The expanding role of angiotensin receptor blockers in the management of the elderly hypertensive

SUMMARY

The world faces the challenge of an ageing population, and for developed countries, the particular challenge is the increasing number of very old people, over 80 years of age. Hypertension is a condition associated with increasing age, but elderly patients with hypertension are often difficult to manage. Nevertheless, treatment of hypertension is of greatest value in older patients who often have additional risk factors or cardiovascular disease. Older patients have generally tolerated antihypertensive therapy well in randomised, placebo-controlled trials. The tolerability of angiotensin receptor blockers (ARBs) is better than that of many other classes of drugs currently used for the management of hypertension and these drugs have virtually no contraindications. Thus, ARBs have a bright future in the management of hypertension and in the treatment of stroke and cognitive decline in the elderly.     

Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal

Introduction: Ranolazine is a novel antianginal and anti-ischemic agent, that, unlike other available antianginal drugs in the United States (beta-blockers, organic nitrates, and calcium channel blockers), has no significant effect on either heart rate or blood pressure. Its exact mechanism of action is unknown. Ranolazine does increase electrocardiographic QTc interval in a dose-related manner, but at therapeutic doses it has no proarrhythmic effects. Ranolazine (ER) at doses of 500 and 1,000 mg twice daily is currently approved for the treatment of angina pectoris either as monotherapy or added to beta-blockers, nitrates, and calcium channel blockers. Ranolazine (ER) is currently not approved for the treatment of unstable angina, silent ischemia, or cardiac arrhythmias. The most common adverse effects reported in clinical trials during ranolazine (ER) treatment are dizziness, headaches, constipation, and nausea.

Areas covered: Recent changes in ranolazine (ER) labeling have led to its increased use for treating patients with ischemic heart disease. This review addresses its appropriate use. All publications were reviewed and those relevant were included.

Expert opinion: Ranolazine (ER) is an effective antianginal and anti-ischemic agent, but I restrict its use to treat patients with stable angina pectoris.     

Transdermal delivery of calcium channel blockers for hypertension

Introduction: Calcium channel blockers are a very important class of antihypertensive drugs. Most calcium channel blockers (CCBs) exhibiting low oral bioavailability are required to be taken more than once a day due to their short half-lives which result in poor patient compliance. There is an ineluctable requirement for improved drug-delivery devices for CCBs because of the quantum of their utilization and shortcoming associated with their conventional dosage forms.

Areas covered: There have been worthwhile research endeavors worldwide to investigate the skin permeation and to develop transdermal formulations of various categories of CCBs. This review explores the investigations on the feasibility and applicability of systemic delivery of various CCBs via skin.

Expert opinion: Transdermal delivery of CCBs has been particularly acknowledged as a potential drug-delivery route in the therapy of hypertension. Several overtures have been made to enhance delivery of these drugs via skin barrier. There have been remarkable research endeavors worldwide to investigate the skin permeation and to develop transdermal systems of various CCBs. Persistent advancement in this area holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.     

Beating the clock: reducing cardiovascular risk by rapid blood pressure reduction with olmesartan

Importance of the field: Hypertension is a major cardiovascular risk factor, and treatment guidelines acknowledge the value not only of reducing elevated blood pressure (BP) to target levels (< 140/90 mmHg and < 130/80 mmHg in patients with diabetes or those at high cardiovascular risk) but also of doing this rapidly.

Areas covered in this review: The importance of rapid BP control has been demonstrated by trials like the Valsartan Antihypertensive Long-term Use Evaluation trial. Combination therapy provides greater efficacy than monotherapy and reduces BP more rapidly. Combining angiotensin receptor blockers (ARBs) with agents from other classes, like calcium channel blockers or diuretics, is an established way to provide effective, rapid and well-tolerated BP reduction.

What the reader will gain: Although ARBs are widely used as mono- and combination therapy, it is not widely appreciated that there are differences between these drugs in efficacy and speed of action. The ARB olmesartan medoxomil provides rapid reductions in BP as monotherapy and combination therapy, with large BP reductions observed within the first few weeks of treatment.

