Use of the recommended drug combination for secondary prevention after a first occurrence of acute coronary syndrome in France

Purpose

The recommended pharmacotherapy for secondary prevention of acute coronary syndrome (ACS) is long-term treatment with a combination of four therapeutic classes: beta-blockers, antiplatelet agents (including aspirin), statins or other lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The aim of this study was to describe use and persistence of the recommended drug combination after the first occurrence of ACS in France.

Methods

This was a database cohort study of patients with first registration for ACS between 2004 and 2007 in a representative sample of the French healthcare insurance database (Echantillon Généraliste de Bénéficiaires, EGB). The drugs of interest were those recommended. Persistence was assessed for patients dispensed three or all four drug classes within 2 months following ACS. Discontinuation was defined by a gap of more than 6 weeks between two dispensations. The follow-up period was 24 months after ACS occurrence.

Results

Of 2,057 patients with incident ACS, 872 (42.4 %) had at least one dispensation of each of the four recommended drug classes, and 684 (33.3 %) had three of the four classes. Persistence to treatment at 24 months was 57.4 % (95 % CI [54.0-60.6]) for patients with four classes, and 55.5 % (95 % CI [51.6-59.1]) with three classes. Discontinuation of initial combination was higher in patients aged ?≥?65 years at ACS occurrence, those with associated ongoing chronic disease, and in those who did not suffer myocardial infarction.

Conclusions

Post-ACS secondary prevention in France is not optimal, especially in patients who did not have myocardial infarction.     

Comparison of Antiplatelet Effect and Safety of Clopidogrel Napadisilate with Clopidogrel Bisulfate in Coronary Artery Disease Patients: Multi-center, Randomized, Double-blind, Phase IV, Non-inferiority Clinical Trial

Background

Clopidogrel napadisilate has better clopidogrel stability than clopidogrel bisulfate. There are no data, however, on the antiplatelet efficacy and tolerability of clopidogrel napadisilate in coronary artery disease (CAD) patients.

Objective

The aim of this study is to demonstrate that the combination therapy of aspirin and clopidogrel napadisilate is not inferior to that of aspirin and clopidogrel bisulfate with respect to its effectiveness in inhibiting platelet aggregation, if it is given for 4 weeks to CAD patients who had been treated with a drug-eluting stent more than 12 months prior and had remained in a stable condition with a single antiplatelet agent, aspirin.

Methods

This study was a prospective, randomized, double-blind, double-dummy, parallel-group, phase IV clinical trial. A total of 162 patients were prospectively recruited from three centers. The subjects were randomized to either the test group that was treated with 75 mg of clopidogrel napadisilate once daily or to the control group that was treated with 75 mg of clopidogrel bisulfate once daily. The primary outcome was the percent inhibition of the platelet aggregation change after the medication, as assessed by a VerifyNow? P2Y12 assay. The secondary outcome was the change in P2Y12 reaction units (PRUs) from the baseline to the end of 4 weeks of treatment. The prevalence of adverse events was assessed at each visit through a direct interview.

Results

The mean increase in the percent inhibition after 4 weeks of treatment was 19.4 % in the clopidogrel napadisilate group and 19.5 % in the clopidogrel bisulfate group. The lower bound of the 95 % two-sided confidence interval for the difference in the change between the two groups (-5.46) was greater than the pre-defined non-inferiority margin of (-10.5). Therefore, clopidogrel napadisilate was deemed non-inferior to clopidogrel bisulfate with respect to its effectiveness in inhibiting platelet aggregation. The PRU decreased by 73.1 ± 30.7 in the clopidogrel napadisilate group, which decreased by -7.8 more than in the clopidogrel bisulfate group (65.3 ± 62.1); but the difference between the two groups was statistically insignificant (p = 0.435). There was no significant difference in the drug-related adverse events between the two groups (12.3 vs. 10.1 %; p = 0.804).

Conclusion

The platelet inhibitory efficacy of clopidogrel napadisilate is not inferior to that of clopidogrel bisulfate. There were also no statistically significant differences between the two treatment groups in the safety analyses. Therefore, clopidogrel napadisilate can be a suitable alternative to clopidogrel bisulfate in stable CAD patients who have undergone a drug-eluting stent placement.

