Bleeding adverse drug reactions (ADRs) in patients exposed to antiplatelet plus serotonin reuptake inhibitor drugs: analysis of the French Spontaneous Reporting Database for a controversial ADR

Aim

The aim of the present study was to investigate bleeding adverse drug reactions (ADRs) in patients exposed to serotonin reuptake inhibitors (SRI) plus antiplatelet agents using the French Pharmacovigilance Database (FPVDB) regarding the controversial data in the literature.

Methods

The case/non-case method was used to measure the association between bleedings and exposure to SRIs plus antiplatelet agents versus antiplatelet drugs alone.

Results

Over 3?years, a total of 1,977 spontaneous reports of ADRs were collected with antiplatelet drugs, and antiplatelet agents plus SRIs in patients aged over 50?years, of which 1,331 (67.3?%) concerned bleeding. Multivariate logistic regression analysis failed to show any significant association [adjusted ROR?=?0.8 (0.5–1.2)].

Conclusion

The data did not demonstrate any significant association between bleeding ADRs and exposure to SRI + antiplatelet agents versus antiplatelets alone. Considering other conflicting results, this risk should be kept in mind by physicians when treating patients with several risk factors.     

Dose-Dependent Antihypertensive Efficacy and Tolerability of Perindopril in a Large, Observational, 12-Week, General Practice-Based Study

Background

Current guidelines recommend the use of full therapeutic dosages of antihypertensive agents, or combination therapy, to improve BP control of hypertensive patients in primary healthcare.

Objective

The aim of this study was to assess the dose-dependent antihypertensive efficacy and safety of perindopril 4 and 8 mg/day in the clinical setting.

Study Design and Setting

The CONFIDENCE study was a prospective, observational, multicenter trial. This was a real-world, clinic-based, outpatient study involving 880 general practitioners/primary-care clinics and 113 specialists in Canada.

Patients

The study included untreated or inadequately managed patients with hypertension (i.e. seated BP≥140/90 mmHg, or ≥130/80 mmHg in the presence of diabetes mellitus, renal disease, or proteinuria) without coronary artery disease (CAD).

Intervention

Treatment consisted of perindopril 4 mg/day, uptitrated to 8 mg/day as required for BP control at visit 2, for 12 weeks. Among the patients already being treated at baseline, perindopril either directly replaced all previous ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), or was added to antihypertensive treatment with calcium channel blockers (CCBs), diuretics, or β-adrenoceptor antagonists (β-blockers).

Main Outcomes Measures

The primary outcomes were the mean changes in BP from baseline following treatment with perindopril 4 and 8 mg/day as well as the proportion of patients achieving BP control (BP <140/90 mmHg, or <130/80 mmHg in diabetic patients) in the intent-to-treat (ITT) population. Secondary analyses included the incidence of adverse events and compliance.

Results

A total of 8298 hypertensive patients entered the study: 56% with newly diagnosed hypertension and 44% with uncontrolled hypertension. Mean SBP/DBP decreased significantly from baseline (152.5 ±10.8/89.5 ±9 mmHg) over 12 weeks (?18.5/?9.7 mmHg; p < 0.001). At visit 2, 23% of patients were uptitrated to perindopril 8 mg/day, which resulted in an additional mean 10.1/5.3 mmHg BP reduction; this reduction was even greater (15.1/5.7 mmHg) among a separate group of severely hypertensive patients (i.e. SBP >170 mmHg or DBP > 109 mmHg at baseline). Target BP was achieved in 54% of the ITT population. Both perindopril 4 mg/day and perindopril 8 mg/day were well tolerated and compliance was high throughout the study.

Conclusion

In the clinical outpatient setting, perindopril was found to be an effective dose-dependent and well tolerated antihypertensive treatment, with good compliance. Uptitration to the full therapeutic dosage of perindopril is an efficient approach for the management of a broad range of hypertensive patients without CAD.     

