Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM-HF.

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.

The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: Findings from the CSPPT.

OBJECTIVE: In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. METHODS: This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). RESULTS: During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (ß = -1.31, P < 0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (ß = -2.79, P < 0.001 for CC homozygotes compared with ß = -0.56, P = 0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction = 0.034). CONCLUSION: In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.

[Experience and comparison of antihypertensive effect of ace inhibitor spirapril and calcium antagonist amlodipinein standard and chronotherapeutic prescription mode].

Arterial pressure is an effect of many physiologic processes of organism effected by daily rhytmus. The introduction of round the 24-hour monitoring of arterial pressure enabled to detect arterial pressure circular fluctuation. Chronotherapy with the application of amlodipin and spirapril due to the data of round the 24-hour arterial pressure monitoring increases the effectiveness of antihypertensive therapy.

Impaired Corneal Sensation and Nerve Loss in a Type 2 Rat Model of Chronic Diabetes Is Reversible With Combination Therapy of Menhaden Oil, α-Lipoic Acid, and Enalapril.

PURPOSE: This study investigated the efficacy of monotherapy versus combination of menhaden oil, α-lipoic acid, and enalapril on corneal sensation and morphometry and other neuropathy-related endpoints in a rat model of type 2 diabetes. METHODS: Male Sprague-Dawley rats (aged 12 weeks) were fed a high-fat diet for 8 weeks followed by 30 mg/kg streptozotocin. After 16 weeks of hyperglycemia, 12-week treatments consisting of menhaden oil, α-lipoic acid, enalapril, or their combination were initiated. Before and after treatments, we performed analyses of multiple neural and vascular endpoints including corneal sensitivity, corneal nerve density, vascular reactivity of epineurial arterioles, motor and sensory nerve conduction velocity, intraepidermal nerve fiber density, and thermal nociception. RESULTS: Before treatment, all the neural and vascular endpoints in diabetic rats were impaired. Treating diabetic rats with monotherapy was effective in improving neural and vascular deficits with menhaden oil being most efficacious. However, the combination therapy provided the greatest benefit and improved/reversed all nerve and vascular deficits. The effect of combination therapy on corneal relative sensitivity and structure (in mm/mm), primary endpoints for this study, for control, diabetic, and diabetic treated rats was 4.2 ± 1.4 and 7.5 ± 0.5, 12.1 ± 1.3* and 3.8 ± 0.2*, and 6.6 ± 2.3 and 7.3 ± 0.5, respectively (*P < 0.05 compared with control rats; P < 0.05 compared with diabetic rats). CONCLUSIONS: These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention.

BACKGROUND AND PURPOSE: Elevated blood homocysteine concentration increases the risk of stroke, especially among hypertensive individuals. Homocysteine is largely affected by the methylenetetrahydrofolate reductase C677T polymorphism and folate status. Among hypertensive patients, we aimed to test the hypothesis that the association between homocysteine and stroke can be modified by the methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. METHODS: We analyzed the data of 20 424 hypertensive adults enrolled in the China Stroke Primary Prevention Trial. The participants, first stratified by methylenetetrahydrofolate reductase genotype, were randomly assigned to receive double-blind treatments of 10-mg enalapril and 0.8-mg folic acid or 10-mg enalapril only. The participants were followed up for a median of 4.5 years. RESULTS: In the control group, baseline log-transformed homocysteine was associated with an increased risk of first stroke among participants with the CC/CT genotype (hazard ratio, 3.1; 1.1-9.2), but not among participants with the TT genotype (hazard ratio, 0.7; 0.2-2.1), indicating a significant gene-homocysteine interaction (P=0.008). In the folic acid intervention group, homocysteine showed no significant effect on stroke regardless of genotype. Consistently, folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes and high homocysteine levels (tertile 3; hazard ratio, 0.73; 0.55-0.97). CONCLUSIONS: In Chinese hypertensive patients, the effect of homocysteine on the first stroke was significantly modified by the methylenetetrahydrofolate reductase C677T genotype and folic acid supplementation. Such information may help to more precisely predict stroke risk and develop folic acid interventions tailored to individual genetic background and nutritional status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial.

