Barry E. Bleske

Chlorthalidone Reduces Cardiovascular Events Compared With Hydrochlorothiazide A Retrospective Cohort Analysis

There is significant controversy around whether chlorthalidone (CTD) is superior to hydrochlorothiazide (HCTZ) in hypertension management. The objective of this analysis was to evaluate the effects of CTD compared with HCTZ on cardiovascular event (CVE) rates. We performed a retrospective observational cohort study from the Multiple Risk Factor Intervention Trial data set from the National Heart, Lung, and Blood Institute. The Multiple Risk Factor Intervention Trial was a cardiovascular primary prevention trial where participants were men 35 to 57 years of age enrolled and followed beginning in 1973. CVEs were measured yearly, and time to event was assessed by Cox regression. Systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, potassium, glucose, and uric acid were measured yearly. The difference between groups was evaluated by repeated-measures mixed modeling, and each model was adjusted for predictors of each variable. CVEs were significantly lower in those on CTD (adjusted hazard ratio: 0.51 [95% CI: 0.43 to 0.61]; P<0.0001) and on HCTZ (adjusted hazard ratio: 0.65 [95% CI: 0.55 to 0.75]; P<0.0001) compared with those who took neither drug. When comparing the 2 drugs, CTD had significantly fewer CVEs compared with HCTZ (P=0.0016). CTD displayed significantly lower SBP (P<0.0001), lower total cholesterol (P<0.0001), lower low-density lipoprotein cholesterol (P=0.0009), lower potassium (P=0.0003), and higher uric acid (P<0.0001) over time compared with HCTZ. In conclusion, both HCTZ and CTD reduce CVEs compared with neither drug. When comparing both drugs, CTD reduces CVEs more than HCTZ, suggesting that CTD may be the preferred thiazide-type diuretic for hypertension in patients at high risk of CVEs.

Vitamin D and cardiovascular disease.

The hormonal derivative of vitamin D, 1,25‐dihydroxyvitamin D (1,25[OH]2D) or calcitriol, has been implicated in many physiologic processes beyond calcium and phosphorus homeostasis, and likely plays a role in several chronic disease states, in particular, cardiovascular disease. Experimental data suggest that 1,25(OH)2D affects cardiac muscle directly, controls parathyroid hormone secretion, regulates the renin‐angiotensin‐aldosterone system, and modulates the immune system. Because of these biologic effects, vitamin D deficiency has been associated with hypertension, several types of vascular diseases, and heart failure. We conducted a MEDLINE search of the English‐language literature (1950–2008) to identify studies that examined these relationships; additional citations were obtained from the articles retrieved from the literature search. Treatment with vitamin D lowered blood pressure in patients with hypertension and modified the cytokine profile in patients with heart failure. Measurement of serum 25‐hydroxyvitamin D concentration usually provides the best assessment of an individuals vitamin D status. Serum levels below 20 ng/ml represent vitamin D deficiency, and levels above 30 ng/ml are considered optimal. Although the observational data linking vitamin D status to cardiovascular disease appear robust, vitamin D supplementation is not recommended as routine treatment for heart disease until definitive prospective, randomized trials can be carried out to assess its effects. However, such supplementation is often appropriate for other reasons and may be beneficial to cardiovascular health in certain patients.

Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha).

Hawthorn, an herbal supplement, is currently being evaluated for the treatment of heart failure. The flavonoid components of hawthorn may be responsible for hawthorns beneficial effects in the treatment of heart failure. However, these components may also affect P‐glycoprotein function and cause interactions with drugs that are P‐glycoprotein substrates, such as digoxin, which is also used to treat heart failure. Therefore, the purpose of this study was to determine the effect of hawthorn on digoxin pharmacokinetic parameters. A randomized, crossover trial with 8 healthy volunteers was performed evaluating digoxin 0.25 mg alone (D) for 10 days and digoxin 0.25 mg with Crataegus special extract WS 1442 (hawthorn leaves with flowers; Dr. Willmar Schwabe Pharmaceuticals) 450 mg twice daily (D + H) for 21 days. Pharmacokinetic studies were performed for 72 hours. There were no statistically significant differences in any measured pharmacokinetic parameters. The AUC0‐∞, Cmax‐Cmin, Cmin, and renal clearance for the D group were 79 ± 26 mcg•h/L, 1.4 ± 0.7mcg/L, 0.84 ± 0.2 mcg/L, and 74 ± 10 mL/min versus 73 ± 20 mcg•h/L, 1.1 ± 0.1 mcg/L, 0.65 ± 0.2 mcg/L, and 81 ± 22 mL/min for the D + H group, respectively (p > 0.05). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter the pharmacokinetic parameters for digoxin. This suggests that both hawthorn and digoxin, in the doses and dosage form studied, maybe coadministered safely.

