Genome-wide association analysis of common genetic variants of resistant hypertension.

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10-4 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2-1.8), p = 7.3 × 10-5) and replicated in SPS3 (OR = 2.0 (1.4-2.8), p = 4.3 × 10-5), with genome-wide significance in meta-analysis (OR = 1.60 (1.3-1.9), p = 3.8 × 10-8). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4-2.5), p = 1.1 × 10-5) and SPS3 (OR = 1.70 (1.2-2.5), p = 4 × 10-3). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3-2.0), p = 3.4 × 10-5) and replicated in SPS3 (OR = 1.60 (1.1-2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10-15). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.

Pharmacogenetic Associations of ß1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes).

BACKGROUND AND PURPOSE: Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and ß-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by ß-blocker treatment in patients with a history of stroke. METHODS: Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). RESULTS: MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, ß-blocker-treated Gly49 carriers had increased MACE versus non-ß-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. CONCLUSION: Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among ß-blocker-treated individuals. Further research is needed to define ß-blocker benefit among ischemic stroke patients by ADRB1 genotype. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial.

BACKGROUND: Among participants in the Secondary Prevention of Small Subcortical Strokes randomized trial, we sought to identify patients with high versus low rates of recurrent ischemic stroke and to assess effects of aggressive blood pressure control and dual antiplatelet therapy according to risk status. METHODS: Multivariable analyses of 3020 participants with recent magnetic resonance imaging-defined lacunar strokes followed for a mean of 3.7 years with 243 recurrent ischemic strokes. RESULTS: Prior symptomatic lacunar stroke or transient ischemic attack (TIA) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.6, 2.9), diabetes (HR 2.0, 95% CI 1.5, 2.5), black race (HR 1.7, 95% CI 1.3, 2.3), and male sex (HR 1.5, 95% CI 1.1, 1.9) were each independently predictive of recurrent ischemic stroke. Recurrent ischemic stroke occurred at a rate of 4.3% per year (95% CI 3.4, 5.5) in patients with prior symptomatic lacunar stroke or TIA (15% of the cohort), 3.1% per year (95% CI 2.6, 3.9) in those with more than 1 of the other 3 risk factors (27% of the cohort), and 1.3% per year (95% CI 1.0, 1.7) in those with 0-1 risk factors (58% of the cohort). There were no significant interactions between treatment effects and stroke risk status. CONCLUSIONS: In this large, carefully followed cohort of patients with recent lacunar stroke and aggressive blood pressure management, prior symptomatic lacunar ischemia, diabetes, black race, and male sex independently predicted ischemic stroke recurrence. The effects of blood pressure targets and dual antiplatelet therapy were similar across the spectrum of independent risk factors and recurrence risk.

The Hispanic Diabetes Management Program: Impact of community pharmacists on clinical outcomes.

OBJECTIVE: To assess the impact of community pharmacists on clinical outcomes in Hispanic patients with type 2 diabetes. METHODS: 126 patients were enrolled in this longitudinal pre/post cohort study that took place in nine community and four workplace pharmacies in San Antonio, TX. Pharmacists provided education, point-of-care testing for glycemic and metabolic parameters, clinical assessment, goal setting, and drug therapy management with physicians. Study outcomes were changes in glycosylated hemoglobin (A1C) and accompanying metabolic parameters (blood pressure, lipid parameters, and body mass index) during a 1-year time frame. RESULTS: In the overall cohort, A1C was not reduced significantly from baseline to 12 months (7.8% vs. 7.6%, P = 0.516). However, statistically significant reductions occurred for fasting plasma glucose, triglycerides, and diastolic blood pressure. None of the other parameters was affected significantly. In the subgroup of patients not at target values at baseline, significant reductions occurred for A1C (9.2% vs. 8.6%, P = 0.001), systolic blood pressure (147 vs. 143 mm Hg, P = 0.031), diastolic blood pressure (91 vs. 87 mm Hg, P < 0.001), triglycerides (259 vs. 219 mg/dL, P < 0.001), LDL cholesterol (139 vs. 123 mg/dL, P < 0.001), and total cholesterol (237 vs. 222 mg/dL, P = 0.008). CONCLUSION: Interventions performed by community pharmacists are effective in improving clinical outcomes in a Hispanic cohort with diabetes. Pharmacists' efforts were most successful in patients not at target glycemic and metabolic levels.

Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention.