The relationship of folic acid supplementation with the risk of cancer remains inconclusive. We aimed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infarction (MI) in the China Stroke Primary Prevention Trial (CSPPT). A total of 20,702 hypertensive adults without history of stroke or MI, stratified by MTHFR C677T genotypes(CC, CT and TT), were randomly assigned to receive double-blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348) or a pill containing 10 mg enalapril alone(n = 10,354). During a median treatment duration of 4.5 years, cancer occurred in 116 participants(1.12%) in the enalapril-folic acid group versus 116 participants(1.12%) in the enalapril group (HR, 1.00; 95%CI, 0.77-1.29). There was also no significant difference in the HRs for specific types of cancer(esophageal, gastric, breast, lung, colorectal, head and neck, liver and gynecologic cancer or lymphoma) or cancer mortality(HR, 1.05; 95%CI, 0.69-1.58). For participants not receiving folic acid treatment (enalapril only group), MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype (HR, 1.86; 95%CI, 1.07-3.22). Consistently, a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels (<9.0 ng/mL; HR, 0.47; 95%CI, 0.24-0.94). There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China. Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels.

Folic Acid Therapy Reduces the First Stroke Risk Associated With Hypercholesterolemia Among Hypertensive Patients.

BACKGROUND AND PURPOSE: We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a subanalysis using data from the CSPPT (China Stroke Primary Prevention Trial), a double-blind, randomized controlled trial. METHODS: A total of 20 702 hypertensive adults without a history of major cardiovascular disease were randomly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. The primary outcome was first stroke. RESULTS: The median treatment duration was 4.5 years. For participants not receiving folic acid treatment (enalapril-only group), high total cholesterol (≥200 mg/dL) was an independent predictor of first stroke when compared with low total cholesterol (<200 mg/dL; 4.0% versus 2.6%; hazard ratio, 1.52; 95% confidence interval, 1.18-1.97; P=0.001). Folic acid supplementation significantly reduced the risk of first stroke among participants with high total cholesterol (4.0% in the enalapril-only group versus 2.7% in the enalapril-folic acid group; hazard ratio, 0.69; 95% confidence interval, 0.56-0.84; P<0.001; number needed to treat, 78; 95% confidence interval, 52-158), independent of baseline folate levels and other important covariates. By contrast, among participants with low total cholesterol, the risk of stroke was 2.6% in the enalapril-only group versus 2.5% in the enalapril-folic acid group (hazard ratio, 1.00; 95% confidence interval, 0.75-1.30; P=0.982). The effect was greater among participants with elevated total cholesterol (P for interaction=0.024). CONCLUSIONS: Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke. Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31% among hypertensive adults without a history of major cardiovascular diseases. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Bartter Syndrome with Normal Aldosterone Level: An Unusual Presentation.

Bartter syndrome (BS) is a hereditary disease, with an autosomal recessive or autosomal dominant mode of transmission. It is characterized by salt wasting hypochloraemic, hypokalaemic metabolic alkalosis and hyperreninaemia with normal blood pressure. The primary defect is in the thick ascending limb of loop of Henle (TAL). Herein, we report a case that had typical features of BS like severe dehydration, severe hypokalaemia, metabolic alkalosis and failure to thrive but had normal aldosterone level which is very uncommon.

Effect of combination therapy consisting of enalapril, α-lipoic acid, and menhaden oil on diabetic neuropathy in a high fat/low dose streptozotocin treated rat.

We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping of blood pressure during night time: protocol for a randomised, placebo-controlled, double-blind, two-way crossover study.

