Use Of Fixed-dose Combinations Research Articles

The Wider Use of Fixed-Dose Combinations Emphasizes the Need for a Global Approach to Regulatory Guideline Development.

A fixed-dose combination (FDC) is a drug product in which two or more separate drug components (active pharmaceutical ingredients) are combined in a single-dosage form. Interest in developing FDCs is increasing in a range of diseases. This project investigated the regulatory environment for FDCs in the EU and US. A review of the FDC guidelines set forth by the EMA, FDA, and ICH, followed by interviews of key informants in industry, identified 5 main industry concerns related to development of FDCs. These concerns were presented to key informants from both the EU and US regulatory authorities. It was clear from the results that the current regulatory environment for FDCs lacks consistency. This may create a barrier to innovation moving from the laboratory to the clinic, as companies cannot clearly see the development path requirements. This project also highlighted certain challenges that currently face the regulatory world: how to improve the role of regulatory science and provide clear quantification in assessment decisions; the role of guidelines and their impact on innovation; and, most important, the question of globalization and how to move toward a more harmonized regulatory system.

Combination Therapy with Olmesartan/Hydrochlorothiazide to Improve Blood Pressure Control

Poor blood pressure (BP) control is a serious clinical problem, being responsible for much of the morbidity and mortality associated with arterial hypertension. Although European Society of Hypertension (ESH)/European Society of Cardiology (ESC) Guidelines for the management of arterial hypertension strongly recommend to pursue the primary therapeutic goal of BP control in the population of hypertensive patients, currently available data indicate that, in the western world, a large proportion of hypertensive patients have poor BP control. Relevant causes of poor BP control are clinical inertia, defined as failure of physicians to modify or intensify treatment of patients who do not achieve BP targets, and low patient adherence to the treatment. Improved BP control can be achieved by using appropriate antihypertensive drugs at adequate dosage and/or improving patients' adherence rate. In the majority of hypertensive patients, a combination of two or more antihypertensive drugs is nearly always necessary in order to achieve adequate BP control as recommended by current ESH/ESC Guidelines. In such cases, the use of fixed-dose combinations can significantly improve patient adherence, through the reduction of daily “pill-burden”. Olmesartan medoxomil (OM) is an antihypertensive agent belonging to the angiotensin II receptor antagonist (ARB) class which, in several clinical studies, has proved to be effective and well tolerated in the treatment of hypertensive patients. In patients in whom olmesartan medoxomil monotherapy fails to achieve the recommended BP goal, the combination of olmesartan medoxomil with the thiazide diuretic hydrochlorothiazide (HCTZ) can enhance the efficacy of the antihypertensive treatment (compared with placebo and monotherapy with either agent), thereby allowing a greater number of patients to achieve BP control. Combination therapy with OM/HCTZ has shown good efficacy and a favorable tolerability profile in a number of clinical trials. In this review, we will examine the evidence in the literature on this subject and advance suggestions on the most rational way to use this therapy in clinical practice.

Treatment of Drug Susceptible Pulmonary Tuberculosis.

Tuberculosis (TB) remains a major global health problem, and the incidence of TB cases has not significantly decreased over the past decade in Korea. The standard short course regimen is highly effective against TB, but requires multiple TB-specific drugs and a long treatment duration. Recent studies using late-generation fluoroquinolones and/or high-dose rifapentine-containing regimens to shorten the duration of TB treatment showed negative results. Extending the treatment duration may be considered in patients with cavitation on the initial chest radiograph and positivity in sputum culture at 2 months of treatment for preventing TB relapse. Current evidence does not support the use of fixed-dose combinations compared to separate drugs for the purpose of improving treatment outcomes. All patients receiving TB treatment should be monitored regularly for response to therapy, facilitation of treatment completion, and management of adverse drug reactions. Mild adverse effects can be managed with symptomatic therapy and changing the timing of the drug administration, but severe adverse effects require a discontinuation of the offending drugs.

Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and hydrochlorothiazide in clinical practice.

BackgroundClinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice.MethodsThis multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC.ResultsThe mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of <140/90 mmHg was attained in 67.5% of patients. At least one adverse drug reaction (ADR) was experienced by 1.2% of patients, with the most common being peripheral edema. Subanalyses demonstrated that the following factors did not have a significant influence on the ADR rate: age (<65 years versus ≥65 years), diabetes mellitus (no/yes), cardiovascular risk (low/high), and concomitant medication (no/yes).ConclusionThis study demonstrates that in clinical practice, treatment with the three-drug combination as an FDC tablet resulted in a very high proportion of patients with a BP response and control, accompanied by a very low rate of ADRs.

Fixed-Dose Combination Therapy in Type 2 Diabetes Mellitus

The management of type 2 diabetes mellitus (T2DM) often requires combinations of antihyperglycemic medications with complementary mechanisms of action. Inadequate adherence to combination therapy, possibly related to pill burden (greater number of pills and higher administration frequency) and poor tolerability, may lead to suboptimal clinical outcomes. One potential means of addressing these problems is the use of fixed-dose combinations (FDCs) that simplify the treatment regimen by reducing pill burden compared with the same combination delivered as separate pills. The present study evaluates the efficacy and tolerability of FDCs in the treatment of T2DM patients and provides an overview of dosing, costs, and adherence. A review of FDCs, with particular attention to those that contain metformin extended-release (XR) and allow once-daily dosing. Many FDCs contain metformin as one of the component drugs. However, the standard immediate-release (IR) formulation of metformin requires twice-daily dosing and may have tolerability problems related to adverse gastrointestinal (GI) effects. The XR formulations of metformin can be administered once daily and have been shown to reduce the occurrence of GI effects frequently observed with metformin IR; consequently, they may have significant advantages for inclusion in FDCs. The long-term cost-effectiveness of FDCs remains to be fully determined. For patients taking metformin, FDCs containing metformin XR offer equivalent efficacy with reduced dose frequency and, potentially, fewer GI events compared with standard IR formulation, as well as a reduced number of pills compared with separate-pill regimens. By reducing pill burden and improving tolerability, FDCs may improve adherence.

Оценка эффективности фиксированной комбинации бисопролола и амлодипина в амбулаторном лечении больных артериальной гипертензией и ишемической болезнью сердца

To evaluate the efficacy and safety of a fixed-term combination of β-blocker bisoprolol and the calcium antagonist amlodipine in the outpatient treatment of patients with arterial hypertension (AH) and coronary heart disease (CHD). The study involved 100 patients with hypertension 1-3 first degree and CHD, which previous antihypertensive therapy was ineffective or irregular. Inclusion in the treatment regimen of amlodipine was associated with significant decrease in blood pressure (BP) with the achievement of the target level of systolic blood pressure of 90%, diastolic blood pressure--in 97% of cases after 4 weeks treatment. Analysis of the dynamics of the heart rate during the visits to the doctor and the patient diary data revealed a significant slowing on the background of the therapy, which is important for patients with coronary artery disease. In carrying out daily monitoring of ECG Holter dynamics observed a decrease in the average duration of episodes of depression segment ST on 50.5% (p < 0.05) and the number of ischemic episodes at 54.8% (p < 0.05). The use of fixed-dose combination of bisoprolol and amlodipine allowed to increase the compliance of patients with treatment 2.2 times.

Ramipril/amlodipine single pill – Effectiveness, tolerance and patient satisfaction with antihypertensive therapy in relation to nutritional status

BackgroundOverweight and obesity decrease the effectiveness of antihypertensive therapy despite the more frequent use of polytherapy. One method for improving therapy effectiveness is by decreasing non-compliance with the use of fixed-dose combinations (FDC).The aim of this study was to assess the effectiveness, tolerance, and satisfaction with ramipril/amlodipine FDC antihypertensive therapy in relation to nutritional status. MethodsThe survey enrolled 24,240 hypertensive patients recently switched to ramipril/amlodipine FDC (EGIRAMLON) at the same doses as previously prescribed separate pills. ResultsThe effectiveness of antihypertensive therapy increased during follow-up from 32.9% to 76.5%. Overweight and obesity were associated with the increased risk of not attaining the recommended BP values [adjusted for age OR=0.74 (95% CI 0.67–0.83) and 0.70 (0.61–0.81) for overweight; 0.54 (0.47–0.60) and 0.49 (0.42–0.57) for obese, at the first and the second examination, respectively].“Very good” or “good” the FDP tolerance was reported by 98.8%, 97.6% and 96.4%, respectively.Adverse events (AE) were reported in 0.35% of patients regardless of nutritional status.High levels of satisfaction with the FDC were reported by 57.0% of patients with normal weight, 54.5% of overweight, and 50.6% with obesity. Effectiveness and convenience were the most important for patients. ConclusionsThe effectiveness of therapy with ramipril/amlodipine FDC in the study population was high, but slightly lower in overweigh and obese. This FDC was well tolerated and a significant number of patients satisfied with the therapy regardless of nutritional status. Although the perceived tolerance and satisfaction with treatment were lower in obese and overweight than in normal weight patients; the incidence of AE and perceived benefit from the use of a single-pill, compared to multiple tablets, were comparable irrespective of nutritional status.