Clinical Trial Registration

Registered at ClinicalTrials.gov as NCT01830491.     

Efficacy and Safety Study of Olmesartan Medoxomil,Amlodipine, and Hydrochlorothiazide Combination Therapy in Patients with Hypertension Not Controlled with Olmesartan Medoxomil and Hydrochlorothiazide Combination Therapy: Results of a Randomized,Double-Blind,Multicenter Trial

Background

This study was to evaluate the efficacy and safety of triple fixed-dose combination (FDC) therapy with olmesartan medoxomil (OM) 20  mg, amlodipine (AML) 5 mg, and hydrochlorothiazide (HCTZ) 12.5 mg (OM/AML/HCTZ 20/5/12.5) in Korean patients with moderate hypertension not controlled with dual FDC therapy (OM/HCTZ 20/12.5).

Methods

In this multicenter, randomized, double-blind, parallel-group study, Korean patients aged 20 to 75 years with stage 2 hypertension who had a mean seated diastolic blood pressure (msDBP) ≥100 mmHg were enrolled when their BP was uncontrolled [mean seated systolic BP (msSBP)/msDBP >140/90 mmHg or msSBP/msDBP >130/80 mmHg with diabetes or chronic kidney disease] with 4-week dual FDC therapy (OM/HCTZ 20/12.5). The patients were randomized to receive either OM/AML/HCTZ 20/5/12.5 or OM/HCTZ 20/12.5 once daily for 8 weeks. At the end of 8 weeks, patients with uncontrolled BP were assigned to receive either OM/AML/HCTZ 40/5/12.5 or OM/AML/HCTZ 20/5/12.5 in an additional 8-week open-label extension period.

Results

A total of 623 patients received a 4-week run-in treatment with OM/HCTZ, 341 patients were randomized, and finally, 167 patients in the OM/AML/HCTZ group and 171 patients in the OM/HCTZ group were analyzed for the full analysis set. Non-responders after the 8 weeks of double-blind treatment continued the 8-week open-label treatment with OM/AML/HCTZ 40/5/12.5 mg (n = 32) or OM/AML/HCTZ 20/5/12.5 mg (n = 71). After 8 weeks of double-blind treatment, the changes in msDBP were ?9.50 (8.46) mmHg in the OM/AML/HCTZ group and ?4.23 (7.41) mmHg in the OM/HCTZ group (both p < 0.0001 vs. baseline; p < 0.0001 between groups). The response rates for both msSBP and msDBP at week 8 were 65.27 % in the OM/AML/HCTZ group and 37.43 % in the OM/HCTZ group (p < 0.0001 between groups). The response rates for both msSBP and msDBP at week 16 after open-label treatment were 18.75 % in the OM/AML/HCTZ 40/5/12.5 group and 46.48 % in the OM/AML/HCTZ 20/5/12.5 group (p = 0.0073 between groups). All medications were well tolerated.

Conclusion

In Korean patients with moderate hypertension not controlled with dual FDC therapy (OM/HCTZ 20/12.5) as first-line therapy, switching to triple FDC therapy (OM/AML/HCTZ 20/5/12.5) was associated with significant BP reductions and greater achievement of BP goals, and was well tolerated (ClinicalTrials.gov Identifier: NCT01838850).

     

Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a prospective randomized study

Purpose

Eradication rates following standard triple therapy for Helicobacter pylori infection are declining. Recent studies, conducted in a number of countries, have shown that sequential therapy for H. pylori infection yields high cure rates.

Aim

To compare the efficacy and tolerability of a sequential regimen as a first-line treatment of H. pylori infection with a standard triple treatment regime in Morocco.

Methods

A total of 281 naive H. pylori-infected patients, confirmed by histological examination, were assigned randomly to one of two treatment groups: standard triple therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) + clarithromycin (500 mg bid) for 7 days] or sequential therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) for 5 days, followed by omeprazole (20 mg bid) + tinidazole (500 mg bid) + clarithromycin (500 mg bid) for an additional 5 days]. H. pylori eradication was checked 4–6 weeks after treatment initiation by using a ¹³C-urea breath test. Compliance and adverse events were assessed.