INTRODUCTION: Cardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes. MATERIALS AND METHODS: In a randomised, double-blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass. ETHICS AND DISSEMINATION: The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT (2012- 002136-90).

Investigating the cardio-protective abilities of supplemental L-arginine on parameters of endothelial function in a hypercholesterolemic animal model.

Endothelial dysfunction is now widely recognized as an early marker of cardiovascular disease, making its treatment, or complete avoidance, an emerging, interesting therapeutic target. This study investigated the ability of the highly intriguing amino acid L-arginine to influence endothelial function. Its therapeutic potential is also compared to that of known cardiovascular medications, namely nitroglycerin [a nitric oxide (NO) donor] and enalapril [an angiotensin-converting enzyme (ACE) inhibitor]. Fifty male New Zealand rabbits were included in the study, divided into 5 equal groups: control, hypercholesterolemia (untreated), hypercholesterolemia (+L-arginine), hypercholesterolemia (+enalapril), and hypercholesterolemia (+nitroglycerin). Biochemical investigations included measurement of circulating NOx, malondialdehyde (MDA), and lipid profile markers, as well as dimethylarginine dimethylaminohydrolase (DDAH) and ACE activities. Furthermore, aortic ACE activity and blood platelet aggregation were estimated. A histopathological examination and intimal thickness measurement were also conducted. Compared to the untreated hypercholesterolemic group, all agents were capable of positively influencing MDA levels, platelet aggregation and intimal thickness; however, only the L-arginine group was capable of beneficially and significantly altering both NOx levels and serum and aortic ACE activities. No agents were capable of modulating serum DDAH activity inhibited by hypercholesterolemia. Based on the results of this study, L-arginine appears to be a novel cardio-protective agent, illustrated by its ability to ameliorate the deleterious effects of hypercholesterolemia on endothelial function, in a manner comparable to, and sometimes more potent than, commonly used cardiovascular medications.

[The application of combined physiotherapeutic methods for the complex treatment of patients with dyscirculatory encephalopathy].

This article reports the results of applying basic pharmacotherapy (enalapril, cytoflavin) and its combination with physical factors (transcranial electrostimulation, combined application oftranscranial electrostimulation and low-frequency magnetic therapy) in the complex treatment of patients with stage I-II dyscirculatory encephalopathy. The study has demonstrated that the combined treatment with cytoflavin, enalapril, transcranial electrostimulation and low-frequency magnetic therapy produced the most pronounced therapeutic effect (82.5%), as confirmed by positive dynamics of clinical and functional parameters.

MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults.

BACKGROUND: This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults. METHODS: A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks. RESULTS: After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989). CONCLUSIONS: This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.

Combination delapril/manidipine as antihypertensive therapy in high-risk patients.

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.

[Assessment of the results of 24-hour arterial pressure monitoring in patients with arterial hypertension treated with fixed combinations of co-renitec and gyzaar with and without acupuncture reflexotherapy].

This study has demonstrated that the treatment of patients with grade II-III arterial hypertension using fixed combinations of corinetec and gyzaar supplemented by acupuncture reflexotherapy resulted in a significantly more pronounced decrease of daily monitored arterial pressure than in patients who received the drug therapy without acupuncture.

Rationale for the use of a fixed-dose combination in the management of hypertension: efficacy and tolerability of lercanidipine/enalapril.

