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Aims: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]., Methods: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use., Results: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03)., Conclusions: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

Stroke is a major cause of morbidity and mortality worldwide. Hypertension is one of the most important risk factors for stroke - increasing the risk significantly. The presence and severity of coronary artery disease (CAD), which often coexists with hypertension, also predicts an increased risk of stroke. Lowering blood pressure (BP) to target in patients with hypertension can significantly reduce the incidence of fatal and non-fatal stroke. Effective BP control is even more important in CAD patients who are at greater risk of stroke. Data regarding the effects of antihypertensive therapy on stroke in patients with angina or CAD are limited and have been variable. To date, BP management strategies in patients with CAD have relied on small subsets of data based on high-risk hypertensive patients. Results with calcium channel blockers (CCBs) have been more positive than those with other classes of antihypertensive agents. Findings from the ACTION trial have provided a significant insight into the benefits of CCBs in patients with CAD and hypertension. Nifedipine gastrointestinal therapeutic system (GITS), in addition to best practice therapy for stable angina pectoris, contributes to a significant reduction in the risk of stroke in patients with CAD and hypertension who are at high risk and require effective BP control. Moreover, the incidence of stroke is significantly related to baseline BP, which may be an important factor to consider when deciding on treatment strategies in high-risk patients with CAD.

Congestive heart failure (CHF) is the most devastating cardiac sequella of long-standing hypertension. Recent data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have shown the risk of CHF to be twice as high with doxazosin than with chlorthalidone. Although some questions remain regarding the diagnosis and mortality of CHF in the doxazosin arm and regarding the risk of dying from malignancy in the diuretic arm of ALLHAT, drugs used to treat hypertension should lower the CHF risk. Therefore, until ironclad safety data are provided, doxazosin, and probably all alpha-blockers, should no longer be used as first-line antihypertensive therapy.

More than 50% of patients with mild uncomplicated hypertension will need combination therapy to reach target blood pressure, as defined by the Joint National Committee. This percentage is even higher in hypertensive patients with diabetes, renal impairment and congestive heart failure in whom target blood pressures are lower. Combination therapy of angiotensin converting enzyme inhibitor and low dose diuretic offers distinct advantages in the treatment of essential hypertension. The two drug classes may have a synergistic effect on hypertensive target organ disease and blood pressure. Triple therapy with a calcium antagonist may be needed to achieve blood pressure control in more severely hypertensive patients.

Aims: To assess the relationship between antihypertensive therapy and malignancy., Methods and Results: A MEDLINE search for English-language articles published between January 1966 and August 1999 identified 29 prospective studies that reported cancer incidence or mortality and 28 case-control studies that reported specific drug use in cancer patients and controls. The association between rauwolfia derivatives and breast cancer was analysed in 5852 cases and 9776 controls, yielding an odds ratio (OR) of 1.25 (95% CI, 1.09-1.44). The association between diuretics and renal cell carcinoma was analysed in 4389 cases and 6566 controls, yielding a pooled OR of 1.54 (95% CI, 1.41-1.68). The association between atenolol and cancer death was analysed pooling three randomized controlled studies, including 1879 treated patients and 3078 non-treated patients, yielding a pooled OR of 1.36 (95% CI, 1.02-1.82); however, data from non-randomized studies did not confirm the latter. The association between calcium antagonists and malignancy was analysed pooling five randomized controlled studies, including 5451 treated patients and 5207 untreated ones, yielding a pooled OR of 0.78 (CI, 0.60-1.00). A meta-analysis of an additional five longitudinal studies, including 9087 treated patients and 15 559 non-treated patients, yielded a pooled OR of 1.04 (CI, 0.91-1.19). The association between ACE inhibitors and malignancy was analysed pooling two randomized controlled trials involving 1585 treated patients and 1567 non-treated patients, yielding a pooled OR of 1.57 (95% CI, 0.97-2.57); however, non-randomized studies showed no association or a decreased risk for malignancy with ACE inhibitors., Conclusions: With the exception of diuretics and renal cell carcinoma, the association between antihypertensive drugs and malignancy was either low grade (rauwolfia), uncertain (atenolol), absent (ACE inhibitors), or absent with a yet to be investigated inverse association (calcium antagonists). Ongoing long-term prospective studies with cardiovascular drugs should carefully monitor the risk of malignancy., (Copyright 2001 The European Society of Cardiology.)

