A systematic review of nicardipine vs labetalol for the management of hypertensive crises

Hypertensive emergencies are acute elevations in blood pressure (BP) that occur in the presence of progressive end-organ damage. Hypertensive urgencies, defined as elevated BP without acute end-organ damage, can often be treated with oral agents, whereas hypertensive emergencies are best treated with intravenous titratable agents. However, a lack of head-to-head studies has made it difficult to establish which intravenous drug is most effective in treating hypertensive crises. This systematic review presents a synthesis of published studies that compare the antihypertensive agents nicardipine and labetalol in patients experiencing acute hypertensive crises. A MEDLINE search was conducted using the term "labetalol AND nicardipine AND hypertension." Conference abstracts were searched manually. Ultimately, 10 studies were included, encompassing patients with hypertensive crises across an array of indications and practice environments (stroke, the emergency department, critical care, surgery, pediatrics, and pregnancy). The results of this systematic review show comparable efficacy and safety for nicardipine and labetalol, although nicardipine appears to provide more predictable and consistent BP control than labetalol.     

Hypertension,Plasma Lipids and Antihypertensive Drugs

Treatment of hypertension is quite effective in preventing cerebrovascular disease. Morbidity and mortality from coronary heart disease, the major complications of high blood pressure are not, however, generally affected when mild to moderate hypertension is treated with antihypertensive drugs. This is probably owing to the multifactorial nature of atherosclerosis, the main cause of coronary heart disease. For example, dyslipidemias and other risk factors are very common among hypertensive patients. Prevention of coronary heart disease among hypertensive subjects is possible only by intervening in the many contributory risks. Non-pharmacological hypolipidemic treatments such as adequate nutrition and exercise are positive steps in the treatment of all hypertensive patients. The role of various antihypertensive agents should also be carefully considered. The associations between hypertension, several metabolic abnormalities, development of organ complications and various antihypertensive drugs should be explored in detail.     

Hypertension, plasma lipids and antihypertensive drugs

Treatment of hypertension is quite effective in preventing cerebrovascular disease. Morbidity and mortality from coronary heart disease, the major complications of high blood pressure are not, however, generally affected when mild to moderate hypertension is treated with antihypertensive drugs. This is probably owing to the multifactorial nature of atherosclerosis, the main cause of coronary heart disease. For example, dyslipidemias and other risk factors are very common among hypertensive patients. Prevention of coronary heart disease among hypertensive subjects is possible only by intervening in the many contributory risks. Non-pharmacological hypolipidemic treatments such as adequate nutrition and exercise are positive steps in the treatment of all hypertensive patients. The role of various antihypertensive agents should also be carefully considered. The associations between hypertension, several metabolic abnormalities, development of organ complications and various antihypertensive drugs should be explored in detail.     

Pharmacologic treatment of hypertensive disorders during pregnancy

Pregnancy complicated by hypertension is a common problem faced by clinicians. It can lead to substantial maternal and/or fetal/neonatal morbidity and mortality. There are a variety of medications that can be used during pregnancy either for treatment of significant chronic hypertension or in cases of acute severe hypertension. Most antihypertensive drugs have been shown to be safe for use in pregnancy. A variety of medications are available to treat more severe hypertension, although the use of pharmacologic therapy to treat mild chronic hypertension during pregnancy has not been supported in the literature. The data are more limited concerning drugs that would be used in the event of hypertensive emergencies or in an intensive care setting; however, in such a situation, maternal health and life become paramount and, despite lack of good studies, appropriate treatment should be rendered.     

Aldosterone antagonists: effective add-on therapy for the treatment of resistant hypertension

Resistant hypertension is defined as blood pressure that remains above target levels despite treatment with three different antihypertensive agents. Cross-sectional analyses and hypertension outcome studies indicate that it is a common clinical problem, which will undoubtedly become increasingly prevalent with an aging and increasingly overweight population. Secondary causes of hypertension are common in patients with resistant hypertension, particularly hyperaldosteronism, with a prevalence of approximately 15-20%. This, however, is likely to be an underestimation of the role excess aldosterone plays in causing resistance to treatment. In subjects with resistant hypertension, suppressed renin levels are common, exceeding 60% in studies conducted by the authors and from centers elsewhere in the world, suggesting occurrence of excess aldosterone beyond cases of true primary aldosteronism. Recent clinical studies indicate that aldosterone antagonists provide significant additional blood pressure reduction when added to treatment regimens of patients with resistant hypertension independent of aldosterone levels. These agents are generally well tolerated. Hyperkalemia is an uncommon complication of aldosterone antagonists, but it can occur. Therefore, biochemical monitoring is necessary, particularly in high-risk patients.     