OBJECTIVE: To review the available literature on the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients. DATA SOURCES: A Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009. STUDY SELECTION: Randomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients. DATA SYNTHESIS: The prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin-angiotensin-aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies. CONCLUSION: A growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention.

Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the managed care setting.

BACKGROUND: Most clinicians recognize the importance of reducing low-density lipoprotein cholesterol (LDL-C) and, therefore, address this therapeutic need to decrease cardiovascular disease risk. In addition to the critical role that LDL-C plays, recent studies have shown the contribution of other lipid fractions, such as high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), to overall cardiovascular health. Managed care initiatives to reduce cardiovascular risk typically focus on highly effective statin therapies, which are primarily LDL-C-lowering agents and have lesser TG-lowering and HDL-C-raising effects. However, clinical and epidemiologic data illustrate the need to expand the scope of therapies to reduce the residual cardiovascular risk associated with low HDL-C levels and elevated TG levels, even when LDL-C is managed successfully. OBJECTIVE: To address the value of treating beyond LDL-C level to improve patient health outcomes and reduce health care-related costs. SUMMARY: Several large trials and meta-analyses have investigated the effects of lipid-lowering statin therapy and have consistently demonstrated that statin therapy significantly reduces LDL-C levels and incidence of cardiovascular events. In spite of the efficacy of statin therapy in these studies, statins did not eliminate cardiovascular risk. Rather, significant residual cardiovascular risk remains after treatment with statins, especially in high-risk patients such as those with diabetes. Residual cardiovascular risk stems, at least partially, from low HDL-C and elevated TG. Low HDL-C levels have been identified as a significant, independent predictor of cardiovascular risk, and increases in HDL-C are associated with reductions in cardiovascular events. High TG levels are a significant risk factor for cardiovascular disease and are a marker for atherogenic remnant lipo-proteins, such as very low-density lipoprotein cholesterol (VLDL-C). Additionally, with elevated TG levels, a combination of LDL-C with VLDL-C in the measure of non-HDL-C may be a better predictor of cardiovascular risk than LDL-C alone. Recent national treatment guidelines suggest that combination therapy may be necessary to address multiple lipid targets (i.e., LDL-C, non-HDL-C, HDL-C, and TG); adding niacin or a fibrate to a statin is a therapeutic option that should be considered. As monotherapy agents, fibrates and niacin have been demonstrated to alter several lipid parameters and reduce cardiovascular events. Niacin appears to exert the greatest beneficial effects on the widest range of lipoprotein abnormalities, in addition to possessing an established safety profile. Moreover, niacin/statin combination therapy may provide greater benefits, as manifested through a correction of atherogenic lipid abnormalities, a slowing of atherosclerosis progression in coronary heart disease (CHD) patients, and a reduction of residual cardiovascular risk. Pharmacoeconomic modeling studies have been used to describe the potential effects on both cardiovascular events and health care costs by the achievement of, or failure to achieve, combined optimal lipid values (OLVs). Achievement of OLVs is predicted to be associated with a reduced risk of cardiovascular events, in which greater magnitudes of risk reduction accompany the achievement of a greater number of lipid goals. Based on patient baseline lipid values and product labeling information, mathematical models estimate that OLVs are achieved more frequently with extended-release niacin (niacin ER)/simvastatin combination therapy than with other high-potency agents. These modeling estimates were maintained in different patient groups, including those with diabetes or the metabolic syndrome. Finally, these modeling studies estimated that a fixed-dose niacin ER/simvastatin combination therapy would reduce direct medical costs of CHD events more effectively than would high-dose simvastatin monotherapy. CONCLUSION: Statins are highly effective for lowering LDL-C levels and, consequently, cardiovascular event rates. However, statins do not eliminate cardiovascular risk. Even in the presence of tightly controlled LDL-C levels, evidence indicates that high TG and low HDL-C levels are independent cardiovascular risk factors. Treating lipid parameters beyond LDL-C may require the addition of niacin or a fibrate to statin therapy. Niacin is the most effective agent for raising HDL-C levels, and pharmacoeconomic modeling suggests that niacin ER/statin combination therapy may promote the cost-effective achievement of OLVs in several at-risk patient populations.

Effectiveness of statins in reducing the rate of severe sepsis: a retrospective evaluation.