Take home message: In addition to controlling BP, speed of onset of action is an important factor in the management of hypertensive patients and treatments that lower BP rapidly should help to reduce cardiovascular risk.     

A review of chemical therapies for treating diabetic hypertension

Introduction: Hypertension and diabetes are two of the most important modifiable risk factors for cardiovascular and renal disease. The majority of patients with diabetes also have high blood pressure (BP) and the presence of hypertension in these patients dramatically increases cardiovascular and renal risk.

Areas covered: This article will discuss chemical therapies for hypertension in patients with diabetes, based on currently available evidence on the effects of antihypertensive treatment on metabolic profile and renal endpoints that are the factors mostly influencing drug choice.

Expert opinion: Several lines of evidence suggest that angiotensin-converting-enzyme-inhibitors (ACEIs), angiotensin-receptor-blockers (ARBs) and calcium-channel-blockers (CCBs) have beneficial or neutral effects on carbohydrate metabolism, whereas old β-blockers and thiazide diuretics have not. Renal outcome trials clearly suggest that in proteinuric diabetic CKD ACEIs and ARBs reduce the rate of disease progression. Thus, an ACEI or an ARB, if tolerated, should be the first choice in diabetic individuals, followed by CCBs, vasodilating β-blockers and diuretics, depending on the individual patient characteristics. Recent studies suggest that the novel antidiabetic class of sodium-glucose co-transporter 2 inhibitors may offer a small reduction in BP together with important decrease in incidence of cardiovascular and renal events in patients with type 2 diabetes.     

Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention

ObjectiveTo review the available literature on the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients.Data sourcesA Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009.Study selectionRandomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients.Data synthesisThe prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin–angiotensin–aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies.ConclusionA growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention.     

Angiotensin receptor blockers: RAAS blockade and renoprotection

ABSTRACT

Introduction: Chronic kidney disease (CKD) is an increasingly prevalent public health concern and is associated with a high risk of adverse cardiovascular outcomes. Renal impairment is frequently associated with hypertension and there is compelling evidence of the benefits of antihypertensive therapy for reducing progression of kidney disease. The central role of the renin-angiotensin-aldosterone system (RAAS) in hypertension and renal disease has led to interest in the ability of RAAS-blocking agents to provide benefits beyond blood pressure control.

Scope: This review explores the mechanisms involved in CKD development, assesses markers of CKD progression, explores the role of the RAAS in renal disease, and examines RAAS blockade as a therapeutic option for renoprotection. For this purpose, a non-systematic literature review was conducted using the Medline database.

Findings: Studies in patients with diabetic renal disease have shown that RAAS blockade with angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs) reduces progression of renal disease. Similarly, several studies have demonstrated the benefits of ACE inhibitors in non-diabetic renal disease, although few studies have been conducted with ARBs in this setting. At present, there is little evidence to determine the relative merits of ARBs and ACE inhibitors in terms of clinical outcomes, although ARBs appear to have advantages in terms of renal haemodynamics and measures of renal function.

Conclusions: The beneficial effects of ARBs, which result from a combination of antihypertensive, haemodynamic, antiproteinuric and pleiotropic mechanisms, provide a strong rationale for considering the use of these agents in the treatment of high-risk patients.     

Age related antihypertensive effect of nitrendipine,a new calcium entry blocking agent

Summary The effect of nitrendipine 20 mg o.d., a new calcium entry blocker similar in structure to nifedipine, on blood pressure has been evaluated in 14 patients (aged 24–62 years) with uncomplicated mild or moderate arterial hypertension. A significant decrease both in systolic (160±12 at baseline vs 141±8 mm Hg, p<0.001) and diastolic (106±8 vs 93±3 mm Hg, p<0.001) blood pressure was observed at the end of 8 weeks of nitrendipine treatment. An inverse correlation was found between age and the reduction in diastolic blood pressure (r=0.772, p<0.001 as absolute reduction; r=0.791, p<0.001 as percentage reduction versus baseline). This peculiar characteristic differentiates the effect of nitrendipine from that of other calcium entry blockers, which appear to be more effective in older patients.     