Loading, pretreatment, and interindividual variability issues with clopidogrel dosing

Clopidogrel, a thienopyridine, decreases adenosine diphosphate (ADP)–induced platelet aggregation. Clopidogrel is an inactive prodrug that requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system to an active metabolite that exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y12.1 The 75-mg once-daily dose was approved by the US Food and Drug Administration (FDA) in November 1997 after the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial2 showed superior reduction of adverse cardiovascular events with clopidogrel versus aspirin. The 75-mg once-daily dose had been used in CAPRIE because it produced inhibition of platelet aggregation equivalent to that produced by ticlopidine 250 mg administered twice daily. FDA approval for the 300-mg loading dose in patients with acute coronary syndromes was granted in February 2002 after the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial3 demonstrated a reduction of adverse cardiovascular events with dual antiplatelet therapy versus aspirin. Clopidogrel is not approved by the FDA for adjunctive antiplatelet therapy in percutaneous coronary intervention (PCI), although it has become the standard of care. It is curious that investigations into the optimal loading and maintenance doses of clopidogrel have been pursued only recently. See p 2560 In this issue of Circulation , Hochholzer et al4 performed optical platelet aggregometry and flow cytometry before and after a 600-mg oral dose of clopidogrel in 1001 potential PCI candidates undergoing cardiac catheterization. The findings are consistent with previous observations from small studies with regard to the 600-mg clopidogrel loading dose: Maximal inhibition of ADP-induced platelet aggregation was achieved ≈2 hours after ingestion,5 interindividual variability of platelet response was considerable,6 and there was no significant effect of concomitant statin therapy on platelet inhibition.7,8 Although …

Nutrition and Heart Failure: Impact of Drug Therapies and Management Strategies

Nutrition impairment commonly occurs in patients with heart failure and affects disease progression. Vitamin and mineral deficiencies are associated with early mortality, particularly in patients classified as cachectic. Guideline-based therapies approved for heart failure, such as loop diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aldosterone antagonists, and beta-adrenergic blockers, can lead to electrolyte abnormalities and predispose to some vitamin and micronutrient deficits. Clinical trial evidence in support of supplementary vitamin and mineral therapies for heart failure patients is limited with the exception of documented calcium and possibly vitamin D, thiamine, and coenzyme Q10 deficiencies. This area is gaining significant attention, and research is ongoing. The clinician can help minimize morbidity from nutrition impairment through appropriate monitoring and correction of baseline and medication-induced electrolyte imbalances, in addition to vitamin and mineral supplementation when appropriate.

Effects of intravenous levosimendan on plasma neurohormone levels in patients with heart failure: relation to hemodynamic response

Abstract The administration of intravenous levosimendan (0.1–0.4 μg/kg per minute) was associated with a statistically significant reduction in plasma levels of endothelin-1 (ET-1) in 79 patients with advanced (New York Heart Association functional class III or IV) heart failure. These data are compatible with the premise that reduction in ET-1 levels contributes to the hemodynamic effects of levosimendan in heart failure, although more extensive investigations are needed to confirm this hypothesis. The present study provided no evidence that levosimendan, in the doses used, had a significant effect on plasma levels of norepine- phrine.

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation

Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.

Comparison of intravenous and intranasal administration of epinephrine during CPR in a canine model

