BACKGROUND:

Most hypertensive patients need more than one agent to achieve blood pressure (BP) control. The fixed dose combinations can provide effective 24-h BP control, which is essential in hypertension management.

AIMS:

The primary objectives of the PErindopril/Amlodipine Reduction of blood pressure Level (PEARL) ABPM substudy were to assess the effect of a perindopril/amlodipine fixed-dose combination on mean 24-h BP, daytime BP, and nighttime BP in a subgroup of PEARL patients. Secondary objectives included assessment of office BP, metabolic parameters (blood glucose and lipids), heart rate, and safety and tolerability.

METHODS:

PEARL was a 3-month observational study with a perindopril/amlodipine fixed-dose combination for treatment of outpatients with essential hypertension uncontrolled by prior treatment (office BP ≥140/90 mmHg or ≥130/80 mmHg in those at high/very high cardiovascular risk). In this ABPM substudy of PEARL, treatment efficacy was assessed by 24-h ABPM. At inclusion, previous angiotensin-converting enzyme (ACE) inhibitors and/or calcium channel blockers (CCBs) were replaced by a perindopril/amlodipine fixed-dose combination at a dosage (5/5, 5/10, 10/5, or 10/10 mg) chosen by the physician and uptitrated at month 1, if required. ABPM and office BP measurements were assessed at inclusion, month 1, and month 3. Metabolic effects, heart rate, and adverse events were also monitored.

RESULTS:

Mean age of the 262 ABPM patients (144 males) was 60.4 ± 11.7 years, and mean baseline office brachial systolic BP/diastolic BP was 159.8 ± 16.0/94.3 ± 10.3 mmHg. After 3 months, the perindopril/amlodipine fixed-dose combination reduced mean 24-h ambulatory BP from 146.1/84.3 to 127.6/75.9 mmHg (p < 0.001). Mean office BP decreased to 131.1/80.0 mmHg (p < 0.001). Results were consistent in subgroups, defined by cardiovascular comorbidities or previous treatments. Favorable metabolic and heart rate effects were observed, and no serious adverse events were reported.

CONCLUSIONS:

Further effective, safe, and sustained 24-h ambulatory BP and office BP reductions were obtained by switching from ACE inhibitors and/or CCBs to a perindopril/amlodipine fixed-dose combination in outpatients with uncontrolled essential hypertension in a practice setting. For this type of patient, the use of a perindopril/amlodipine fixed-dose combination can be considered an effective and safe option to normalize BP.

The use of multiple drug regimens is increasingly recognized as a tacit requirement for the management of hypertension, a necessity fueled in part by rising rates of metabolic syndrome and diabetes. By targeting complementary pathways, combinations of antihypertensive drugs can be applied to provide effective blood pressure control while minimizing side effects and reducing exposure to high doses of individual medications. In addition, combination therapies, including angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs), have the added benefit of reducing cardiovascular mortality and morbidity over other dual therapies while providing equivalent blood pressure control. It is possible that angiotensin receptor blockers (ARBs), which unlike ACE inhibitors are minimally affected by upregulation of alternative pathways for angiotensin II accumulation following long-term treatment, would also provide such outcome benefits. At issue, however, is maintaining patient compliance, as adding medications is known to reduce adherence to treatment regimens. The purpose of this review is to summarize existing trial data for the long-term safety and efficacy of a recent addition to the armamentarium of dual-antihypertensive therapeutic options, the telmisartan/amlodipine single pill combination. The areas where long-term data are lacking, notably clinical information regarding minorities and women, will also be discussed.

Systemic hypertension is highly prevalent in stable coronary artery disease, a pervasive comorbidity complicating the diagnostic performance and interpretation of non-invasive provocative tests in chest pain patients because of the ischaemic signals generated, despite normal or near normal coronary arteries, by hearts structurally readapted by long-term exposure to raised systemic blood pressure. Additional and unresolved problems posed by arterial hypertension in patients with stable coronary artery disease regard the benefits of antihypertensive treatment due to reports of irrelevant, if not detrimental, effect of blood pressure (BP) lowering in averting coronary relapses as well as the lack of association between BP levels and incident coronary events in survivors from acute myocardial infarction. Uncertainties extend to BP-independent cardioprotective effects of antihypertensive drugs, although the efficacy of renin-angiotensin system blockers in the long-term prevention of cardiovascular events in stable coronary artery disease patients has been shown by several studies, particularly when combined with amlodipine, a dihydropiridine calcium channel blocker. In contrast, the long-term effect of beta-blockers, the antihypertensive class most used in that clinical category, is not supported by strong evidence except that generated in patients with systolic dysfunction and early postmyocardial infarction recovery periods.