Results

The two groups did not differ significantly in gender, age, previous disease history, endoscopic and histological features and smoking. The intention-to-treat and per-protocol eradication rates were 65.9 and 71 % in the standard triple therapy group, and 82.8 and 89.9 % in the sequential therapy group, respectively. The eradication rate was significantly higher in the sequential therapy group than in the standard triple therapy group (p?<?0.001), There was no statistically significant difference in compliance (97.5  vs. 96.3 %) and incidence of side-effects (27.5 vs. 27.9 %) between the two groups.

Conclusions

Based on our results, we conclude that for eradication of H. pylori infection, the 10-day sequential therapy is more effective than the standard triple therapy and is equally tolerated. These results confirm those of other studies in other countries.     

Meta-Analysis of Oral Anticoagulants with Dual versus Single Antiplatelet Therapy in Patients after Percutaneous Coronary Intervention

Background

The combined use of dual antiplatelet therapy with oral anticoagulation (OAC) is required after coronary artery stenting or acute coronary syndromes (ACS).

Methods and Results

We performed a meta-analysis (Embase and MEDLINE search) of the comparative effects of triple antithrombotic therapy (TT) versus OAC with single antiplatelet therapy (dual therapy [DT]) on all-cause mortality, stroke, cardiovascular death, myocardial infarction (MI), target vessel revascularization, and major bleeding. Three prospective controlled studies and five cohort studies compared TT versus DT. We identified three prospective controlled and five cohort studies with 4564 patients on TT and 1848 on DT with an average follow-up duration of 10.1 months. TT is associated with similar rates of all-cause mortality, stroke, and major bleeding but significantly lower rates of MI compared with DT.

Conclusions

Triple antithrombotic therapy is associated with similar mortality and bleeding rates but fewer MIs compared with OAC and single antiplatelet therapy.

     

Risks for stroke and bleeding with warfarin or aspirin treatment in patients with atrial fibrillation at different CHA2DS2VASc scores: experience from the Stockholm region

Purpose

This study evaluated the benefits of and possible contraindications to warfarin treatment in patients with atrial fibrillation (AF) prior to the introduction of new oral anticoagulants using health registry data from inpatient care, specialist ambulatory care, and primary care.

Methods

This is a cohort study including all patients in the region of Stockholm, Sweden (2.1 million inhabitants) with a diagnosis of non-valvular AF (n?=?41 810) recorded during 2005–2009. The risks of suffering ischemic stroke, bleeding, or death with warfarin, aspirin, or no antithrombotic treatment during 2010 were related to CHA₂DS₂VASc scores, age, and complicating co-morbidities.

Results

One-year risks for ischemic stroke were 1.0–1.2 % with aspirin, 0–0.3 % with warfarin, and 0.1–0.2 % without treatment at CHA₂DS₂VASc scores 0–1. Among the aspirin-treated patients with CHA₂DS₂VASc scores ≥2, half had possible contraindications and high risks for ischemic stroke (5.2 %), bleeding (5.0 %), and death (19.3 %). The other half of the patients with no identified contraindications had a high risk for ischemic stroke (4.0 %) but a low bleeding risk (1.8 %) and a moderate mortality rate (8.4 %).

Conclusions

The present observations confirm earlier findings of undertreatment with warfarin and half of the high-risk patients treated with aspirin were obvious candidates for anticoagulant treatment. However, the other half of the patients had complicating co-morbidities, high bleeding risk, and poor prognosis. This and possible overtreatment of low-risk patients should be taken into account when considering more aggressive use of anticoagulant treatment.     

Predicting the Impact of Polypill Use in a Metabolic Syndrome Population: An Effectiveness and Cost-Effectiveness Analysis

Background

Individuals with metabolic syndrome (MetS) are at increased risk of cardiovascular disease (CVD), often requiring combination drug therapy for control of risk factors and subsequent risk reduction. This study aims to compare the long-term effectiveness and cost effectiveness of the polypill (a multi-component tablet), and its components (alone or in combination), in a MetS population.