An overview of fixed-dose combinations of antihypertensive drugs in South Africa

Hypertension is a pressing global health issue, contributing to an increase in cardiovascular risk, as well as being the most common condition seen in South Africa. Lack of compliance with the prescribed therapy is one of the largest obstacles to achieving goal blood pressure in antihypertensive patients. The complexity of the drug therapy is a very important factor that is associated with noncompliance, as most patients require treatment with two or more drugs. The use of fixed-dose combination (FDC) therapy has various advantages, including simplification of the regimen, resulting in improved adherence. However, there are also disadvantages, e.g. the inability to provide individualised dose flexibility. This article provides an overview of available FDC therapy for hypertension in South Africa and the rational use thereof, by taking into account each combination’s complementary action, efficacy, safety and tolerability.

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting β2-agonist and an inhaled corticosteroid, and combinations of long-acting β2-agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of "triple-inhaler" fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called "bifunctional drugs". In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/anti-inflammatory drugs and bifunctional anti-inflammatory drugs.

Abstract P445: A Randomized Controlled Trial Of A Cardiovascular Fixed-dose Combination Pill (polypill) Treatment Strategy Compared With Usual Care On Carotid Intima Media Thickness Progression In Individuals At High Risk Of Cardiovascular Disease

Aim: The use of fixed-dose combination (FDC) pills, frequently called polypills, containing aspirin, a statin and blood pressure (BP) lowering medication may improve medication adherence and consequently reduce cardiovascular risk. Carotid intima-media thickness (CIMT) and CIMT progression have been used as surrogate measures of cardiovascular risk. This study evaluated the effect of a polypill-based treatment strategy compared to usual care on CIMT progression. Methods: A study nested within the UMPIRE trial was performed to assess whether a polypill-based treatment strategy reduces CIMT progression compared to usual care. The study was a randomized, open label, blinded endpoint clinical trial in participants with established cardiovascular disease or at equivalent high risk (estimated five year cardiovascular risk of ≥15%). Two versions of the polypill were available. These contained aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide. The choices of polypill version and the components of usual care were made at the discretion of the physician. (http://clinicaltrials.gov/show/NCT01326676). Results: In total 296 participants in the polypill group and 290 participants in the usual care group had both a baseline and follow-up CIMT scan. Allocation to a polypill compared to usual care resulted in similar levels of low-density lipoprotein (LDL)-cholesterol (mean difference: 0.0 mmol/L; 95%-confidence interval (CI): -0.1 to 0.1; p=0.41) and systolic BP (mean difference -1.7 mmHg; 95%-CI:-4.5 to 1.1; p=0.23) after a median follow-up duration of 1.00 year [IQR: 0.93 to 1.04 year]. The annualized rate of change in common CIMT in the polypill-based treatment strategy group (6.56 μm/year; standard error (SE): 4.76 μm/year) did not differ significantly from the rate of change in the usual care group (10.72 μm/year; SE: 4.76 μm/year; mean difference: -4.2 μm/year; 95%-CI: -17.0 to 8.7; p=0.53). Conclusion: This study demonstrated that a polypill-based cardiovascular treatment strategy compared to usual care did not reduce the rate of progression of common CIMT during a one year follow-up interval in a well-treated population with cardiovascular disease. Importantly, CIMT progression was not adversely effected by the polypill-based treatment strategy.