Combination of Amlodipine plus Angiotensin Receptor Blocker or Diuretics in High-Risk Hypertensive Patients

Background and Objectives

Antihypertensive therapy is effective in reducing the risk of major adverse cardiovascular events. However, blood pressure (BP) control rate remains poor and the optimal combination therapy against hypertension is not established in China. The objective of this study was to evaluate the long-term efficacy and safety of two antihypertensive regimens, amlodipine plus telmisartan and amlodipine plus amiloride/hydrochlorothiazide, in patients with essential hypertension and at least one cardiovascular risk factor.

Methods

In a multicenter open-label clinical trial, eligible patients were randomized to receive treatment with amlodipine 2.5–5 mg plus amiloride/hydrochlorothiazide 1.25–2.5 mg/12.5–25 mg (Group A) or amlodipine 2.5–5 mg plus telmisartan 40–80 mg (Group T). If a target BP was not reached, other antihypertensive agents would be added. The target BP was <130/80mmHg for patients with diabetes mellitus or chronic kidney disease and <140/90mmHg for others. Efficacy variables were changes from baseline in systolic BP and diastolic BP at the endpoint of 96 weeks. Safety evaluations included monitoring of any adverse events (AEs).

Results

Of 13 542 patients randomized, 13 080 (96.6%) completed the study: 6529 in Group A and 6551 in Group T. At endpoint, the BP levels were reduced by 27.4/14.3 mmHg in Group A and 27.1/14.5 mmHg in Group T. The BP control rates were similar for the two therapeutic regimens (87.5% vs 86.1%). Less than 4% of patients in each group discontinued their drugs during follow-up. Peripheral edema was one of the most common AEs, and occurred in only 24 patients in Group A and 19 in Group T.

Conclusions

Long-term combination therapy with amlodipine plus telmisartan or amlodipine plus amiloride/hydrochlorothiazide was not only well tolerated but also efficacious in reducing BP levels with acceptable control rates in the majority of hypertensive patients.

Clinical Trials Registration

ClinicalTrials.gov number NCT01011660.     

Non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension treatment intensification: a population-based cohort study

Purpose

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to antagonize the effects of antihypertensive drugs, and these associations can lead to an increase in arterial blood pressure. However, the impact of NSAIDs on hypertension treatment management in large-scale populations remains poorly evaluated. We examined whether the introduction of NSAID into the treatment regimen would induce an intensification of hypertension treatment (defined as the introduction of a new antihypertensive drug).

Methods

We conducted a cohort study involving 5,710 hypertensive subjects included in the French health insurance system database who had been treated and stabilized with their antihypertensive therapy and not exposed to any NSAID between 1 April 2005 and 1 April 2006. The maximum follow-up duration was 4?years.

Results

Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95?% confidence interval (CI) 1.05–1.71] for NSAIDs in general, 1.79 (95?% CI 1.15–2.78) for diclofenac and 2.02 (95?% CI:1.09–3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACEIs; HR? 4.09, 95?% CI 2.02–8.27) or angiotensin receptor blockers (ARBs; HR?3.62, 95?% CI 1.80–7.31), but not with other antihypertensive drugs.

Conclusions

Exposure to NSAIDs leads to an intensification of hypertension treatment, especially in patients treated with ACEIs or ARBs. Renin–angiotensin system blockers should be avoided whenever NSAIDs are prescribed.     

Assessment of time to follow-up visits in newly-treated hypertensive patients using an electronic medical record database

Abstract

Objective:

Use of electronic medical record (EMR) data for evaluating healthcare processes and outcomes is relatively new. Using EMR data, this study evaluated the time from antihypertensive initiation to the first follow-up office visit controlling for adverse events (AEs) and other factors that could influence follow-up timing. Findings were compared to treatment guidelines which recommend monthly follow-up in treatment naive patients until blood pressure (BP) levels are controlled.     

Characterization and Evaluation of Multi-Component Crystals of Hydrochlorothiazide

Purpose

The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC).

Methods

The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats.

Results

Both 1 and 2 crystallized in the orthorhombic space group P2₁2₁2₁ and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals.

Conclusions

The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome.     

Washington poison center as perceived by our state’s emergency physicians

Introduction

In 1986, we conducted the first survey of Washington emergency physicians about their perceptions of the performance of the Washington Poison Center (WPC); the results were summarized and published. The exercise was repeated in 1993, 1997 and in 2005.