STUDY OBJECTIVES: To determine whether use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is associated with a reduced rate of severe sepsis, and to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis. DESIGN: Retrospective cohort study. SETTING: University-associated teaching hospital. PATIENTS: Fifty-three patients admitted with sepsis; 16 were receiving statins and 37 were not receiving statins (controls) before admission. MEASUREMENTS AND MAIN RESULTS: Patients were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patient demographics, vital signs, and laboratory values were collected from their electronic medical records. The primary end point was rate of severe sepsis, defined in accordance with guidelines from the American College of Chest Physicians and the Society of Critical Care Medicine. Secondary end points were in-hospital mortality rate and rate of five categories of organ dysfunction (cardiovascular, renal, pulmonary, hematologic, and metabolic). Preadmission statin therapy, compared with no statin therapy, was associated with a 30% lower rate of severe sepsis (56% vs 86%, p<0.02). In-hospital mortality was not significantly different between groups (38% vs 49%, p=0.33); however, the rate of cardiovascular dysfunction, defined as hypotension requiring vasopressor therapy, was significantly lower in the statin group (38% vs 73%, p<0.02). No significant differences in the other organ dysfunction categories were noted between groups. CONCLUSION: Statins appear to prevent sepsis from becoming severe, most notably through prevention of sepsis-induced hypotension. This potential role for statins in the prevention and treatment of severe sepsis should be further evaluated in a randomized controlled trial.

Murine airway histology and intracellular uptake of inhaled amorphous itraconazole.

Aerosolization of amorphous itraconazole may be a safe and effective method of pulmonary delivery. Our objective was to evaluate the histologic effects, immunogenic potential, and cellular uptake of aerosolized amorphous itraconazole. Mice received amorphous itraconazole (30mg/kg), excipient placebo, or saline control by nebulization every 12h for up to 12 days. Broncho-alveolar lavage (BAL) and formalin fixation of both lungs were conducted. BAL supernatant was assayed for IL-12 by ELISA, and cellular components were analyzed by high performance liquid chromatography-mass spectroscopy. Coronal sections of the entire lung were stained, viewed by light microscopy, and the Cimolai histopathologic inflammatory score was obtained for each lobe. No evidence of bronchiolar, peribronchiolar or perivascular inflammation was found in any treatment group, nor were epithelial ulceration or repair observed. The Cimolai histopathologic scores for amorphous itraconazole, excipient, and saline control on days 3 and 8 did not differ between groups. ELISA analysis showed no cytokine induction of IL-12. Itraconazole was detected within cells collected from BAL fluid on days 1, 3, 8 and 12. Aerosolized administration of amorphous itraconazole or excipients does not cause inflammation or changes in pulmonary histology and are not associated with pro-inflammatory cytokine production.

The challenge of blood pressure management in neurologic emergencies.

Hypertensive crises are commonly seen in the emergency department, and acute stroke is often the inciting etiology of a hypertensive crisis. Cerebral autoregulation is disrupted in acute stroke, and efforts to lower blood pressure may reduce cerebral perfusion and worsen outcomes. Although most patients with stroke have elevated blood pressure, evidence from clinical trials to guide therapy are scarce. Current national guidelines recommend lowering blood pressure after stroke only if end-organ damage is present or if systolic/diastolic blood pressures exceed 220/120 or 185/110 mm Hg in patients ineligible and in those eligible to receive thrombolytic drug therapy, respectively. Recommended pharmacologic interventions for elevated blood pressure after acute ischemic stroke include labetalol, nicardipine, or nitroprusside, depending on the severity of the elevation. Similar recommendations have been made for intracerebral hemorrhage. Subarachnoid hemorrhage is managed with nimodipine and other calcium channel blockers to prevent vasospasm and improve clinical outcomes. Data from ongoing clinical trials may improve guidance about the management of elevated blood pressure after acute stroke.

Statin-associated pleiotropy: possible beneficial effects beyond cholesterol reduction.

Because elevated serum cholesterol levels are strongly associated with coronary heart disease, cholesterol reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) has been assumed to be the predominant, if not the only, mechanism underlying the beneficial effects of these drugs in cardiovascular diseases. Subgroup analyses of large clinical trials, however, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins may be mediated through improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation.

Single dose and multiple dose studies of itraconazole nanoparticles.