Effectiveness and tolerability of fixed dose combination of amlodipine/valsartan in treatment of hypertension in the real-life setting among Egyptian patients

Introduction Many hypertension international guidelines recommend the use of fixed-dose combination of antihypertensive therapies as a first- line in high-risk hypertensive patients, in whom more rapid and pronounced blood pressure (BP) control is desired. The aim of this study was to evaluate the effectiveness, safety and tolerability of the single-pill combination of amlodipine/valsartan among Egyptian patients with arterial hypertension in a real-life setting. Method This prospective, open-label, multi-center, non-comparative post-marketing surveillance study enrolled adults with arterial hypertension (systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg) treated with single-pill combination (SPC) of amlodipine/valsartan; 5/160 mg or 10/160 mg once daily dose. Patients were observed over a 3-months period with approximately monthly intervals between clinic visits. Primary objectives were comparison of systolic and diastolic blood pressure and heart rate at study start and after 12 weeks of therapy. Secondary objectives were evaluation of the blood pressure lowering effect in terms of response rates, evaluation of safety and tolerability of study medication. Results A total of 2489 patients were enrolled and 2357 completed the study. Mean age was 54 years and 85% of patients had received prior antihypertensive therapy. At study end, a significant mean BP reduction of −39.4/−21.7 mmHg (baseline: 171.5/103.4 mmHg; p 0.001) was seen in the overall population. The corresponding mean BP reduction for patients on amlodipine/valsartan 5/160 mg was −34.6/−19.2 mmHg (baseline: 166/101 mmHg; p 0.001) and for patients on amlodipine/valsartan 10/160 mg was −47.1/−24.3 mmHg (baseline: 178.6/106.4 mmHg; p 0.001). In a post-hoc analysis for subgroups with important co-morbid conditions, the corresponding mean BP reductions were: patients with diabetes; −41.1/−21.6 mmHg (baseline 173.2/103.5 mmHg; p = 0.00001), patients with history of heart failure; −45.2/−22.8 mmHg (baseline 175.9/104.6 mmHg; p = 0.00001), patients with history of coronary heart diseases; −43/22.7 mmHg (baseline: 175.8/105 mmHg; p = 0.00001). A small change in the heart rate was noticed (82 bpm at baseline and 78.4 bpm at the end of study; p 0.001). 70.3% of patients had their blood pressure controlled (BP 140/90 mmHg). Subjective investigators assessment as “excellent to very good” for amlodipine/valsartan SPC was 97.3% for effectiveness and 96.8% for tolerability. The corresponding investigators and patients assessment for compliance was 96.6% and 93.3% respectively. Adverse events were reported in 4.4% of patients mainly due to edema in 3.6%. Amlodipine/valsartan SPC was generally well tolerated. Conclusion The Results of this study showed that Single-pill combination of amlodipine/valsartan effectively reduced BP among Egyptian hypertensive patients with high tolerability profile and provided evidence that most of hypertensive patients may benefit from this combination.

Temporal changes in antihypertensive prescribing trend in Bahrain over a decade: emerging issues in iatrogenic sexual dysfunction

To elucidate temporality of antihypertensive drug prescribing trends over a decade in terms of emerging views on iatrogenic sexual dysfunctions (SD). The antihypertensive prescribing trend in 2007 was compared with baseline data collected in 1998 using prescription audit. Angiotensin converting enzyme (ACE) inhibitors were deemed first and second ranked antihypertensives for patients with diabetic hypertension and hypertension in 2007, respectively. Between 1998 and 2007 β-blockers such as atenolol, and methyldopa use has declined in both male and female patients. In 2007, the rate of prescribing atenolol at inappropriately high doses has declined as compared to 1998, especially in males. Methyldopa overall use has declined in 2007, although it is often prescribed to females. Compared to baseline of 1998 there was a significant upturn in diuretic use. Nonetheless the trend towards prescribing indapamide ≤ 1.5 mg/day and 12.5 mg/day hydrochlorothiazide, at doses least likely to cause SD, was evident in both male and females. This trend appears to be related to the use of fixed-dose combinations (FDCs) and antihypertensive combination therapies which have significantly increased in recent years (p < 0.0001). With respect to the prescribing rate and dose appropriateness, antihypertensives that are likely to cause SD appear to be more rationally prescribed in 2007 as compared to 1998. Introducing FDCs had an important role in resurgence of appropriate low dose of drugs implicated with SD and diuretic-based antihypertensive combination therapies.