Diagnosis and management of hypertensive emergencies

It has been estimated that approximately 600,000 to 800,000 Americans will develop a hypertensive crisis (Calhoun and Oparil, 1990). Although such numbers represent only about 1% of the estimated 60 million Americans with hypertension, hypertensive crisis often constitutes a major medical emergency, necessitating a focused, assertive, and reasoned therapeutic intervention. When such patients are seen in the emergency department or in a physician's office with a critical elevation in blood pressure (BP), appropriate and efficacious management is essential to avoid catastrophic injury to vital target organs, including the central nervous system, the heart, and the kidneys. Delays in initiating effective therapy or, equally important, overzealous therapy leading to a too-rapid reduction in BP can produce severe complications involving these target organs. This article reviews the spectrum of clinical syndromes that comprise hypertensive emergencies, highlighting 2 to illustrate the complexities of clinical presentation and management. The newly advocated treatment guidelines based on the category of acute severe hypertension (including asymptomatic hypertensive urgencies) are also considered, as are therapeutic strategies utilizing currently available antihypertensive agents.     

Rationale for combination therapy in hypertension management: focus on angiotensin receptor blockers and thiazide diuretics

Despite recognition that hypertension is a major risk factor for cardiovascular events and mortality, blood pressure control rates remain low in the US population. Reflecting clinical trial results, hypertension management guidelines assert the clinical benefit of achieving current blood pressure goals and indicate that most patients will require 2 or more drugs to reach goal. Well-designed drug combinations counter hypertension via complementary mechanisms that increase antihypertensive efficacy, potentially with lower rates of adverse events than higher dose monotherapy regimens. Lower adverse event rates, in turn, may contribute to greater adherence with treatment. The combination of a low-dose diuretic with agents that block the effects of the renin-angiotensin system (RAS), such as angiotensin receptor blockers, has been found in numerous clinical trials to be highly effective for lowering blood pressure in patients with uncomplicated as well as high-risk hypertension, with a comparable favorable side effect profile compared with monotherapy. Moreover, agents that block the RAS are associated with a lower risk of new-onset diabetes mellitus than other antihypertensive classes. Complementary combinations of antihypertensive agents provide an efficient and effective approach to hypertension management.     

Advancing management of hypertension through pharmacogenomics

Hypertension is the most common, chronic disease in the world, and there are many effective pharmacological agents available for its treatment. Despite the plethora of treatment options, data across the globe suggest that blood pressure control rates are < 50%, a fact likely influenced in part by the inability to predict the antihypertensive drug likely to be most effective for an individual patient. Pharmacogenomics in hypertension holds the promise of identifying genetic biomarkers for antihypertensive drug response, which might be used in the future in treatment selection. Research in the field is also likely to enhance our understanding of hypertension and the mechanisms by which the various drugs produce efficacy. There are several examples in the literature of genes with relatively strong data on associations of genetic polymorphisms with antihypertensive response; the data on ADRB1, CACNB2, and NEDD4L are detailed as examples. Substantial additional data in hypertension pharmacogenomics are expected to be forthcoming from recently completed genome-wide association studies. Increased collaboration among research groups will help insure successful discoveries from these large-scale studies. The next decade should clearly define the potential clinical implications of the research in hypertension pharmacogenomics that is currently in progress.     

Current therapeutic concepts in diabetic hypertension

Diabetes mellitus and hypertension are both prevalent in the adult population. The development of hypertension in the diabetic patient is likely to increase the morbidity and mortality in a subgroup already at high risk for atherosclerosis and deserves special consideration. Several studies have confirmed the beneficial effects of antihypertensive therapy on complications such as diabetic nephropathy. This emphasizes the importance of normalizing blood pressure in the diabetic population. It has been suggested that the threshold for initiating antihypertensive therapy should be lower in diabetic patients. All antihypertensive agents have potential disadvantages in patients with diabetes. The commonly encountered effects include deterioration of diabetic control, sexual dysfunction, electrolyte imbalance, and lipid disorders. The adverse effects of these agents on serum lipids have been implicated in the less-than-expected reduction in coronary heart disease noted in some studies. The recent Lipid Research Council study has emphasized the importance of elevated lipid levels and increased cardiovascular mortality. Antihypertensive therapy has advanced rapidly in the last 5 yr. The special problems in the treatment of hypertension within the diabetic population are now receiving greater attention. Undesirable biochemical side effects of drugs used to treat hypertension have become publicized, and the long-term consequences of these abnormalities are under critical scrutiny. The new antihypertensive medications offer exciting alternative approaches to the more traditional agents with less chance of significant metabolic side effects.     