Pharmacist impact on health outcomes in a homeless population

ObjectiveThe aim of this study was to analyze the effect of clinical pharmacy services on health outcomes and medication adherence concerning hypertension and diabetes in the homeless population.MethodsThis was a retrospective quasi-experimental study conducted between January 1, 2015, and December 31, 2016. The primary outcomes included median blood pressure and median glycosylated hemoglobin (A1C) change from baseline. The secondary end points included adherence to hypertension and diabetes medication, in addition to the differences in the number of admissions to urgent care clinics, emergency departments, or hospitals pre- and postpharmacist clinic visit.ResultsOne-hundred ninety-eight homeless patients were seen by a pharmacist over the study time frame, and 116 of these patients were included. There was a decrease in systolic and diastolic blood pressure in the 6-months postpharmacist visit (139 mm Hg vs. 135 mm Hg, P = 0.413, and 85 mm Hg vs. 82 mm Hg, P = 0.197, respectively). The percentage of patients who met the blood pressure goals increased from 55% to 66% (P = 0.093). A statistically significant decrease in A1C was found (7.7% vs 7.2%, P = 0.038). The number of patients who met the A1C goal increased from 20% to 41% (P = 0.267) after pharmacist intervention. No medication class was associated with a median proportion of days covered of 80% or greater. However, differences were seen with biguanides (34% vs. 43%, P = 0.004), calcium channel blockers (44% vs. 59%, P < 0.001), and thiazides (28% vs. 39%, P = 0.039) pre- and postintervention. There was no difference in the number of visits to emergency departments or urgent care clinics, or hospitalizations.ConclusionHomeless patients with hypertension and type 2 diabetes who had at least 1 visit with a pharmacist showed some improved health outcomes. Statistically significant benefits were seen in diabetes management, but not for blood pressure control.     

The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension

Hypertension remains a significant health problem, affecting approximately 30% of the US population. Of these, only 36.8% have BP controlled to recommended levels of <140/90mmHg for uncomplicated hypertension and <130/80 mmHg for patients with diabetes mellitus or renal disease. For those with uncontrolled hypertension, the risk of diabetes, renal disease, stroke, and cardiovascular disease is increased. Therapeutic options for the treatment of hypertension include several major classes of drugs: diuretics, ß-adrenoceptor antagonists (ß-blockers), ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), renin inhibitors, calcium channel blockers, and central sympatholytics, alone or in combination. Guidelines recommend thiazide diuretics as preferred first-line monotherapy. However, only 50% of patients will respond adequately to this therapy and the rest will require two or more antihypertensive agents to achieve BP goals. Clinical evidence demonstrates that some drugs have advantages when used in combination rather than as monotherapy. Drugs that block the renin-angiotensin-aldosterone system not only provide BP control but may also provide vascular protection and are metabolically neutral. This is a concise review of the safety and efficacy of ARBs in combination with amlodipine for the treatment of hypertension, with focus on the telmisartan-amlodipine combination. A MEDLINE search of the English literature from 2006 to 2009 of amlodipine in combination with ARBs revealed six publications, which are included in this review.     

Renal protection with calcium antagonists: the role of lercanidipine

Abstract

Background:

Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date.     