Methods and Results

A Markov state transition model, using individual subject data from the Australian Diabetes, Obesity and Lifestyle study, was constructed to simulate the effects of the treatment versus no treatment on CVD events, and costs over 10 years. In 1,991 individuals classified as MetS and free of existing diabetes mellitus or CVD, treatment with the polypill (or its components) was effective at reducing cardiovascular events [statin: 171, aspirin (actetylsalicylic acid): 201, antihypertensive: 186 per 1,000 individuals]. The more drug therapies employed the greater the reduction, with the polypill reducing up to 351 cardiovascular events per 10,000 individuals. Cost-effectiveness analyses were sensitive to drug treatment costs and effectiveness of treatment. At a cost of AUD$42 per person per annum, aspirin was considered cost saving. All other treatment strategies, including the polypill, were not cost effective.

Conclusion

The polypill is likely to be effective in the reduction of cardiovascular events in a MetS population. It is, however, not cost effective. Nevertheless, in a high-risk population, among whom combination therapy is often prescribed, the polypill is likely to be more cost effective than antihypertensive therapy alone or dual therapy with a statin and antihypertensive combination.     

Impact of Ranolazine on Clinical Outcomes and Healthcare Resource Utilization in Patients with Refractory Angina Pectoris

Background

Ranolazine is a novel antianginal medication approved for the treatment of chronic angina. There are only limited data concerning the efficacy of ranolazine in reducing healthcare resource utilization in patients with refractory angina pectoris.

Objective

The primary objective of this analysis was to evaluate the efficacy and safety of ranolazine in refractory angina pectoris. In addition, the impact of ranolazine on healthcare resource utilization was assessed.

Methods

Consecutive patients with refractory angina pectoris treated with ranolazine at two cardiology practices in the state of Nebraska were included in this analysis. The Canadian Cardiovascular Society (CCS) angina class and frequency and type of healthcare resource consumption were determined during the 12 months prior to and the 12 months after initiation of ranolazine.

Results

A total of 150 pts (64 % men) with a mean age of 66 ± 12 years were included in this analysis. All patients had previously undergone coronary revascularization. Nitrates, β-adrenoceptor antagonists (β-blockers), and calcium antagonists (calcium channel blockers) were being used in 83, 97, and 75 % of patients, respectively. During ranolazine treatment, a significant improvement in CCS angina class was observed, with 23 patients improving by one class and no patient experiencing a deterioration in functional class (p = 0.025). A total of 53 side effects occurred in 28 (19 %) patients receiving ranolazine. Of those patients with side effects, four required dose reduction and seven required drug discontinuation. The frequency of clinic visits and emergency room visits was lower during ranolazine treatment, but the differences in frequency were not significant. The number of patients hospitalized and the number of hospitalizations were significantly lower during ranolazine therapy than in the pre-ranolazine study period (p = 0.002).

Conclusion

Ranolazine improved the CCS angina class and reduced hospitalizations over a 12-month follow-up period in a group of patients with difficult-to-treat refractory angina pectoris.     

Prior Antiplatelet Use and Cardiovascular Outcomes in Patients Presenting with Acute Coronary Syndromes

Background

Although antiplatelet therapy effectively reduces ischemic events, the cardiovascular (CV) outcome in some cases is still unpredictable.

Objective

The objective of this study was to evaluate the impact of prior single or dual antiplatelet (PAP) use in patients presenting with acute coronary syndromes (ACS).

Methods

Data were collected from the 2nd Gulf Registry of Acute Coronary Events between October 2008 and June 2009. Patients were grouped according to whether they were PAP users or not (NAP). Patients’ characteristics and outcomes were analyzed and compared. Mortality was assessed at 1 and 12 months.

Results

Among 7827 consecutive ACS patients, 41% were PAP users (70% aspirin, 1% clopidogrel, and 29% dual antiplatelet agents). In comparison with NAP use, PAP use was associated with a higher rate of comorbidities, atypical presentation, severe left ventricular dysfunction, three-vessel disease, and a high GRACE risk score. After adjustment for relevant covariates, PAP use was an independent predictor for recurrent ischemia in unstable angina (odds ratio [OR] 1.7; 95% CI 1.17, 2.57) and non-ST-elevation myocardial infarction (NSTEMI) [OR 1.9; 95% CI 1.38, 2.65] and for heart failure in NSTEMI (OR 1.5; 95% CI 1.11, 2.15) and STEMI (OR 1.4; 95% CI 1.08, 1.93). Although PAP use was associated with high mortality in STEMI and NSTEMI, it was not an independent predictor for mortality. Among PAP patients, percutaneous coronary intervention independently reduced the risk of hospital (adjusted OR 0.25; 95% CI 0.20, 0.32), 1-month (OR 0.31; 95% CI 0.26, 0.37), and 12-month mortality (OR 0.28; 95% CI 0.24, 0.33).