Objective: To compare the efficacy, tolerability, and safety of once-daily therapy with amlodipine 5 mg/benazepril 10 mg vs amlodipine 5 mg, benazepril 10 mg, and placebo., Design: Randomised, double-blind, placebo-controlled, parallel-group, multicentre trial., Setting: Twenty-two clinical centres, including private practice groups and academic research clinics., Patients: A total of 530 patients between 21 and 80 years of age with essential hypertension were screened for the study, and 454 were randomised to treatment with amlodipine 5 mg/benazepril 10 mg, amlodipine 5 mg, benazepril 10 mg, or placebo for 8 weeks., Results: Amlodipine 5 mg/benazepril 10 mg produced greater reductions from baseline in sitting diastolic blood pressure than amlodipine 5 mg (P < 0.03), benazepril 10 mg (P < 0.001), and placebo (P < 0.001). The response rate in the amlodipine 5-mg/benazepril 10-mg treatment group (66.4%) was better than that observed in the amlodipine 5-mg (50.0% P < 0.02), benazepril 10-mg (38.3% P < 0.001), and placebo (24.4% P < 0.001) groups. There was no significant difference in heart rate among the four groups. The incidence of oedema in the amlodipine 5-mg/benazepril 10-mg (1.7%) group was somewhat less than that in the amlodipine 5-mg (4.5%) group., Conclusions: Therapy with amlodipine 5 mg/benazepril 10 mg was well tolerated and was superior to amlodipine 5 mg, benazepril 10 mg, and placebo in reducing sitting diastolic blood pressure in patients with essential hypertension.

Background: We analyzed the available data to assess the benefits of antihypertensive therapy in hypertensive patients with diabetes mellitus., Procedure: A MEDLINE search of English-language articles published until June 1999 was undertaken using the terms diabetes mellitus, hypertension or blood pressure (BP), and therapy. Included were only prospective randomized studies of more than 12 months' duration that evaluated the effect of drug treatment on morbidity and mortality in diabetic hypertensive patients., Results: The coexistence of diabetes mellitus doubled the risk of cardiovascular events, cardiovascular mortality, and total mortality in hypertensive patients (approximate relative risk of 1.73 to 2.77 for cardiovascular events, 2.25 to 3.66 for cardiovascular mortality, and 1.73 to 2.18 for total mortality). Intensive BP control to levels lower than 130/85 mm Hg was beneficial in diabetic hypertensive patients. All four drug classes--diuretics, beta-blockers, angiotensin converting enzyme inhibitors, and calcium antagonists--were effective in reducing cardiovascular events in diabetic hypertensive patients. In elderly diabetic patients with isolated systolic hypertension, calcium antagonists reduced the rate of cardiac end points by 63%, stroke by 73%, and total mortality by 55%. In more than 60% of diabetic hypertensive patients, combination therapy was required to control BP., Conclusions: Intensive control of BP reduced cardiovascular morbidity and mortality in diabetic patients regardless of whether low-dose diuretics, beta-blockers, angiotensin converting enzyme inhibitors, or calcium antagonists were used as a first-line treatment. Combination of more than one drug is frequently required to control BP and may be more beneficial than monotherapy.

The role of the renin-angiotensin-aldosterone system in the pathogenesis of hypertensive disease has long been recognized, and the interruption of this cascade with angiotensin-converting enzyme-I has been beneficial in the management of hypertension. Recently, a new class of drugs, the angiotensin receptor blockers, emerged, enlarging the antihypertensive armamentarium. Since elderly patients are more prone to adverse drug reactions, in this paper we review several trials, most of which were of short duration, on the efficacy and safety of angiotensin receptor blockers in the geriatric population with mild to moderate hypertension. These studies established that the drugs are well-tolerated, safe, and in most instances as efficacious as other classes of antihypertensive medications. Combination therapy with angiotensin receptor blockers and hydrochlorothiazide was additive, without any significant effect on the safety profile.