The objective of this study was to determine and compare the lung and serum concentrations in mice following oral and pulmonary dosing of amorphous nanoparticulate itraconazole (ITZ) compositions as well as the Sporanox oral solution (itraconazole/Janssen). Second, the steady state partitioning of ITZ in lung tissue and circulatory compartments following repeated oral and pulmonary dosing was determined. The pulmonary formulation (ITZ-pulmonary) consisted of ITZ, polysorbate 80, and poloxamer 407 in a 1:0.75:0.75 ratio and the oral formulation (ITZ-oral) consisted of ITZ, PEG 8000, poloxamer 188, and sorbitan monooleate 80 in a 1:1:2:1 ratio. Mice were dosed every 12 h by nebulization with ITZ-pulmonary, or by oral gavage with ITZ-oral or Sporanox oral solution (n = 12 per study arm). ITZ-pulmonary achieved significantly greater (>10-fold) lung tissue concentrations compared to the Sporanox oral solution and ITZ-oral. There were no statistical differences between the two oral formulations. ITZ-pulmonary achieved significantly greater lung levels per unit serum concentration compared to the orally dosed ITZ compositions. High and sustained lung tissue concentrations were achieved via inhalation of an amorphous nanoparticulate ITZ-pulmonary composition while maintaining serum levels which are above the minimum lethal concentration (MLC) of Aspergillus fumigatus.

Aspirin resistance: an evaluation of current evidence and measurement methods.

Aspirin resistance is a poorly characterized phenomenon, whereby certain patients do not benefit from the antithrombotic effect of aspirin. The frequency of aspirin resistance is unknown, but estimates range from 5-60%. The mechanism of aspirin resistance also is unknown; proposed mechanisms are poor patient compliance, poor aspirin absorption, increased isoprostane activity, platelet hypersensitivity to agonists, increased cyclooxygenase-2 activity, a cyclooxygenase-1 polymorphism, and the platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa. Aspirin resistance appears to be dose related in some patients and therefore may be overcome with high doses. Evidence indicates that aspirin resistance is a dynamic state, with significant intrapatient variability in aspirin sensitivity with time. To date, a sensitive and specific assay of aspirin effect that reliably predicts treatment failure has not emerged. However, several commercially available products are being marketed for this purpose without convincing clinical data. Despite a wealth of literature on the topic, aspirin resistance remains an enigma. Further investigation is needed regarding strategies to identify and treat patients resistant to aspirin.

Lessons from the Stroke Prevention in Atrial Fibrillation trials.

Atrial fibrillation predisposes to left atrial thrombus formation and carries a sixfold increased risk for stroke. Antithrombotic therapies are the mainstay for stroke prevention. The National Institute of Neurological Disorders and Stroke-sponsored Stroke Prevention in Atrial Fibrillation (SPAF) studies assessed the value of warfarin, aspirin, and their combination for preventing stroke in six multicenter trials involving 3950 participants. This review presents the major results and implications, which offer unique perspectives on antithrombotic therapies for stroke prevention in atrial fibrillation. Warfarin and aspirin reduce stroke. Anticoagulation substantially benefits high-risk patients with atrial fibrillation, while many younger patients with atrial fibrillation have a low stroke rate when given aspirin. Pathogenetic and transesophageal echocardiographic correlations shed light on mechanisms by which antithrombotic agents prevent stroke. Warfarin inhibits formation of atrial appendage thrombi and markedly reduces cardioembolic strokes, while aspirin primarily prevents smaller, noncardioembolic strokes. The SPAF III stroke risk stratification scheme has been validated for identifying patients with high versus moderate versus low risk for stroke. Women with atrial fibrillation benefit from anticoagulation significantly more than men do. Many elderly patients with recurrent paroxysmal atrial fibrillation have high rates of stroke. Antithrombotic prophylaxis should be individualized on the basis of the estimated risk for stroke during aspirin therapy and the risk for bleeding during anticoagulation. Overall, nearly one third of patients with atrial fibrillation are low risk and should be treated with aspirin, and about one third are high risk and should receive warfarin if it can be given safely. For patients at moderate risk for stroke, patient preferences and access to reliable anticoagulation monitoring are particularly relevant.

Recurrence of prostate cancer in patients receiving testosterone supplementation for hypogonadism.