Comprehensive Glaucoma Management – Novel Insights

The satellite symposium ‘Comprehensive Glaucoma management – Novel Insights’ was convened at the 2014 European Glaucoma Society Congress and included presentations from four experts who identified several factors in current practice for the assessment and treatment of glaucoma and provided valuable solutions to potentially improve outcomes. In glaucoma, there are multiple risk factors associated with disease progression: some cannot be controlled (e.g. age and the extent of existing glaucoma damage); others such as ocular perfusion pressure can be determined and sometimes influenced. The use of 24-hour intraocular pressure (IOP) monitoring provides a much more complete assessment of the effects of glaucoma treatments than is possible with single IOP measurements and adds to the clinical evaluation. Various eye medications for use in glaucoma contain benzalkonium chloride (BAK), which is known to cause superficial inflammation. The extent of BAK penetration into deep ocular tissue and associated damage is only now being realised with the use of novel chemical and imaging techniques. These findings highlight the importance of preservative-free medications. Treatment of glaucoma is also being improved with the use of fixed-dose combinations of molecules that facilitate treatment and, in terms of IOP lowering, are non-inferior to medications used separately. These improvements in glaucoma management are therefore likely to improve understanding of disease status, improve efficacy and ultimately decrease the risk of vision loss.

Characterization of a new degradation product of nifedipine formed on catalysis by atenolol: A typical case of alteration of degradation pathway of one drug by another

An increasing interest is being shown throughout the world on the use of fixed-dose combinations of drugs in the therapy of select diseases, like cardiovascular diseases, due to their multiple advantages. Though the main criterion for combining drugs in a single dosage form is the rationale, but consideration like stability of formulation is equally important, due to an added aspect of drug–drug interaction. The objective of this study was to evaluate interaction among the drugs in an antihypertensive combination of nifedipine and atenolol. Nifedipine is a known light sensitive drug, which degrades via intra-molecular mechanisms to nitro- and nitroso-pyridine analogs, along with a few minor secondary products that are formed through inter-molecular interactions amongst primary degradation products and their intermediates. Atenolol is reasonably stable weakly basic drug that is mainly hydrolyzed at acetamide terminal amide moiety to its corresponding carboxylic acid. To the best of our knowledge, there is no known information on chemical compatibility among the two drugs. The present study involved subjecting of nifedipine, atenolol and their combination to a variety of accelerated and stress conditions. HPLC studies revealed formation of a new product in the mixture of two drugs (∼2%), which was also generated from nifedipine alone, but at trace levels (<0.1%). The product was isolated by preparative chromatography and subjected to indepth studies for its characterization. Ultra-violet, FT-IR, mass spectrometric and nuclear magnetic resonance spectroscopic studies highlighted that the principal photo-degradation pathway of nifedipine was modified and diverted in the presence of atenolol. To verify the same, a study was conducted employing two other β–blockers with similar structures to atenolol, and the same product was formed in relatively higher quantity therein also. The new product is postulated to be produced as a result of rearrangement of hydroxylamine intermediate, known to be involved in the generation of nitro- and nitroso-pyridine photo-degradation products of nifedipine.

Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD

Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012. Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups. Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. clinicaltrials.gov Identifier: NCT01057537.

Évolution dans l’usage des traitements antihypertenseurs en France entre 2002 et 2012 : enquêtes FLAHS