Objective: To analyze the available data to assess the benefits of antihypertensive therapy in hypertensive patients with diabetes mellitus., Methods: A MEDLINE search of English-language articles published until June 1999 was undertaken with the use of the terms diabetes mellitus, hypertension or blood pressure, and therapy. Pertinent articles cited in the identified reports were also reviewed. Included were only prospective randomized studies of more than 12 months' duration that evaluated the effect of drug treatment on morbidity and mortality in diabetic hypertensive patients. We estimated the risk associated with combination of diabetes mellitus and hypertension and the effect of treatment on morbidity and mortality., Results: The coexistence of diabetes mellitus doubled the risk of cardiovascular events, cardiovascular mortality, and total mortality in hypertensive patients (approximate relative risk of 1.73-2.77 for cardiovascular events, 2.25-3.66 for cardiovascular mortality, and 1.73-2.18 for total mortality). Intensive blood pressure control to levels lower than 130/85 mm Hg was beneficial in diabetic hypertensive patients. All 4 drug classes-diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium antagonists-were effective in reducing cardiovascular events in diabetic hypertensive patients. In elderly diabetic patients with isolated systolic hypertension, calcium antagonists reduced the rate of cardiac end points by 63%, stroke by 73%, and total mortality by 55%. In more than 60% of diabetic hypertensive patients, combination therapy was required to control blood pressure., Conclusions: Intensive control of blood pressure reduced cardiovascular morbidity and mortality in diabetic patients regardless of whether low-dose diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists were used as a first-line treatment. A combination of more than 1 drug is frequently required to control blood pressure and may be more beneficial than monotherapy.

Background: National Health and Nutritional Examination surveys have documented poor rates of hypertension treatment and control, leading to preventable morbidity and mortality., Objectives: To examine covariation in the medication and health lifestyle beliefs and behaviors of persons with hypertension to identify and profile distinct subgroups of patients., Methods: A sample of 727 patients with hypertension, weighted to match the 1992 National Health Interview Survey age and sex distribution of patients with hypertension, was interviewed by telephone about their beliefs and behaviors regarding hypertension and its management. Cluster analysis of key variables was used to identify 4 patient types., Results: Subgroups differed significantly. Group A members use an effective mix of medication and health lifestyle regimens to control blood pressure. Group B members are most likely to depend on medication and have high adherence rates. Yet they also have high rates of smoking (29%) and alcohol use (average, 104 times per year) and are less likely to exercise regularly. Group C members are most likely to forget to take medication, are likely to be obese, and find it most difficult to comply with lifestyle changes (except for very low rates of smoking and alcohol use). Group D members are least likely to take medication, most likely to change or stop medication without consulting their physician (20%), most likely to smoke (40%), and least likely to control diet (29%). Group A and B members have better health outcomes than group C and D members., Conclusions: Optimal management strategies are likely to differ for the 4 patient types. Further research should be conducted to validate these findings on a separate sample and to devise and test tailored management algorithms for hypertension compliance and control.

Despite a proven efficacy in lowering blood pressure, centrally acting antihypertensive drugs are no longer widely used because of the relative high incidence of adverse effects. Most central side-effects occurring with these drugs are mediated by the alpha2-receptor. Moxonidine is an imidazoline receptor agonist that is highly selective for the I1-imidazoline receptor with little effect at the central alpha2-receptor. Moxonidine has been shown to diminish sympathetic activity, as measured by norepinephrine, epinephrine and plasma renin activity. Acute and long-term hemodynamic studies show that moxonidine reduces arterial pressure by lowering systemic vascular resistance while sparing heart rate, cardiac output and stroke volume. Moxonidine has been shown to reduce left ventricular hypertrophy and is metabolically neutral; it may have a favourable effect on insulin resistance. Clinical studies have documented efficacy of moxonidine as an antihypertensive agent. Most patients' blood pressure was satisfactorily controlled with a dose between 0.2 and 0.4 mg per day. Comparative studies are available with most other antihypertensive drug classes, such as clonidine, diuretics, alpha-blockers, beta-blockers, calcium antagonists, and ACE inhibitors, and document similar blood pressure control with moxonidine as with other agents. Specifically, by using 24-h ambulatory blood pressure monitoring, blood pressure control was found to be similar with moxonidine and enalapril. The side-effect profile of moxonidine has been shown to be favorable as might be expected from its lack of an alpha2-receptor mediated central effect. Moxonidine, therefore, represents an advance in the tolerability of anti-adrenergic drugs without apparent reduction in efficacy. All of these observations suggest that moxonidine may offer advantages over other antihypertensive drugs, but clearly these potential advantages need to be properly evaluated in a prospective morbidity and mortality study.