PURPOSE: The relationship between recurrent prostate cancer risk and testosterone replacement therapy (TRT) for hypogonadal men is explored. SUMMARY: The medical literature was searched to identify articles evaluating the use of TRT in symptomatic hypogonadal men with a history of prostate cancer. Eight English-language articles investigating TRT use in hypogonadal men with a history of prostate cancer were analyzed. For evaluative purposes, the normal ranges used for prostate-specific antigen (PSA) and total testosterone levels were less than 4.0 ng/mL and 300-1000 ng/dL, respectively. Most trials were small and involved patients with localized prostate cancer treated with radical prostatectomy or radiotherapy, though patients with metastatic disease or a Gleason score of ≥8 were included in a few studies. TRT was administered in a variety of dosages and dosage forms for up to nine years to manage hypogonadal symptoms. Testosterone concentrations increased, as expected, after TRT, but serum PSA levels remained below 0.1 ng/mL in the majority of patients. PSA levels were found to increase in select patients with high-risk and metastatic disease, but these elevations were not accompanied by disease progression. These studies have suggested a potential benefit for TRT use in select symptomatic hypogonadal men with a history of prostate cancer. Data were limited, however, by the retrospective nature of most studies, the lack of control groups, small sample sizes, and short follow-up periods. CONCLUSION: There is insufficient evidence to withhold TRT in certain populations of men with a history of prostate cancer.

CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.

BACKGROUND: The role of the CYP2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss-of-function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel. METHODS AND RESULTS: CYP2C19*2 and CYP2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes (SPS3) study. CYP2C19 metabolizer status was inferred from genotype, and associations with the risk of recurrent stroke and major bleeding were assessed in the overall cohort and by race/ethnic group with logistic regression modeling. In the overall cohort, there were no differences in outcomes by CYP2C19 metabolizer status (recurrent stroke, odds ratio 1.81 [95% CI 0.76 to 4.30]; major bleeding, odds ratio 0.67 [95% CI 0.22 to 2.03]). In white participants, those with CYP2C19 intermediate or poor metabolizer status had higher odds of recurrent stroke (odds ratio 5.19 [95% CI 1.08 to 24.90]) than those with extensive or ultrarapid metabolizer status, but there was no evidence of difference in major bleeding. CONCLUSIONS: There were significant differences in recurrent stroke by CYP2C19 genotype-inferred metabolizer status in white subcortical stroke patients receiving dual antiplatelet therapy with aspirin and clopidogrel, consistent with cardiovascular studies on CYP2C19 and clopidogrel; however, the bleeding risk that led to early termination of the antiplatelet arm of the SPS3 trial does not appear to be explained by CYP2C19 genotype. This study was relatively underpowered; therefore, these findings should be interpreted with caution and warrant replication. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00059306.

Effect of fluvastatin and pravastatin, HMG-CoA reductase inhibitors, on fluconazole activity against Candida albicans.

Synergy between fluvastatin, at clinically unachievable concentrations, and fluconazole against Candida albicans has been reported. The purpose of the present study was to evaluate the in-vitro activity of fluconazole alone and in combination with clinically achievable concentrations of pravastatin and fluvastatin against C. albicans. In-vitro susceptibility and synergy testing were performed against clinical isolates of C. albicans with fluconazole, pravastatin and fluvastatin. Both checkerboard method and time-kill studies were performed. MICs for fluconazole ranged from 0.5 (susceptible) to >256 mg/L (resistant) at 24 h. All isolates had MICs >2 mg/L for both statins. No synergy or antagonism was observed with fluconazole in combination with either agent against any isolate of C. albicans by the checkerboard assay or time-kill studies. Clinically achievable concentrations of pravastatin and fluvastatin did not affect the in-vitro activity of fluconazole against C. albicans.

Modification of high-density lipoprotein cholesterol in the management of cardiovascular risk.

Although several clinical trials clearly demonstrate a decrease in mortality and morbidity rates for various patient populations with cardiovascular disease, this disease continues to be the leading cause of death in the United States. Based on various practice surveys and descriptive reports, clinicians apparently are not identifying patients at risk or not treating them to established goals set by national guidelines. Most evidence, including the updated National Cholesterol Education Program Adult Treatment Panel III guidelines, support low-density lipoprotein cholesterol (LDL) as the principal target for intervention. The guidelines also emphasize that a low level of high-density lipoprotein cholesterol (HDL) alone or in association with hypertriglyceridemia increases the risk of cardiovascular disease; also, epidemiologic data taken as a whole signify that a 1% decrease in HDL levels is associated with a 2-3% increase in risk of coronary heart disease. Low HDL levels occur more frequently than once thought, especially in selected populations such as patients with type 2 diabetes and men. Therapeutic lifestyle changes should be implemented first for any lipid disorder. In patients for whom this approach is not adequate, LDL levels need to be lowered to goals based on risk assessment. In addition, low HDL levels and/or hypertriglyceridemia should be managed with a niacin or fibrate product. However, increases in HDL levels and reductions in triglyceride levels are modest with fibrates compared with the dose-related changes seen with niacin products. Reformulation of niacin into an extended-release form minimizes common adverse effects seen with crystalline or sustained-release niacin, and the beneficial effects on the lipid profile are maintained.