Management of nocturnal hypertension

Nocturnal hypertension is a common complication of essential and secondary hypertension. Abnormal circadian blood pressure patterns associated with elevated sleep blood pressure include nondipping and reverse dipping, both of which are associated with increased target-organ damage and adverse cardiovascular outcomes. Nocturnal hypertension can be treated with several approaches that include both lifestyle changes, such as sodium restriction and potassium supplementation, and pharmacological treatments, primarily through the use of bedtime dosing of antihypertensive agents. Evening administration of blockers of the renin–angiotensin–aldosterone system is the most consistently effective of these treatment strategies. In this review, we provide a detailed discussion of the options available for the management of nocturnal hypertension.     

Effect of antihypertensive agents on the development of type 2 diabetes mellitus

People with hypertension have a high prevalence of insulin resistance and are at relatively high risk of developing type 2 diabetes mellitus. It is becoming increasingly evident that antihypertensive agents have disparate metabolic effects. For example, recent clinical trials indicate that agents that interrupt the renin-angiotensin axis reduce the risk of developing diabetes compared with other classes of antihypertensive agents. Blockade of the effects of angiotensin II might improve blood flow to insulin-sensitive tissues. Furthermore, interruption of the renin-angiotensin system might provide metabolic benefit through such mechanisms as reduced oxidative stress and restored nitric oxide production, which could lead to improved insulin signaling. Alternatively, collective trials suggest that both diuretics and beta-blockers accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension. Therefore, the risk of new-onset diabetes-associated cardiovascular risks should be factored into future treatment recommendations for patients who require antihypertensive therapy. This will become even more important as the number of insulin-resistant patients with hypertension increases in parallel with the steady growth in the number of sedentary, obese, and aged persons in our population.     

Current management of hypertension

Treatment of hypertension is best accomplished in stepwise fashion, beginning with nondrug therapy followed by a knowledgeable selection of antihypertensive drugs. Consideration must be given to the side effect profile as well as the cost of the medication. Diuretics are still useful, both as first-step drugs and as second-step and third-step drugs to overcome the sodium retention associated with many antihypertensive agents.     

Valsartan-amlodipine-hydrochlorothiazide: the definitive fixed combination?

A significant proportion of patients with hypertension will need three or more antihypertensive agents to achieve blood pressure goals, particularly those at higher risk. On the other hand, fixed combinations provide an extra beneficial effect, as they improve medication adherence and, secondarily, the attainment of blood pressure goals during follow-up. Triple therapy is recommended in the treatment of hypertension in those patients not adequately controlled with two antihypertensive drugs. In this context, guidelines recommend the combination of a renin-angiotensin system inhibitor, a calcium channel blocker and a diuretic. The triple fixed combination of valsartan-amlodipine-hydrochlorothiazide has been shown to be an effective and safe therapy for treating hypertension and seems a logical approach for those patients uncontrolled with two antihypertensive agents as well as in those patients already treated with three drugs to improve treatment compliance. In this article, available evidence about the efficacy and tolerability of the triple fixed combined therapy valsartan-amlodipine-hydrochlorothiazide for the treatment of hypertension is updated.     

Other antihyperuricemic agents

It has been reported that hyperuricemia might be responsible for cardiovascular diseases as well as gout and renal injury. Hypertension and hyperlipidemia, which are also responsible for cardiovascular diseases, are often associated with hyperuricemia. Thus, the treatment of hypertension and hyperlipidemia associated with hyperuricemia is also important. Losartan, an antihypertensive agent, and fenofibrate, an antihyperlipidemic agent, are known to have uric acid lowering effects. Both agents are useful for hyperuricemia with associated with hypertension and hyperlipidemia. In this section, we reported the characteristics and usefulness of these two agents in hyperuricemic patients with hypertension and hyperlipidemia.     

Left ventricular hypertrophy and antihypertensive therapy.

Left ventricular hypertrophy is more common in hypertensive individuals than in normotensive persons. Its presence in hypertensive patients is associated with an increased incidence of ventricular arrhythmias, myocardial infarction, congestive heart failure, stroke and cardiovascular mortality. Echocardiography is more sensitive than electrocardiography in detecting left ventricular hypertrophy. Echocardiographic evidence of this condition in patients with borderline hypertension may identify those who need treatment. Weight reduction and drug therapy can prevent or reverse ventricular hypertrophy in hypertensive patients. Recent studies suggest that some antihypertensive drugs are more effective than others in reducing left ventricular hypertrophy. These agents include beta-adrenergic blockers, angiotensin converting enzyme inhibitors, calcium channel blockers and sympatholytic agents. Although little evidence exists to show that reduction of left ventricular mass decreases cardiovascular morbidity and mortality, avoidance of antihypertensive agents that may aggravate hypertrophy would seem prudent.     

