Perindopril arginine and amlodipine besylate for hypertension: a safety evaluation.

INTRODUCTION: Controlling blood pressure is a global health priority; single-pill antihypertensive combinations may improve adherence, persistence, and outcomes. Areas covered: A novel combination of perindopril arginine and amlodipine besylate was recently approved. A systematic review of the literature revealed its most common adverse effects as: peripheral edema (depending on the dose of amlodipine, but attenuated by perindopril), cough, dizziness and hypotension. Dose-dependent hyperkalemia, impairment of renal function (especially in renovascular hypertension), angioedema, and teratogenicity were derived from experience with other ACE-inhibitors. Expert opinion: Substantial clinical trial experience with amlodipine or perindopril suggests that these two agents effectively lower blood pressure, and can reduce the risk of major adverse cardiovascular events, as in the Anglo-Scandinavian Cardiac Outcomes Trial. The incidence of adverse effects reported in clinical trials is lower than expected, likely due to exclusion of subjects previously exposed to its components; the nature of open-label, uncontrolled observational studies; and difficulty in recognizing and measuring cough and pedal edema. This new formulation of perindopril arginine protects its ethyl ester, without requiring physical separation from amlodipine in a single tablet, and is less hygroscopic than perindopril erbumine. These and other attributes may make this combination an attractive addition to the antihypertensive armamentarium.

Reducing the Expenditures and Workload Associated With VA Partial-Fill Prescription Processing.

Implementing the VA partial-fill guidance and refill education within a pharmacy operation may reduce prescription processing costs.

Quality of Meta-Analyses for Randomized Trials in the Field of Hypertension: an Updated and Improved Systematic Review.

Publications of hypertension-related meta-analyses (MAs) have increased exponentially in the past 25 years and now average 8/month. Theoretically, this is facilitating evidence-based management of patients. However, some practitioners and authors of guidelines have questioned the quality of published MAs. By extending a prior review, we have assessed the quality of 212 hypertension-related meta-analyses over 5 years based on systematically searching three computerized libraries. Seventeen criteria grouped into four domains of quality yielded the following results: (1) Assessment of trial quality was accomplished in 89% of MAs, and 38% analyzed trials in subgroups of trial quality where appropriate. (2) All three measures of heterogeneity (I 2, tau, and P for heterogeneity) were reported in 36%, reflecting the failure to report tau, the standard deviation of the main effect. (3) Publication bias was assessed in 75%, and 43% of MAs used a statistical test for publication bias. (4) Regarding transparency, 9 to 31% of MAs reported problems in the previous three domains in the article's abstract. Journal impact factor reporting the MAs declined significantly over 5 years. The percent with criteria of quality in a MA was modestly correlated with journal impact factor (R 2 = 0.05, P = 0.001). False-positive results from inappropriate application of the DerSimonian-Laird model affected 25% of articles, which reported these false positives in the article's abstract in 72%. No more than 25% of MAs had 67% or more of the criteria of quality. In conclusion, skepticism of hypertension-related MAs is justified, but their quality can be readily corrected.

Expertise: no longer a sine qua non for guideline authors?

: Several sets of guidelines have been published recently and more are in the works. The very recent American College of Physicians/American Academy of Family Practitioners guidelines were put together by a set of authors and consultants without any expertise in the topic under discussion, that is, hypertension. Although we are not maintaining that all guidelines should be written exclusively by experts, complete lack of expertise among guideline authors is not acceptable.

Quality of meta-analyses for randomized trials in the field of hypertension: a systematic review.

OBJECTIVES: Doubling on average every 6 years, hypertension-related meta-analyses are now published twice weekly and are often considered the highest level of evidence for clinical practice. However, some hypertension specialists and guideline authors view meta-analyses with skepticism. This article evaluates the quality of hypertension-related meta-analyses of clinical trials. METHODS: A systematic search was conducted for meta-analyses of clinical trials recently published over 3.3 years. Specific criteria reproducibly assessed 26 features in the four domains of meta-analysis quality, domains justified by fundamental analytics and extensive research: analyzing trial quality, analyzing heterogeneity, analyzing publication bias, and providing transparency. RESULTS: A total of 143 meta-analyses were identified. A total of 44% had 8+ deficient features with no relation to journal impact factor: odds ratio relating 8+ deficient features to the upper third versus lower third of impact factor = 1.3 (95% confidence limit 0.6-2.9). A total of 56% had all four domains deficient. Quality did not improve over time. Thirty articles (21%) reported statistically significant results (P < 0.05) from inappropriate DerSimonian-Laird models, whereas unreported, appropriate, Knapp-Hartung models gave statistical nonsignificance; 88% of these 30 articles reported the incorrect results in their abstracts. A total of 60% of all meta-analyses failed to conduct analyses in subgroups of quality when indicated, 63% failed to report Tau and Tau, 57% omitted testing for publication bias, none conducted a cumulative analysis for publication bias, and 71-77% omitted mentioning in their abstracts problems of trial quality, heterogeneity, and publication bias. CONCLUSION: Although widespread, deficiencies in hypertension-related meta-analyses are readily corrected and do not represent flaws inherent in the meta-analytic method.

Common Substances That May Contribute to Resistant Hypertension, and Recommendations for Limiting Their Clinical Effects.