Hypertension, a significant factor in the development of cerebrovascular disorders, heart disease and renal failure, is a common disorder worldwide. Despite the availability of a wide range of antihypertensive agents, almost two-thirds of hypertensive patients have poorly controlled blood pressure (BP). Numerous clinical trials have shown that most patients require at least two antihypertensive agents to achieve adequate BP control and associated significant reductions in cardiovascular morbidity and mortality. Combination therapy using two drugs with different, complementary mechanisms of action achieves better efficacy and tolerability outcomes than treatment with either component drug alone. When such a combination is administered as a fixed-dose formulation, other benefits, such as improved compliance and potentially lower costs, are also likely. The good efficacy and tolerability of the combination of a calcium channel antagonist and an angiotensin-converting enzyme inhibitor is well established, and this combination is recommended by European Society of Hypertension/European Society of Cardiology guidelines as a first choice in high-risk hypertensive patients, including those with type 2 diabetes mellitus. Lercanidipine/enalapril is a promising example of a fixed-dose combination of these drug classes. In clinical trials in hypertensive patients, including those with type 2 diabetes, lercanidipine/enalapril improved BP to a greater extent than either drug as monotherapy (in patients who were previous non-responders to lercanidipine or enalapril) or the combination of lercanidipine/hydrochlorothiazide, and was equally well tolerated. Further studies are required to evaluate the cardiovascular protective effects of lercanidipine/enalapril.

Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial.

BACKGROUND: The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven. METHODS: We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160-219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment. RESULTS: During the double-blind trial, adding enalapril to nitrendipine (n = 515), compared with the equivalent combination of placebos (n = 559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P = 0.0035) and heart failure by 66% (P = 0.032), with similar trends for stroke (-51%; P = 0.066) and cardiac events (-44%; P = 0.075). Over the whole duration of follow-up, combination therapy (n = 871), compared with nitrendipine monotherapy (n = 1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (-32%; P = 0.023), with similar trends for all cardiovascular events (-23%; P = 0.081) and stroke (-42%; P = 0.054). CONCLUSION: Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy.

Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

BACKGROUND AND OBJECTIVE: Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. METHODS: This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP (<140/90 mmHg for nondiabetic patients, or <130/85 mmHg for diabetic patients); 'response' meant controlled BP, or a decrease in SBP of > or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. RESULTS: Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of 71.1% of the patients presented at least one clinical cardiovascular risk factor other than hypertension, with the most frequent being dyslipidaemia (42.3%), obesity (29.2%) and diabetes (23.9%). After 3 months of treatment, SBP and DBP showed mean (+/- SD) decreases of 26.5 (+/- 14.4) mmHg and 14.9 (+/- 9.0) mmHg, respectively, and 73.0% of patients responded to treatment while 40.9% achieved BP control (70.8%/36.1% in 2658 patients aged >65 years; 61.7%/46.8% in 1521 patients with diabetes; 55.3%/44.2% in 731 patients with ISH; 72.0%/36.4% in 1762 obese patients). Adverse events were reported in 10.8% of patients (n = 689). During the follow-up period, ten patients died and seven patients had serious adverse events; in no case was a causal relationship attributed to the study product. CONCLUSIONS: The rate of SBP/DBP control achieved demonstrates the effectiveness of the fixed-dose enalapril/nitrendipine 10 mg/20 mg combination administered as a single daily dose in patients with essential hypertension not adequately controlled with monotherapy or with any combination other than enalapril + nitrendipine. The proportion and type of adverse events reported were as expected and have already been described for both components of the enalapril/nitrendipine 10 mg/20 mg combination. These results confirm the effectiveness of a strategy based on a fixed-dose enalapril/nitrendipine 10 mg/20 mg combination in reducing BP and achieving BP control goals.

The role of fixed-dose combinations in the management of hypertension: focus on lercanidipine-enalapril.

Achieving optimal blood pressure (BP) control is the most important single issue in the management of hypertension, and in most patients, it is difficult or impossible to achieve target levels with one drug. Blocking two or more regulatory systems provides a more effective and more physiologic reduction in BP, and current guidelines have recommended the use of combination therapy as first-line treatment, or early in the management of hypertension. Fixed-dose combination therapy is an efficacious, relatively safe and cost-effective treatment option in most patients with essential hypertension. Of note, the once-daily administration of a fixed-dose enalapril/lercanidipine, by bringing together two distinct and complementary mechanisms of action, reduces BP effectively and has the potential for improved target organ protection relative to either class agent alone.