Methods

The original conventional 2-page survey was updated and distributed with an explanatory letter and return envelope to a mailing list obtained from the state chapter of the American College of Emergency Physicians. Responses were tallied, summarized and compared to prior surveys.

Results

For 2005, 612 surveys were distributed; 221 were returned. The average respondent had been in practice for 14 years, with more than 50% functioning in “urban” communities. They reported calling the WPC an average of 19 times per year, and particularly valued being able to consult with a board-certified medical toxicologist in a virtually “STAT” manner. In more than 80% of calls, the information played a positive role in management of the patient.

Conclusions

Washington’s emergency physicians continue to highly value the WPC’s services, with increasing numbers in favor of governmental support of the operation.     

Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice

Background

Current clinical guidelines recognize that the use of more than one agent is necessary to achieve target BP in the majority of patients. The ASCOT-BPLA trial demonstrated that the free combination of amlodipine and perindopril effectively controlled BP and was better than a β-adrenoceptor antagonist (β-blocker)/diuretic combination in reducing total mortality and cardiovascular outcomes.

Objective

To evaluate the efficacy and tolerability of a fixed combination of perindopril and amlodipine in the clinical setting.

Study design

The STRONG (SafeTy & efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension) study was a prospective, observational, multicenter trial.

Setting

This was a naturalistic, real-world, clinic-based, outpatient study involving 336 general practitioners/ primary care physicians in 65 cities in India.

Patients

Adults aged 40–70 years with newly diagnosed/untreated stage 2 hypertension (BP ≥ 160/100 mmHg), hypertension uncontrolled with monotherapy (BP > 140/90 mmHg), or hypertension inadequately managed with another combination therapy.

Intervention

Fixed combination perindopril 4 mg/amlodipine 5 mg once daily for 60 days.

Main outcomes measure

The primary outcomes were the mean change in BP from baseline and the proportion of patients achieving adequate BP control (≤ 140/90 mmHg, or ≤ 130/80 mmHg in patients with diabetes mellitus) in the intent-to-treat (ITT) population. Secondary analyses included incidence of adverse events (ITT) and treatment adherence rate (completers).

Results

In total, 1250 patients comprised the ITT population: 32.6% with newly diagnosed hypertension; 40.5% with hypertension uncontrolled with monotherapy; and 26.9% with hypertension inadequately managed with another combination therapy. Mean SBP/DBP decreased significantly from baseline (167.4±15.2/101.4±9.1 mmHg) over 60 days (?41.9 ± 34.8/?23.2 ± 21.8 mmHg; p<0.0001). Target BP was achieved in 66.1% of patients in the total population, 68.3% of untreated patients, 68.4% of patients uncontrolled with monotherapy, and 59.9% of patients inadequately managed with combination therapy. In 161 patients with SBP >180 mmHg at baseline (newly diagnosed: n = 50; uncontrolled on monotherapy: n = 53; inadequately managed on combination therapy: n = 58), BP was reduced by 63.2 ± 32.5/29.0 ± 21.9 mmHg (p<0.0001) at day 60. The fixed combination was safe and well tolerated. All 1175 patients completing the 60-day study (94%) adhered to their treatment regimen.

Conclusion

Fixed combination perindopril/amlodipine was found to be an effective and well tolerated antihypertensive treatment, with an excellent rate of treatment adherence in the clinical setting. Fixed combination perindopril/amlodipine is expected to be useful in the management of hypertension in primary healthcare, with a positive impact on treatment adherence.     

Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database

Purpose

Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs.

Methods

The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated.

Results

Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a ‘certain’ causality score (I4) and 13 (7.5 %) a ‘likely’ score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded.

Conclusion

This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.     

High Times, Low Sats: Diffuse Pulmonary Infiltrates Associated with Chronic Synthetic Cannabinoid Use

Introduction

In recent years, cases of severe adverse effects from recreational use of synthetic cannabinoids (SC) have established that these agents represent a novel toxicologic hazard.