ABSTRACT:Although cyclosporine (CsA) and calcium channel blockers (CCBs) parallel to each other may provoke gingival enlargement (GE), there are few considerations about combined effects of CsA and CCBs on gingival tissues.This study aimed to determine prevalence of GE among renal transplant recipients and to compare its occurrence in patients who received only CsA and those who were on CsA and amlodipine.We conducted a prospective randomized case-control trial including 213 renal transplant recipients between February 2010 and August 2010. They were randomly divided into two groups including control group (on continuous treatment with CsA alone; n = 112) and trial group (treated with combined CsA and amlodipine; n = 101). Buccal, lingual, and inter-proximal membranes at last 12 anterior teeth were assessed for GE and packet depth (PD) using Gingival Index of McGaw and others, and Packet Index of Turesky-Gilmore-Glickman, respectively.Marked GE was observed in 26 patients (25.7%) in trial group and only in 4 individuals (3.6%) in control group (P = 0.000). In logistic regression analysis, obese (OR = 3, P = 0.04), older (OR = 2.8, P = 0.03), and female (OR = 1.3, P = 0.03) recipients as well as who received high dose amlodipine (OR = 4.4, P = 0.000) were at risk for marked GE.There is a strong correlation between GE, in particular marked GE, and combination therapy with CsA and amlodipine in transplant patients compared to those treated by CsA alone. We suggest CsA dose reduction may restrain this adverse effect.

BACKGROUND:

A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved.

METHODS:

Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0 ± 7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n = 71) or olmesartan plus trichlormethiazide (1 mg/day; n = 72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization.

RESULTS:

At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period.

CONCLUSIONS:

Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Circulating NEFAs (non-esterified fatty acids) from adipose tissue lipolysis lead to endothelial dysfunction and insulin resistance in patients with the metabolic syndrome or Type 2 diabetes mellitus. The aim of the present study was to test the hypothesis that DHP (dihydropyridine) CCBs (calcium channel blockers) prevent NEFA-induced endothelial and haemorheological dysfunction independently of their antihypertensive properties. Using a double-blind cross-over study design, nifedipine, amlodipine, diltiazem or placebo were administered to eight healthy subjects for 2 days before each study day. On the study days, the following were assessed before and after the infusion of lipid and heparin to raise serum NEFAs: endothelial function, by measuring FBF (forearm blood flow) responses to ACh (acetylcholine); leucocyte activation, by ex vivo measurement of plasma MPO (myeloperoxidase) levels, adherent leucocyte numbers and whole blood transit time through microchannels; and oxidative stress, by determining plasma levels of d-ROMs (derivatives of reactive oxygen metabolites). Effects of the CCBs on NF-κB (nuclear factor κB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in vitro. Elevated NEFAs reduced the responses to ACh and significantly increased whole blood transit time, adherent leucocyte numbers and d-ROMs. Nifedipine and amlodipine, but not diltiazem, prevented NEFA-induced endothelial dysfunction, leucocyte activation and enhancement of oxidative stress without affecting BP (blood pressure), whereas all these drugs prevented NEFA-induced p65 activation in vitro. These results suggest that DHP CCBs, independent of their antihypertensive properties in humans, prevent NEFA-induced endothelial and haemorheological dysfunction through inhibition of NEFA-induced leucocyte activation, although the sensitivity to drugs of leucocyte Ca2+ channels may differ among cells.

The management of cardiovascular disorders poses a dilemma for the medical fraternity. Calcium channel blockers are one of the most commonly used drugs for the management of this disorder, and it is also a well known fact that they are one of the most common group of drugs responsible for causing gingival over growth as one of their adverse effects. Amlodipine is a new generation hypertensive, which has found wide acceptance and usage due to its duration of action. Even with all its benefits as a potent hypertensive, its effect on gingival tissues is what causes concern to the patient and dental surgeon equally. The objective of this article is to create awareness regarding the adverse oral effects of amlodipine, its underlying mechanism of action in bringing about this adverse reaction, along with providing a brief review of the pharmacologic profile of this drug.