Conclusion

PAP use identified a high-risk population across the ACS spectrum. Early coronary revascularization may improve CV outcomes in these patients.     

Placebo Effect and Efficacy of Nebivolol in Patients with Hypertension not Controlled with Lisinopril or Losartan: A Phase IV, Randomized, Placebo-Controlled Trial

Background

Most patients with hypertension require more than one antihypertensive to achieve blood pressure (BP) control.

Objective

The purpose of this trial was to assess the efficacy and tolerability of add-on nebivolol, a vasodilatory β-blocker, in patients with untreated or poorly controlled hypertension, receiving stable therapy with lisinopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin II receptor blocker).

Study Design

This was a phase IV double-blind, placebo-controlled trial conducted from August 2008 to March 2010 (ClinicalTrials.gov identifier: NCT00734630). Patients entered a 2-week, single-blind, placebo-only washout phase, followed by a 3- to 4-week open-label lead-in phase (lisinopril, 10–20 mg/day, or losartan, 50–100 mg/day), and a 12-week randomized, double-blind add-on treatment phase with placebo or nebivolol (5–40 mg/day).

Setting

This study was conducted at 76 outpatient centers in the United States.

Patients

Participants were men and women aged 18–85 years with a diagnosis of primary hypertension and seated trough systolic BP (SBP) at screening in the range of 170–200 mmHg if untreated, 155–180 mmHg if taking 1 antihypertensive medication, or 140–170 mmHg if taking 2 antihypertensive medications.

Intervention

The intervention was 12 weeks’ treatment with nebivolol 5–40 mg/day added to a background therapy of lisinopril 10–20 mg/day or losartan 50–100 mg/day.

Main Outcome Measures

Primary and secondary efficacy parameters were changes from baseline in seated trough cuff SBP and diastolic BP (DBP) at Week 12, respectively. Tolerability was assessed by monitoring treatment-emergent adverse events (TEAEs).

Results

A total of 491 patients were randomized to receive nebivolol (n = 258) or placebo (n = 233). Efficacy analyses were conducted for 256 nebivolol and 232 placebo patients (intent-to-treat population); completion rates were 88.8 % and 85.8 %, respectively. Mean baseline SBP/DBP values were 163.1/98.2 mmHg (nebivolol) and 162.4/96.8 mmHg (placebo). Nebivolol was associated with a non-significant mean ± SD reduction in SBP (?10.1 ± 16.9 mmHg) versus placebo (?7.3 ± 15.9 mmHg, P = 0.093) and significant mean DBP reduction (?7.8 ± 10.1 mmHg vs ?3.5 ± 10.6 mmHg, P < 0.001). Subgroup analysis suggested a significant effect on DBP for patients receiving background losartan treatment (?8.1 ± 9.2 mmHg vs ?3.1 ± 9.4 mmHg, P < 0.001), but not for those receiving lisinopril (?7.6 ± 10.8 mmHg vs ?3.8 ± 11.6 mmHg, P = 0.076). A total of 28 % nebivolol-treated and 22 % placebo-treated patients reported a TEAE, the most frequent being upper respiratory tract infection (4.3 % and 2.1 %, respectively), bradycardia (2.7 % and 0 %), headache (2.3 % and 2.1 %), and nasopharyngitis (2.3 % and 0.9 %).

Conclusion

These data suggest that nebivolol, when added to lisinopril or losartan, results in an additional BP reduction; however, only the effect on DBP reached statistical significance. A subanalysis suggests that the effect on DBP may be stronger in losartan-treated than lisinopril-treated patients. A relatively strong placebo effect may limit data interpretation. Nebivolol was well tolerated, as there was no difference in TEAEs between nebivolol and placebo.