STUDY OBJECTIVES Epinephrine improves coronary perfusion pressure during CPR. However, administration of epinephrine during CPR may be delayed or omitted if IV or endotracheal access is not established. Therefore, the objective of this study was to determine if intranasal administration of epinephrine during CPR would provide an alternate route of drug administration that is readily accessible and requires no special technical skills. DESIGN AND SETTING Randomized blinded study performed in a controlled laboratory environment. TYPE OF PARTICIPANTS Twenty mongrel dogs weighing 19.5 +/- 4.6 kg. INTERVENTIONS All dogs received either IV epinephrine 0.015 mg/kg or intranasal epinephrine 14 mg per nostril. Phentolamine (5 mg per nostril) was administered intranasally one minute before nasal administration of epinephrine to improve absorption. Each dog underwent three minutes of ventricular fibrillation followed by seven minutes of CPR with a pneumatic chest compression device. Epinephrine was administered at two minutes into CPR. MEASUREMENTS AND MAIN RESULTS Seven dogs were excluded because of inadequate baseline coronary perfusion pressure or compression device displacement, leaving a total of 13 dogs for analysis (six IV epinephrine, seven intranasal epinephrine). Baseline coronary perfusion pressure (mean +/- SD) was similar for IV epinephrine and intranasal epinephrine (16.9 +/- 7.1 mm Hg versus 18.2 +/- 13.8 mm Hg, respectively, P = .84). For IV and intranasal epinephrine, coronary perfusion pressure increased to 21.4 +/- 9.2 mm Hg and 24.4 +/- 18.7 mm Hg one minute after epinephrine, respectively (P = .73). Five minutes after epinephrine coronary perfusion pressure was 18.2 +/- 8.7 mm Hg and 24.3 +/- 13.9 mm Hg for IV epinephrine and intranasal epinephrine, respectively (P = .38). The rate of successful resuscitation was similar for both groups, five of seven dogs for intranasal epinephrine and four of six dogs for IV epinephrine (P = .66). CONCLUSION Intranasal epinephrine has similar effects on coronary perfusion pressure and resuscitation compared with standard-dose IV epinephrine. Therefore, the nasal route for administration of epinephrine appears to be an acceptable alternate method of drug delivery during CPR and compares favorably with standard IV therapy in the canine model. Because of the obvious benefits to human patients, these observations suggest further investigation.

Team-based learning to improve learning outcomes in a therapeutics course sequence.

Objective. To compare the effectiveness of team-based learning (TBL) to that of traditional lectures on learning outcomes in a therapeutics course sequence. Design. A revised TBL curriculum was implemented in a therapeutic course sequence. Multiple choice and essay questions identical to those used to test third-year students (P3) taught using a traditional lecture format were administered to the second-year pharmacy students (P2) taught using the new TBL format. Assessment. One hundred thirty-one multiple-choice questions were evaluated; 79 tested recall of knowledge and 52 tested higher level, application of knowledge. For the recall questions, students taught through traditional lectures scored significantly higher compared to the TBL students (88%±12% vs 82%±16%, p=0.01). For the questions assessing application of knowledge, no differences were seen between teaching pedagogies (81%±16% vs 77%±20%, p=0.24). Scores on essay questions and the number of students who achieved 100% were also similar between groups. Conclusion. Transition to a TBL format from a traditional lecture-based pedagogy allowed P2 students to perform at a similar level as students with an additional year of pharmacy education on application of knowledge type questions. However, P3 students outperformed P2 students regarding recall type questions and overall. Further assessment of long-term learning outcomes is needed to determine if TBL produces more persistent learning and improved application in clinical settings.

The Effect of Dosage Release Formulations on the Pharmacokinetics of Propranolol Stereoisomers in Humans

Recent studies in dogs have suggested that the disposition of S‐ and R‐propranolol may depend on the input rate of drug delivered to the liver. Therefore, this study was designed to determine whether differences in the disposition of S‐ and R‐propranolol occur in humans when altering the input rate of propranolol by giving different dosage forms of the drug. Twelve healthy subjects were enrolled in a single‐dose, 4‐way crossover pharmacokinetic study in which racemic propranolol was given according to 1 of 4 treatments: one 80‐mg immediate‐release (IR) tablet, phase A; two 80‐mg IR tablets, phase B; a 160‐mg controlled‐release capsule, phase C; or a 10‐mg IV bolus, phase D. The results showed no significant differences in the ratios of S/R‐propranolol for AUC, clearance, or overall mean concentration among the oral dosage groups. Significant differences in these parameters including Cmax S/R ratio were seen between the oral phases and the IV phase. These differences appear to be related more to the route of administration than to the low input rate. However, at high concentrations there may be input‐rate alteration in S/R ratios. Specifically, for phase B, which had the highest Cmax concentrations, the Cmax S/R ratio was significantly lower than the other oral dosage groups A and C (Cmax S/R ratios: 1.44 versus 1.54 and 1.54, respectively; P < .05). These results suggest, as shown by the Cmax S/R ratio, that at high concentrations as seen after 160‐mg IR propranolol, the disposition of S‐ and R‐enantiomers may be different (i.e., input‐rate dependent) compared with dosage forms that result in lower drug concentrations. This may have important clinical implications, because the pharmacodynamic response may be altered.