The uses and expenses of antihypertensive medications among hypertensive adults

BackgroundThe literature lacks information about the use and cost of prescribed antihypertensive medications, especially by the type and class of medication prescribed.ObjectiveThis study investigated the uses and expenses of antihypertensive medications among hypertensive adults in the United States.MethodsUsing the 2014–2015 Medical Expenditure Panel Survey data, adult men and nonpregnant women aged 18 or older who had a diagnosis code of hypertension and used any prescribed antihypertensive medication were included in the study (n = 10,971). Adults with hypertension who were using a single antihypertensive medication were defined as single medication users, and those using two or more medications were defined as multiple medication users. Medications were classified into angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), thiazide-type diuretics (TDs), β-blockers (BBs), and others. The average annual total antihypertensive medication expenses and the expenditures of each medication class were estimated by using generalized linear models with a log link and gamma distribution and were adjusted to 2015 US dollars.ResultsAmong 10,971 hypertensive adults, 4759 (44.1%) were single medication users, and 6212 (55.9%) were multiple medication users. The average annual total cost for antihypertensive medications was $336 per person (95% confidence interval [CI] = $319–$353); $199 (95% CI = $177–$221) for single medication users and $436 (95% CI = $413–$459) for multiple medication users. The average annual costs for each medication class were estimated at $438 (95% CI = $384–$492) for ARBs and $49 for TDs (95% CI = $44–$55).ConclusionsUsers of multiple medications incurred more than twice the expense than single medication users. When comparing classes of medications, the cost for ARBs was the highest, whereas the cost for TDs was the lowest. This information can be used in evaluating the cost-effectiveness of antihypertension therapies.     

Candesartan cilexetil – a review of effects on cardiovascular complications in hypertension and chronic heart failure

ABSTRACT

Therapeutic interventions that block the renin–angiotensin–aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk factors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an angiotensin-converting enzyme inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24?h blood pressure (BP) control with a trough:peak ratio close to 100%.

Scope: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).

Findings: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction ≤ 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.

Conclusions: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complica­tions across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.     

The development of new-onset type 2 diabetes associated with choosing a calcium channel blocker compared to a diuretic or beta-blocker

ABSTRACT

Objective: It has been acknowledged that patients who receive a beta-blocker or diuretic based regimen are at increased risk of developing new-onset diabetes. Recently, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to decrease patients’ odds of developing new-onset type 2 diabetes. A number of large placebo-controlled multi-center trials in post-myocardial infarction and heart failure patients have shown the ability of renin-angiotensin-aldosterone system medications to reduce the onset of type 2 diabetes. Pharmacologic data has shown improved insulin sensitivity with ACEIs and ARBs. Controversy persists regarding the influence of calcium channel blockers on the development of new-onset diabetes.

Research design and methods: Two reviewers conducted a systematic literature search of Medline, EMBASE, CINAHL, and the Cochrane Library (1966 to December 2006) to extract a consensus of trial data involving calcium channel blockers versus diuretics or beta-blockers with an endpoint of new-onset type 2 diabetes. Studies were included if they were randomized controlled trials versus routine treatment, not observational studies of clinical practice. A random-effects model was utilized. Subgroup and sensitivity analyses were conducted.

Results: Out of 1721 trials, six meeting inclusion criteria were identified, including 99?006 patients. Calcium channel blockers were associated with a reduced incidence of new-onset type 2 diabetes (odds ratio 0.81; 95% confidence interval [CI] 0.73–0.90; p = 0.0001) compared with diuretic or beta-blocker therapy. The reduction in new-onset type 2 diabetes was maintained when a calcium channel blocker was compared to only thiazide diuretics (OR 0.86; 95% CI 0.75–0.99; p = 0.0346). The meta-analysis was limited by the varying definition of new-onset type 2 diabetes mellitus, as well as the potential for publication bias, which is a limit of any meta-analysis.

Conclusions: Calcium channel blockers may be associated with reduced odds of developing new-onset type 2 diabetes compared to diuretics and beta-blockers.     