PURPOSE OF REVIEW: The purpose of this review is to highlight common or important substances or habits that elevate blood pressure and offer suggestions, based on recent literature, to limit their use or effects. RECENT FINDINGS: Despite decades of advice to the general populace from public health authorities to avoid or reduce dietary sodium and non-steroidal anti-inflammatory drug (NSAID) use, more evidence has accumulated from nationwide surveys, clinical trials, and pathophysiological or mechanistic studies that show how important these modalities can (and should) be for hypertensive and prehypertensive individuals and the general population. Other common stimuli that increase blood pressure can be divided into many that are easily avoided (e.g., phenethylamines, anabolic steroids), those that must be continued for important medical reasons (e.g., erythropoietin, tyrosine kinase inhibitors) and therefore require intensified antihypertensive therapy, and a few (e.g., glucocorticoids, hormonal contraceptives) that fall between these two paradigms.

Perindopril arginine + amlodipine for the treatment of hypertension in the USA.

INTRODUCTION: Controlling blood pressure is a global health priority; single-pill combinations of antihypertensive agents are often prescribed to improve adherence, persistence, and outcomes. AREAS COVERED: A novel preparation of perindopril arginine and amlodipine besylate was approved by the US Food and Drug Administration on 21 Jan 2015, based primarily on a 837-subject, 6-week, randomized, multicenter, prospective, clinical trial. The maximal marketed dose of the combination (14/10 mg daily) lowered both systolic and diastolic blood pressure significantly more than either monotherapy, with a reduction in adverse effects (especially ankle edema), compared to amlodipine alone. EXPERT OPINION: Substantial clinical trial experience with amlodipine or perindopril suggests that these two agents effectively lower blood pressure, and may reduce the risk of major adverse cardiovascular events. In the Anglo-Scandinavian Cardiac Outcomes Trial, hypertensive subjects randomized to receive these two drugs (in sequence) had a significantly lower incidence of several types of clinical events, compared to those who received atenolol ± bendroflumethiazide. The new formulation of perindopril arginine protects its ethyl ester, without requiring physical separation from amlodipine in a single pill, and is less hydroscopic than perindopril erbumine. These and other attributes may make this combination an attractive addition to the antihypertensive armamentarium.

Rationale for a single-pill combination of perindopril arginine and amlodipine besylate.

A systematic review identified 86 outcome-based clinical trials involving perindopril, amlodipine, or other antihypertensive drugs. In fixed-effects meta-analyses of 11 clinical trials (90,208 subjects), amlodipine was associated with a significant 24% increase in heart failure, but a significant decrease in death, cardiovascular death, stroke, coronary heart disease, and first major cardiovascular adverse event. In five clinical trials (52,565 subjects), perindopril was associated with a significant reduction in all six cardiovascular endpoints. Network and Bayesian meta-analyses suggested that (with the exception of amlodipine and heart failure), each agent was at least as effective as an initial diuretic to prevent these events. Short-term trials have demonstrated that the combination of perindopril and amlodipine is safe and effective, with statistically greater lowering of blood pressure than either agent alone and a potential synergistic effect on pedal edema. The single-pill combination of perindopril and amlodipine may be a useful addition to the antihypertensive armamentarium.

Efficacy and safety of perindopril arginine + amlodipine in hypertension.

To study the efficacy and safety of a new combination of perindopril arginine and amlodipine besylate, 837 subjects were enrolled in a three-arm, prospective, 59-center, randomized clinical trial. For 42 days, subjects (average seated blood pressure [BP], 158 ± 12/101 ± 5 mm Hg; age, 52 ± 10 years; 52% male; 34% black; 20% diabetic) received amlodipine/perindopril arginine (10/14 mg/d), perindopril erbumine (16 mg/d), or amlodipine (10 mg/d). Goal BP was <140/90 or <130/80 mm Hg in diabetics, per JNC 7 guidelines. The combination showed the largest change in seated BP (-23.7/-15.7 vs. -13.7/-9.5 vs. -19.3/-13.2 mm Hg, respectively; P < .0001), the highest proportion at goal BP (51% vs. 26% vs. 37%; P < .0001), and a lower incidence of pedal edema and adverse events compared with amlodipine. No deaths or significant differences across groups in early discontinuation, serum potassium, or rates of total or serious adverse events or glomerular filtration, were observed.

Rationale for establishing a mechanism to increase reimbursement to hypertension specialists.

Hypertension is an important public health problem both in the United States and worldwide, contributing to many forms of cardiovascular and renal diseases. Although great strides have been made in the proportion of the US population that achieves recommended blood pressure targets, many Americans still have undertreated and uncontrolled blood pressure that increases the risk of expensive strokes, heart attacks, heart failure, and dialysis. Because hypertension is a common but heterogeneous and sometimes complex condition, the American Society of Hypertension (ASH) has, since 1999, designated physicians as "ASH Hypertension Specialists." Such Hypertension Specialists (as defined by ASH's Specialist Program) are fully licensed physicians with a primary board certification who are competent in all aspects of the diagnosis and treatment of hypertension, as evidenced by passing a specific examination on these topics offered by ASH's Specialist Program. These physicians have a proven track record of controlling blood pressure in "resistant hypertensive" patients, the general population whom they serve, and educating other physicians to help them achieve higher blood pressure control rates among their patient populations. This report sets out a rationale for increased reimbursement for care of hypertensive patients by ASH-Designated Hypertension Specialists.