cases of UGIB were enrolled; among them, 10,428 cases from 9,375 patients were confirmed to have PUB, and 577 (6.2%) patients died. There were significantly more patients who died of non-ulcer bleeding causes (79.7%) than bleeding causes (18.4%). The mean (s.d.) age of those who died of bleeding-related causes was higher (75.4 (12.6) years) than that of those who died of non-bleeding causes (71.7 (13.1) years) (P=0.010). Most bleeding-related deaths occurred when immediate control of bleeding failed (29.2%) or when patients died within 48 h after endoscopic therapy (25.5%). Among those who died of non-bleeding-related causes, multiorgan failure (23.9%), pulmonary conditions (23.5%), and terminal malignancy (33.7%) were most common. CONCLUSIONS: The majority of PUB patients died of non-bleeding-related causes. Optimization of management should aim at reducing the risk of multiorgan failure and cardiopulmonary death instead of focusing merely on successful hemostasis.

Endoscopy for upper gastrointestinal bleeding: how urgent is it?

Early endoscopy has been advocated for the management of upper gastrointestinal bleeding, but the optimal timing for early endoscopy is still uncertain. The aim of this Review is to evaluate the optimal timing of early endoscopy by examining the findings of randomized clinical trials and retrospective cohort studies that used comparable outcome measures and have been reported in the literature. Outcome measurements included recurrent bleeding, surgery, mortality, length of hospital stay, and blood transfusion. Studies were categorized into those in which endoscopy was performed within 2-3 h, 6-8 h, 12 h or 24 h of the patient's presentation to hospital. We conclude that early endoscopy aids risk stratification of patients and reduces the need for hospitalization. However, it may also expose additional cases of active bleeding and hence increase the use of therapeutic endoscopy. No evidence exists that very early endoscopy (within a few hours of presentation) can reduce the risk of rebleeding or improve survival.

The establishment of a radioactive waste disposal facility in Western Australia for low level waste.

The Radiation Health Section of the Health Department of Western Australia has been a repository for unwanted radioactive sources for many years. They had been placed in the radioactive store located on the Queen Elizabeth II Medical Centre Campus. After a collection period of more than 20 years the storage facilities of the Radiation Health Section were nearing capacity. A decision was made to relocate these sources into a permanent near surface burial facility. Following extensive community consultation and site investigations, waste originating in Western Australia was disposed of at Mt Walton (East), 80 km North East of Koolyanobbing, Western Australia in November 1992.

Alpha self-absorption in monazite dusts.

Measurements have been made of the self-absorption effects in monazite of alpha particles of the 232Th decay series. Samples of six size fractions of monazite were deposited on filters at different dust concentrations and then the gross alpha activity determined. Self-absorption effects were negligible in monazite particles up to 8 microns diameter provided dust concentrations were less than 1 mg cm-2. Significant self-absorption effects occurred for both larger particle sizes and higher dust loadings. As reported AMAD values in the mineral sands industry range up to 15 microns, which is equivalent to an actual mean size of 8 microns diameter monazite particle, minimal self-absorption occurs in samples collected in air monitoring programs conducted in the industry provided that dust concentrations on the filters are less than 1 mg cm-2.

Thorium lung burdens of mineral sands workers.

Thorium lung burdens have been measured in workers in the dry separation plants operated by the mineral sands industry in Western Australia. The data have been compared with historical employment records of the worker's exposure to thorium-bearing airborne dusts in order to assess the reliability of personal air sampling and with the predictions of the new Task Group lung model. The thoron exhaled in the breath of 62 workers was measured using a double filter tube. Six of the workers also underwent in-vivo gamma counting to determine their thorium lung burden. A thoron exhalation rate of 4.7% was obtained from a comparison of the two data sets. The estimated thorium lung burdens from the thoron-in-breath measurements had a geometric mean value of 10 Bq. The workers had a geometric mean employment period in the industry of 9.2 y and a geometric mean total inhaled alpha activity of 9,000 Bq, estimated from contemporary personal air sampling data and a retrospective assessment of previous workplace conditions. This exposure corresponds to a mean daily intake of 232Th of 0.45 Bq. Predictions from the new Task Group lung model indicate that, for the 45 workers with a thorium lung burden in excess of the minimum detectable level (6 Bq), the daily intake of 232Th is a factor of 1.6 higher than expected. This result suggests that previous intake of radioactive dust was higher than generally assumed for some workers. The application of the new Task Group lung models to the bioassay data results in an estimated mean annual committed effective dose for the workers of 8 mSv. Two workers (3%) were found to have been exposed for many years in excess of the 50 mSv y-1 annual limit for occupational exposure, while eight workers (13%) exceeded the ICRP's proposed new occupational standard of an average of 20 mSv y-1. All eight had been employed for more than 6 y and the majority of their exposure was attributed to early employment years, prior to extensive workplace improvements in dust control.

Thorium excretion in feces by mineral sands workers.

An attempt has been made to correlate the thorium excreted in the feces of two male workers in the monazite section of a mineral sands dry separation plant over a ten-day period with personal air sampling measurements. The air-borne radioactivity was measured on a daily basis using a total (inspirable) dust filter, an integrating personal dosimeter, and a personal cascade impactor. The thorium content of the feces was measured using inductively coupled plasma mass spectrometry. The results suggest that thorium fecal analyses are able to detect acute and chronic exposures to the inhalation of thorium bearing dusts and to confirm the amount of inhaled thorium predicted from air sampling programs and metabolic models.