OBJECTIVE::

Combination therapy with angiotensin receptor blockers (ARBs) and calcium channel blockers or diuretics is common for hypertensive patients. This study aimed to determine which combination is better for elderly hypertensive patients.

METHODS::

In this prospective, randomized, open-label trial, hypertensive outpatients aged at least 65 years who had not achieved their target blood pressure (BP) with standard ARB dosages were randomly assigned to receive either a fixed-dose combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg) (ARB+D; n = 72) or a combination of amlodipine (5 mg) and the typical dosage of ARBs (ARB+C; n = 68) to evaluate the change in the BP, laboratory values and cognitive function.

RESULTS::

At 3 months, the SBP/DBP was found to have significantly decreased from 156/83 ± 15/11 mmHg to 139/76 ± 14/10 mmHg in the ARB+D group and 155/83 ± 11/10 mmHg to 132/72 ± 14/10 mmHg in the ARB+C group. The BP reduction efficacy was greater in the ARB+C group than in the ARB+D group. At 6 months, the SBP/DBP reached the same level in both groups. At 12 months, the urine albumin/creatinine ratio was significantly decreased from the geometric mean of 17.1 to 9.6 mg/g in the ARB+D group, whereas it was increased from 19.8 to 23.7 mg/g in the ARB+C group. Conversely, the estimated glomerular filtration rate tended to show a decrease in the ARB+D group. There was no significant difference in mini-mental state examination after 1 year.

CONCLUSION:

: ARB+amlodipine (5 mg) yielded a greater BP reduction, whereas ARB+HCTZ (12.5 mg) resulted in a greater reduction in the albuminuria, suggesting that each combination therapy is advantageous in a different manner for elderly hypertensive patients.

Many hypertensive patients require ≥2 drugs to achieve blood pressure targets. This study aims to review and analyze the clinical studies conducted with dual or triple combination of angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics. Medical literature between January 1990 and April 2012 was reviewed systematically and data from eligible studies were abstracted. Data were analyzed using random-effects models. Of the 224 studies screened, 7563 eligible patients from 11 studies were included. Triple combinations of ARBs (olmesartan or valsartan), CCBs (amlodipine), and diuretics (hydrochlorothiazide) at any dose provided more blood pressure reduction in office and 24-hour ambulatory measurements than any dual combination of these molecules (P<.0001 for both). Significantly more patients achieved blood pressure targets with triple combinations (odds ratio, 2.16; P<.0001). Triple combinations did not increase adverse event risk (odds ratio, 0.96; P=.426). Triple combinations at any dose seem to decrease blood pressure more effectively than dual combination of the same molecules without any remarkable risk elevation for adverse events. Further prospective studies evaluating the efficacy and safety of triple combinations, especially in the form of single pills, are required.

The aim of this study is to compare the efficiency of different fixed-dose combinations of renin-angiotensin-aldosterone system (RAAS) blockers and calcium channel blockers, to use it as a guide to assist the rational prescribing in antihypertensive therapy.The efficacy of each drug was obtained from intervention studies randomized, double-blind, made with these combinations and a utility-cost modeling from the model proposed and used by NICE. The perspective of our analysis is the National Health System and the time horizon is long enough to achieve therapeutic goals.Cost per mmHg reduction in BP, percentage of reduction necessary to achieve the therapeutic goals for hypertension control and cost, and finally quantity and quality of life gained with these treatments in patients with hypertension, diabetes.We studied three fixed-dose combinations: amlodipine/olmesartán, amlodipine/valsartan and manidipine/delapril. The cost per mmHg systolic BP ranged from 24.93 to 12.34 €/mmHg, and diastolic BP ranged from 34.24 to 18.76 €/mmHg, depending on the drug used. For an initial value of 165mmHg systolic BP the most efficient treatment to achieve the therapeutic goal of hypertension control (<140mmHg) is manidipine/delapril with a cost of 67.76 €. The use of these drugs to control diabetic and hypertensive patients resulted in all cases being cost-effective (more effective and lower cost compared to "no treatment"). Manidipine/delapril showed the best relation cost-utility (1,970 €/QALY (quality-adjusted life year)) followed by amlodipine/olmesartan and amlodipine/valsartan (2,087 and 2,237 €/QALY, respectively).