Acute hypertensive crisis in pregnancy

Severe pre-eclampsia is a state of acute afterload increase where compensation may be total by use of the Frank-Starling mechanism and/or increased adrenergic drive, or may be uncompensated in a patient with limited or exhausted preload reserve. As such, we are presented with a diverse group of patients and antihypertensive therapy ideally should be individualized. In reality we are dealing with a complex situation because of the presence of the fetus raising concerns about direct effects on the fetus as well as on uteroplacental blood flow. This limits our choice of agents to those with extensive use in pregnancy except in complicated or resistant cases. For these reasons, hydralazine is the antihypertensive agent of choice for treatment of acute hypertensive emergencies in pregnancy. In the complicated case other agents such as sodium nitroprusside or nitroglycerin may be more appropriate and, in these cases, hemodynamic monitoring should be performed to allow not only greater safety, but also to tailor therapy to the individual hemodynamic profile.     

Valsartan–amlodipine–hydrochlorothiazide: the definitive fixed combination?

A significant proportion of patients with hypertension will need three or more antihypertensive agents to achieve blood pressure goals, particularly those at higher risk. On the other hand, fixed combinations provide an extra beneficial effect, as they improve medication adherence and, secondarily, the attainment of blood pressure goals during follow-up. Triple therapy is recommended in the treatment of hypertension in those patients not adequately controlled with two antihypertensive drugs. In this context, guidelines recommend the combination of a renin–angiotensin system inhibitor, a calcium channel blocker and a diuretic. The triple fixed combination of valsartan–amlodipine–hydrochlorothiazide has been shown to be an effective and safe therapy for treating hypertension and seems a logical approach for those patients uncontrolled with two antihypertensive agents as well as in those patients already treated with three drugs to improve treatment compliance. In this article, available evidence about the efficacy and tolerability of the triple fixed combined therapy valsartan–amlodipine–hydrochlorothiazide for the treatment of hypertension is updated.     

Untoward effects of blood transfusion

Abstract

Hypertension affects approximately 73 million individuals in the United States. Clinical studies have shown that antihypertensive therapy can reduce blood pressure (BP) and the risk of cardiovascular events. However, the majority of patients with hypertension do not achieve the recommended BP goal of < 140/90 mm Hg (or < 130/80 mm Hg for patients with diabetes) with antihypertensive monotherapy, and require therapy with 2 or more antihypertensive agents. Combination therapy utilizes antihypertensive agents from different drug classes, which act via distinct pharmacologic mechanisms to improve overall efficacy and tolerability. Although combination therapy is superior to monotherapy in achieving BP goals across the entire spectrum of hypertension, the proportion of patients achieving the recommended BP goal can be further improved by the use of new antihypertensive drug combinations. The beneficial antihypertensive characteristics of both angiotensin receptor blockers and calcium channel blockers suggest that combining these classes may result in a highly efficacious antihypertensive therapy with regard to both activity and safety when used as a fixed-dose combination. In particular, a fixed-dose combination of olmesartan medoxomil plus amlodipine besylate has been demonstrated to be an efficacious antihypertensive combination due in part to the benefits associated with each of these agents within their respective drug classes.     

Target organ involvement in hypertension: a realistic promise of prevention and reversal

The major message from this discussion is that the end points from hypertensive disease (stroke, CHD, and hypertensive emergencies) are now preventable. Cardiac failure and ESRD, however, two exceedingly common end points from long-standing hypertension, remain as major disabilities and causes of death. The former is the most common cause of hospitalization in industrialized societies; hypertension and diabetes mellitus are the most common causes of the latter. The mechanisms of risk of these target organ diseases is not LVH per se, or the elevated arterial pressure alone in the kidney, but the coronary and renal ischemia, organ fibrosis, and, perhaps, apoptosis. Present day therapy now can effectively reverse these costly (economically and by human suffering) complications. Recent experimental studies suggest that, when used early enough, these newer pharmacologic agents may even prevent their occurrences and consequences. The very practical lesson from these experiences is that early detection and treatment of hypertension, effective control of arterial pressure, and the suppression of the underlying disease mechanisms markedly reduce the now increasing prevalence of both cardiac and renal failure.