Case Report

A 21-year-old male presenting as a vehicular trauma victim was noted with diffuse pulmonary infiltrates related to chronic inhalation of multiple synthetic cannabinoid-containing products. Chest imaging revealed bilateral, subacute lung infiltrates; histopathological analysis of bronchial and alveolar tissues revealed an inflammatory process. An extensive workup failed to identify infectious, malignant, autoimmune, or hematologic causes of the syndrome, and toxicological analysis of the blood and body fluids confirmed the presence of multiple synthetic cannabinoids and metabolites. The patient recovered after an 8-day ICU course, wherein he received antibiotics, steroids, and mechanical ventilation.

Discussion

This case contributes to the currently evolving knowledge about SC agents, adding a rarely described pulmonary complication to the growing list of adverse effects associated with these products.     

What guidelines tell us about acute pancreatitis. A review of the last international guidelines

Background

Since the Atlanta Symposium several guidelines and consensus conferences have been published to improve the management and understanding of patients with acute pancreatitis. Herein, a review of the most recent guidelines on acute pancreatitis is carried out, trying to find differences and similarities.

Methods

Five of the last international guidelines on acute pancreatitis as well as the last consensus conference are critically reviewed.

Conclusions

There is more consensus than disagreement between guidelines, which is why the knowledge of them is of great importance when treating AP.     

Effect of angiotensin II type I receptor A1166C polymorphism on benazepril action in hypertensive patients: A family-based association test study

Background

Few studies have examined the effect of the angiotensin II type I receptor (AT1R) A1166C polymorphism on the antihypertensive effect of the angiotensin-converting-enzyme inhibitor benazepril in patients with hypertension, and no such studies have performed analysis using the Family-Based Association Test (FBAT), The aim of our study was to examine the association between AT1R A1166C gene polymorphism and the antihypertensive effect of benazepril using the FBAT.

Methods and Results

A total of 864 patients (aged, 26–62 years) with essential hypertension were identified in an epidemiological survey and enrolled in this study. Blood pressure (BP) was measured before and after 16 days of treatment with benazepril (10 mg/day). The association between the A1166C gene polymorphism and the antihypertensive effect of benazepril was assessed by FBAT. The frequencies of alleles A and C were 95.1% and 4.9%, respectively. FBAT analysis revealed that the C allele was significantly associated with high baseline diastolic BP (Z = 2.041, p = 0.041), decreased systolic BP after treatment (Z = 2.549, p = 0.011), and decreased diastolic BP after treatment (Z = 2.320, p = 0.020).

Conclusion

Our results, determined using the FBAT, are the first evidence that the AT1R A1166C polymorphism may increase the antihypertensive effect of benazepril in patients with hypertension.     

Adverse effects from antidepressant treatment: randomised controlled trial of 601 depressed individuals

Rationale

Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment.

Objectives

To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment.

Methods

Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation.

Results

Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p?=?0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p?=?0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants.

Conclusions

The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects.     

Interactions of Everolimus and Sorafenib in Whole Blood Lymphocyte Proliferation

Purpose

Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of hematopoietic cells by targeting the mammalian target of rapamycin (mTOR). Sorafenib is a multikinase inhibitor that inhibits cell proliferation by arresting cells in the G0-G1 phase of the cell cycle. These agents are under investigation as combination therapy for various cancers. Because the two drugs individually inhibit lymphocyte proliferation, this study examined the effects of everolimus and sorafenib on lymphocyte proliferation in order to anticipate possible immunosuppression.

Methods

Inhibition of lymphocyte proliferation was evaluated ex vivo over a range of concentrations of these drugs, alone and in combination. Data analysis, using a population approach to characterize interactions, employed the Ariens noncompetitive interaction model, which was modified to accommodate interactions of the two drugs.

Results

Everolimus alone caused partial inhibition of lymphocyte proliferation, with a mean IC₅₀ of 4.5 nM for females and 10.5 nM in males. Sorafenib alone caused complete inhibition, with a mean IC₅₀ of 11.4 μM and no difference between genders.

Conclusion

The population estimate for the interaction term was greater than 1, suggesting that the two drugs exert slight antagonism in terms of inhibition of lymphocyte proliferation.