Funding

This trial (NCT00734630) was funded by Forest Laboratories, Inc.     

Non-linear Increases in Danazol Exposure with Dose in Older vs. Younger Beagle Dogs: The Potential Role of Differences in Bile Salt Concentration,Thermodynamic Activity,and Formulation Digestion

Purpose

To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol.

Methods

Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations. Changes to lipolytic enzyme activity and intestinal bile salt concentration were evaluated using in vitro lipolysis.

Results

Drug exposure increased linearly with dose in younger animals. In older animals, bioavailability increased with increasing dose to a tipping point, beyond which bioavailability reduced (consistent with initiation of precipitation). No differences in hepatic function were apparent across cohorts. Changes to enzyme concentrations in lipolysis studies had little impact on drug precipitation/solubilisation. In contrast, higher bile salt concentrations better supported supersaturation at higher drug loads.

Conclusions

Differences in animal cohort can have a significant impact on drug absorption from lipid based formulation. For danazol, bioavailability was enhanced under some circumstances in older animals. In vitro experiments suggest that this was unlikely to reflect changes to metabolism or lipolysis, but might be explained by increases in luminal bile salt/phospholipid concentrations in older animals.     

Clinical Inertia in Poorly Controlled Elderly Hypertensive Patients: A Cross-Sectional Study in Spanish Physicians to Ascertain Reasons for Not Intensifying Treatment

Background

Clinical inertia, the failure of physicians to initiate or intensify therapy when indicated, is a major problem in the management of hypertension and may be more prevalent in elderly patients. Overcoming clinical inertia requires understanding its causes and evaluating certain factors, particularly those related to physicians.

Objective

The objective of our study was to determine the rate of clinical inertia and the physician-reported reasons for it.

Methods

An observational, cross-sectional, multi-center study was carried out in a primary care setting. We included 512 physicians, with a consecutive sampling of 1,499 hypertensive patients with clinical inertia.

Main Outcome Measure

Clinical inertia was defined when physicians did not modify treatment despite knowing that the therapeutic target had not been reached. Clinical inertia was considered to be justified (JCI) when physicians provided an explanation for not intensifying treatment and as not justified (nJCI) when no reasons were given.

Results

JCI was observed in 30.1 % (95 % CI 27.8–32.4) of patients (n = 451) and nJCI in 69.9 % (95 % CI 67.6–72.2) (n = 1,058). JCI was associated with higher blood pressure (BP) values (both systolic and diastolic) and diabetes (p = 0.012) than nJCI. nJCI was associated with patients having an isolated increase of systolic or diastolic or high borderline BP values or cardiovascular disease.

Conclusion

Physicians provided reasons for not intensifying treatment in poorly controlled patients in only 30 % of instances. Main reasons for not intensifying treatment were borderline BP values, co-morbidity, suspected white coat effect, or perceived difficulty achieving target. nJCI was associated with high borderline BP values and cardiovascular disease.     

Mipomersen is a Promising Therapy in the Management of Hypercholesterolemia: A Meta-Analysis of Randomized Controlled Trials

Introduction

By inhibiting apolipoprotein B (ApoB) synthesis, mipomersen can significantly reduce ApoB-containing lipoproteins in hypercholesterolemic patients.

Objective

This study sought to ascertain both the extent to which mipomersen can decrease ApoB-containing lipoproteins and the safety of mipomersen therapy.

Methods

Studies were identified through PubMed, CENTRAL, Embase, Clinical Trials, reviews, and reference lists of relevant papers. The efficacy endpoints were the changes in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), ApoB, and lipoprotein (a) [Lp(a)]. The safety endpoints were the incidence of injection-site reactions, flu-like symptoms, and elevated transaminases.

Results

Six randomized controlled trials with 444 patients were included in the analysis. Compared with the placebo group, patients who received mipomersen therapy had a significant reduction in LDL-C (33.13 %), as well as a reduction in non-HDL-C (31.70 %), ApoB (33.27 %), and LP(a) (26.34 %). Mipomersen therapy was also associated with an obvious increase in injection-site reactions with an odds ratio (OR) of 14.15, flu-like symptoms with an OR of 2.07, and alanine aminotransferase levels ≥3 × the upper limit of normal with an OR of 11.21.