ObjectiveTo evaluate from studies conducted between 2002 and 2012, trends in the use of antihypertensive drugs in France. MethodFrench League Against Hypertension Survey (FLAHS) were conducted in a representative sample of subjects aged 35 and over living in France. A list including the names for all antihypertensive drugs marketed at the time of each survey made it possible to detail drug therapies employed. Data analysis has taken the patient as a unity. The data obtained in 2002, 2007 and 2012 are subject to this analysis. ResultsIn 2012, 30% of the French population aged 35 and older was treated with antihypertensive drugs (11.4 million), while 24% were treated in 2002 (8.2 million). On average, prescription of antihypertensive included 1.4±0.7 pills in 2002, 1.5±0.8 in 2007 and 1.8±0.9 in 2012, which corresponds to a pharmacological monotherapy prescribed in 47% of subjects in 2012, a different percentage than in 2007 (46%) and 2002 (56%). Over the period, the percentage of prescriptions of diuretics (41% to 42%) and ACE inhibitors (24% to 23%) and beta-blockers (35% to36%) is stable, but they are increasing with ARBs (23% to 47%) and calcium antagonists (24% to 34%). The prescriptions of fixed-dose combinations were also increased (19% to 30%). In 2012, fixed-dose combinations included a diuretic (79%), an ARB (65%), an ACEI (23%) and a calcium antagonist (20%). Blood pressure control estimated with home blood pressure monitoring increases from 38% in 2002 to 50% in 2007 and 2012. ConclusionChanges in the use of antihypertensive drugs in France between 2002 and 2012 led to the prescription of antihypertensive treatment with associations in the majority. ARBs or ACEI are present on 70% of prescriptions with diuretics combined in 80%. Extensive use of fixed-dose combinations with diuretics and ARA2 characterizes this period in which it was observed an increase in blood pressure control in France.

Combination Therapy in Hypertension

Hypertension is recognized as a major risk factor for cardiovascular and renal diseases and represents the leading cause of mortality worldwide. In spite of proven benefits of hypertension treatment, blood pressure control rates are poor, even in high-income countries with virtually full-access to therapies. Nearly 75% of hypertensive patients do not achieve adequate control with monotherapy, thus needing combination treatment. Strategies to improve blood pressure control include the prompt shift from monotherapy to combination therapy, the initial treatment with a two-drug combination, and the use of fixed-dose combinations in a single pill. Currently, preferred combinations include a renin-angiotensin blocker, either an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker plus a calcium channel blocker or a diuretic. Some patients will also require a triple combination to achieve blood pressure control.

Dynamic View on Affordability of Fixed-Dose Combination Antihypertensive Drug Therapy

The use of fixed-dose combinations (FDCs) has been increasing since the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended using ≥2 drugs as the first-line drug therapy for patients with stage 2 hypertension. FDCs simplify the drug therapy regimen and reportedly lower the drug therapy cost compared with the free combination (FC) of 2 single-agent drugs. This study hypothesized that the affordability of FDCs over FCs would change over time depending on the availability of generic single-agent drugs. This study used the 2009 Medical Expenditure Panel Survey. Antihypertensive drugs were identified based on the Food and Drug Administration national drug directory. Based on the 2 databases, regression models were run to predict average monthly drug cost as well as out-of-pocket cost for each prescription along with their 95% confidence intervals (CIs). Overall, FDCs (n = 26) had average monthly drug costs similar to respective FCs when FCs were not generically available. However, when FCs were generically available, FDCs (n = 11) had average drugs costs much higher than their respective FCs. For example, Lotrel as an FDC had an average monthly drug cost of $115.97 (95% CI = $96.59-$135.36), whereas its counterpart FC had an average monthly drug cost of $21.00 (95% CI = $18.23-$23.79). The cost advantage of FDCs over FCs was reversed when FCs were generically available. The finding of this study informs patients, health-care providers, and drug plans of the importance of making dynamic decisions on preferred drug therapy options depending on the availability of generic drugs.

Improve adherence to antihypertensive therapy by using fixed-dose combinations

Suboptimal blood pressure control is common, with poor patient compliance contributing to its development. Compliance may be improved by simplifying antihypertensive treatment (e.g. by reducing the pill burden through the use of fixed-dose combinations).

How do Compliance, Convenience, and Tolerability Affect Blood Pressure Goal Rates?

Uncontrolled hypertension imposes a substantial global health burden, and poor patient compliance with prescribed antihypertensive medication makes a major contribution to the development of suboptimal blood pressure (BP) control. The asymptomatic nature of hypertension, side effects of medication, treatment complexity, and high pill burdens all have a negative impact on patient compliance. It is important to address the issue of poor patient compliance as studies have shown that good compliance is associated with improvement of BP control and positive health outcomes. As the majority of hypertensive patients require treatment with two or more agents to achieve goal BP, treatment guidelines have acknowledged the value of simplifying treatment through the use of fixed-dose combination (FDC) therapy. Triple FDC therapy comprising an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker), calcium channel blocker, and thiazide diuretic is a novel treatment strategy for the improvement of BP control in hard-to-treat patients.