Antiproteinuric effects of antihypertensive agents in non-diabetic hypertensive population

Arterial hypertension and proteinuria are important factors associated with the progression of both diabetic and nondiabetic chronic kidney disease. The objective of the present study was to determine the influence of different antihypertensive drug groups on urinary albumin excretion (UAE) as related to blood pressure in non-diabetic population. Subjects (n=39) with chronic renal disease accompanied by mild to moderate hypertension and varying degrees of proteinuria were divided into 3 groups based on UAE values and placed on nonpharmacological and/or treatment with an antihypertensive drug regimen (consisting of one or more antihypertensive drugs [beta blocker, ACE inhibitor or calcium-channel blocker]) to achieve a target blood pressure ≤ 130/85 mmHg. Periodic UAE measurements were performed. A reduction was observed over time in most patients, however, it reached statistical significance only in the microalbuminuric group (P<0.01). Patients were further stratified into 5 groups depending on assigned therapy: 0, nonpharmacological treatment; 1-drug group 1; 12-drug groups 1 and 2; 13-drug groups 1 and 3; 123-all 3 drug groups (1-ACE inhibitors, 2-beta blockers, 3-calcium channel blockers). A statistically significant change in mean UAE values at the start and end of the study period in patients assigned to drug groups 12, 13, and 123 was achieved (P < 0.05). Also, there was a statistically significant difference in the average reduction of proteinuria under varying antihypertensive drug regimens (P < 0.05). In conclusion, in patients with hypertension, changes in UAE depend on initial UAE values and administered antihypertensive treatment. ACE inhibitors combined with calcium channel blockers resulted in a higher UAE reduction than other drug groups.     

Pharmacological management of hypertension in the elderly and frail populations

Introduction: Cardiovascular disease is a leading cause of mortality in the elderly. Hypertension is an important modifiable risk factor that contributes to cardiovascular morbidity and mortality. The prevalence of hypertension is known to increase with age, and hypertension has been associated with an increase in risk for cardiovascular disease in the elderly. There is a wealth of evidence that supports aggressive control of blood pressure to lower cardiovascular risk in the general population. However, there are limited data to guide management of hypertension in the elderly and frail patient subgroups. These subgroups are inadequately treated due to lack of clarity regarding blood pressure thresholds, treatment targets, comorbidities, frailty, drug interactions from polypharmacy, and high cost of care.

Areas covered: We review the current evidence behind the definition, goals, and treatments for hypertension in the elderly and frail and outline a strategy that can be used to guide antihypertensive pharmacotherapy in this population.

Expert commentary: Lower blood pressure to < 130/80 mm Hg in elderly patients if tolerated and promote use of combination therapy if the blood pressure is > 20/10 mm Hg over the goal blood pressure. Antihypertensive treatment regimens must be tailored to each individual based on their comorbidities, risk for adverse effects, and potential drug interactions (Figure 1).     

Switch strategies in the management of hypertension: a cost minimisation analysis of angiotensin receptor blocker based regimen

ABSTRACT

Background and objective: Budgetary pressures within health care systems have led many health care providers to consider the switching of patients on long term anti­hypertensive medication to agents with the lowest acquisition price. The long term success of this strategy hinges on price differentials remaining stable, an assumption that may not be valid in drug classes where patent expiry times vary. The treatment of hypertension using angiotensin receptor blockers (ARBs) represents just such a case. The present study, therefore, modelled the 5-year cost consequences of treatment based on losartan, candesartan, valsartan and irbesartan, based on expected patent expiry dates.

Methods: A Markov model was constructed, applying dose-specific blood-pressure lowering and costs to a cohort of uncontrolled mild–moderate hypertensive patients and assessing the anticipated cost of treatment over a 5 year period. A probabilistic approach was adopted to account for between-patient and between-treatment differences.

Results: For both undiscounted and discounted models, a losartan-based regimen represents the least costly option of the four agents tested. Median (IQR) discounted expenditure per patient for each agent was: losartan: £506 (£441–£650), candesartan: £610 (£542–£766), valsartan: £809 (£796–£1078), irbesartan £696 (£694–£934).

Conclusion: Switching hypertensive patients taking ARBs to the agent with the lowest current acquisition cost may yield only transient budgetary savings. Once patent expiry is taken into account, this model suggests that maintaining or switching patients to losartan would yield considerably greater savings over 5 years.