Conclusions

Mipomersen therapy is effective for lowering ApoB-containing lipoproteins in patients with severe hypercholesterolemia. Future studies exploring how to minimize side effects of mipomersen therapy are needed.     

Epoetin alpha improves the response to antiviral treatment in HCV-related chronic hepatitis

Background

The conventional antiviral treatment of chronic hepatitis related to hepatitis C virus (HCV) often leads to anemia. In this case, it is necessary to reduce ribavirin dose or stop treatment, thus reducing the rate of sustained virological response.

Aim

We investigated whether epoetin alpha administration improves treatment adherence and leads to higher percentage of response at the end of therapy and sustained virological response.

Methods

Two hundred and fourteen individuals with genotype 1b HCV-related chronic hepatitis underwent treatment with pegylated (peg)-interferon alpha-2A 180 μg once weekly and ribavirin 1,000–1,200 mg/day; 174 were responders. Forty individuals completed treatment with no hemoglobin reduction; 134 developed anemia during therapy. Anemic responders were distributed randomly into two groups: group 1 continued therapy with epoetin alpha addiction; group 2 continued antiviral therapy with ribavirin reduction only.

Results

Patients in group 1 achieved better control of hemoglobin levels (13.8?±?1.2 g/dl at the end of therapy) than tthose in group 2 (11.5?±?0.8 g/dl). Sustained virological response was 59.7% in group 1 compared with 34.4% in group 2 (p?<?0.01).

Conclusions

In patients with 1b HCV-related chronic hepatitis who develop anemia during antiviral treatment, administration of epoetin alpha increases hemoglobin levels and the end-of-treatment rate and sustains virological response by improving treatment adherence.     

Pharmacokinetics and Pharmacodynamics of the Antiplatelet Combination Aspirin (Acetylsalicylic Acid) Plus Extended-Release Dipyridamole Are Not Altered by Coadministration with the Potent CYP2C19 Inhibitor Omeprazole

Background

The fixed-dose combination of aspirin (acetylsalicylic acid) 25 mg plus extended-release dipyridamole 200 mg (ASA + ER-DP) is used for long-term secondary stroke prevention in patients who have experienced non-cardioembolic stroke or transient ischemic attack. Although the theoretical risk is low that the antiplatelet activity of ASA + ER-DP will be affected by concomitant use of a proton pump inhibitor (PPI), no formal drug-drug interaction studies have been conducted.

Objective

This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA + ER-DP.

Study Design and Setting

This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit.

Participants

Sixty healthy male and female volunteers aged 18–50 years were included in the study.

Intervention

Participants were randomized to one of two treatment sequences (ABCD or CDAB), each comprising four 7-day treatments with a washout of ≥14 days between the second and third treatments. Treatment A = ASA + ER-DP 25 mg/200 mg (Aggrenox^®) twice daily (BID) alone; B = ASA + ER-DP 25 mg/200 mg BID + omeprazole (Prilosec^®) 80 mg once daily (QD) following ASA + ER-DP alone for 7 days; C = omeprazole 80 mg QD alone; D = omeprazole 80 mg QD + ASA + ER-DP 25 mg/200 mg BID following omeprazole alone for 7 days.

Main Outcome Measures

The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation.

Results

Systemic exposure to ER-DP was similar with and without omeprazole, based on steady-state area under the concentration-time curve (AUC) from 0 to 12 h (AUC_0–12,ss, ng·h/mL) and maximum plasma concentration (C_max,ss, ng/mL). For the treatment comparison D versus A, the percent mean ratios were 96.38 (90 % confidence interval [CI] 90.96–102.13) for AUC_0–12,ss and 92.03 (86.95–97.40) for C_max,ss. The ER-DP concentration versus time profiles were nearly superimposable. There was no effect on the PDs of the ASA component: the extent of ASA inhibition of arachidonic acid-induced platelet aggregation was almost identical with and without omeprazole, with a percent mean ratio for treatment D versus A = 99.02 (90 % CI 98.32–99.72) at 4 h after last dose. All treatments were well tolerated.

Conclusion

The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.