A review of vasopeptidase inhibitors: a new modality in the treatment of hypertension and chronic heart failure.

Vasopeptidase inhibitors are a group of agents capable of inhibiting neutral endopeptidase and angiotensin-converting enzymes, which leads to potentiation of natriuretic peptide actions and suppression of the renin-angiotensin-aldosterone system. With this distinctively characteristic mechanism, these agents have emerged as a new drug class for management of hypertension and heart failure. Several vasopeptidase inhibitors are under clinical investigation. Omapatrilat is the most studied agent in this class. Clinical studies of omapatrilat in hypertension have consistently shown the agent's effectiveness in a variety of patient populations. In patients with heart failure, omapatrilat significantly improved neurohormonal and hemodynamic status. Long-term effects of omapatrilat in patients with heart failure recently were compared with those of conventional therapy in a large phase II trial. Results of the study appear promising. Large clinical trials are ongoing, and additional information regarding safety and efficacy from these studies may help define the place in therapy for this agent.

Impact of atypical coverage for patients with community-acquired pneumonia managed on the medical ward: results from the United States Community-Acquired Pneumonia Project.

STUDY OBJECTIVE: As current guidelines for treatment of community-acquired pneumonia (CAP) recommend empiric antimicrobial coverage for atypical pathogens, we evaluated the need for atypical coverage by examining length of hospital stay (LOS) and mortality in patients with CAP who were managed on the medical ward. METHODS: Medical records of patients with CAP admitted from January 1, 1997-December 31, 2001, from 176 United States nonteaching community hospitals were reviewed. Patients were divided into one of three mutually exclusive groups on the basis of intravenous antimicrobials received on days 1 or 2 of hospital stay: ceftriaxone monotherapy, ceftriaxone plus a macrolide, or levofloxacin. Variables evaluated for their ability to predict outcome were patient age, year of hospital admission, geographic region, preadmission setting, preadmission antimicrobial treatment, timing of antimicrobial administration, comorbid disease, and duration of intravenous antimicrobial treatment. The impact of initial antimicrobial regimen on LOS and mortality was evaluated in regression models while controlling for significant predictors of outcome. RESULTS: Of 8975 patients evaluated, 2453 met the inclusion criteria. Significant differences were noted among patients who received ceftriaxone (932 patients), ceftriaxone plus a macrolide (872), and levofloxacin (649) with respect to mean +/- SD age (72 +/- 16, 67 +/- 18, and 70 +/- 17 yrs, respectively; p<0.0001), admission from a nursing home (21%, 11%, and 15%, respectively; p<0.0001), and duration of intravenous antimicrobial treatment (4.4 +/- 2.7, 4.0 +/- 2.6, and 3.6 +/- 2.5 days, respectively; p<0.0001). The LOS predictors were age, geographic region, coexisting heart failure, and duration of intravenous antimicrobial therapy. Mortality predictors were age, admission from a nursing home, coexisting heart failure, and coexisting cancer. After controlling for these predictors of outcome, no significant differences were noted among the three groups for LOS (5.5 +/- 3.5, 4.8 +/- 2.9, and 4.8 +/- 2.9 days, respectively; p=0.2791) or mortality (3.1%, 2.0%, and 2.6%, respectively; p=0.8461). CONCLUSION: Initial coverage for atypical pathogens does not affect LOS or mortality among patients with CAP managed on the medical ward.

Combination antiplatelet therapy: implications for pharmacists.

OBJECTIVES: To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes. DATA SOURCES: Personal observation by the authors, and clinical practice guidelines and related clinical trials of the American Heart Association and the American College of Cardiology. SUMMARY: The American College of Cardiology and the American Heart Association revised the guidelines for administration of antiplatelet and anticoagulant therapy in patients with unstable angina and non-ST-segment elevation myocardial infarction in March 2002. Two cases observed by the authors illustrate the consequences of suboptimal antiplatelet therapy when a combination of two antiplatelet drugs should have been administered. CONCLUSION: Evidence from recent randomized controlled trials led to changes in the national guidelines for administration of oral antiplatelet therapy in patients with acute coronary syndromes. Pharmacists should be aware of these changes and counsel patients about appropriate administration of antiplatelet drugs.