Antihypertensive treatment may promote cancer through unknown mechanisms. Early retrospective studies implicated reserpine in breast cancer, but the drug was later absolved by prospective analyses. Data from case-controlled studies and several cohort studies suggested an association between the use of a diuretic and the occurrence of renal cell cancer. Several prospective studies showed that treatment with atenolol may increase mortality from malignancy. However, other studies that analyzed data from several thousand patients could not confirm this association. In two prospective studies, angiotensin-converting enzyme (ACE) inhibitors were associated with increased mortality from malignancy, but a few case-controlled studies showed no association between use of ACE inhibitors and malignancy. In addition, a recent retrospective study showed that long-term use of ACE inhibitors had a protective effect against malignancy. In some studies, calcium antagonists were implicated in increasing the risk for cancer; however, two large case-controlled studies and the combined data from nine observational studies showed a similar risk for malignancy among users and nonusers of a calcium antagonist. Ongoing long-term prospective studies will tell us more about the carcinogenicity of cardiovascular drugs.

Hypertensive crisis is defined as a severe elevation in BP and is classified as either urgency or emergency. In hypertensive urgency there is no end-organ injury and no evidence that acute BP lowering is beneficial. Indeed, rapid uncontrolled pressure reduction may be harmful. Therefore, in hypertensive urgencies BP should be lowered gradually over 24 to 48 hours using oral antihypertensives. When the cause of transient BP elevations is easily identified, appropriate treatment should be given. When the cause is unknown, an oral antihypertensive should be given. The efficacy of available treatments appear similar; however, the underlying pathophysiological and clinical findings, mechanism of action and potential for adverse effects should guide choice. Captopril should be avoided in patients with bilateral renal artery stenosis or unilateral renal artery stenosis in patients with a solitary kidney. Nifedipine and other dihydropyridines increase heart rate whereas clonidine, beta-blockers and labetalol tend to decrease it. This is particularly important in patients with ischaemic heart disease. Labetalol and beta-blockers are contraindicated in patients with bronchospasm and bradycardia or heart blocks. Clonidine should be avoided if mental acuity is desired. In hypertensive emergency there is an immediate threat to the integrity of the cardiovascular system. BP should be immediately reduced to avoid further end organ damage. Sodium nitroprusside is the most popular agent. Nitroglycerin (glyceryl trinitrate) is preferred when there is acute coronary insufficiency. A beta-blocker may be added in some patients. Loop diuretics, nitroglycerin and sodium nitroprusside are effective in patients with concomitant pulmonary oedema. Enalaprilat is also theoretically helpful, especially when the renin system might be activated. Initial treatment of aortic dissection involves rapid, controlled titration of arterial pressure to normal levels using intravenous sodium nitroprusside and a beta-blocker. If beta-blockers are contraindicated, urapidil or trimetaphan camsilate are alternatives. Hydralazine is the drug of choice for patients with eclampsia. Labetalol, urapidil or calcium antagonists are possible alternatives if hydralazine fails or is contraindicated. For patients with catecholamine-induced crises, an alpha-blocker such as phentolamine should be given; labetalol or sodium nitroprusside with beta-blockers are alternatives. There are few, if any, comparative or randomised trials providing definitive conclusions about the efficacy and safety of comparative agents. Some investigators recommend decreasing the diastolic BP to no less than 100 to 110 mm Hg. A reasonable approach for most patients with hypertensive emergencies is to lower the mean arterial pressure by 25% over the initial 2 to 4 hours with the most specific antihypertensive regimen.

Objective: To assess antihypertensive efficacy of beta-blockers and their effects on cardiovascular morbidity and mortality and all-cause morbidity compared with diuretics in elderly patients with hypertension., Data Source: A MEDLINE search of English-language articles published between January 1966 and January 1998 using the terms hypertension (drug therapy) and elderly or aged or geriatric, and cerebrovascular or cardiovascular diseases, and morbidity or mortality. References from identified articles were also reviewed., Data Selection: Randomized trials lasting at least 1 year, which used as first-line agents diuretics and/or beta-blockers, and reported morbidity and mortality outcomes in elderly patients with hypertension. DATA SYNTHESIS AND RESULTS: Ten trials involving a total of 16164 elderly patients (> or =60 years) were included. Two thirds of the patients assigned to diuretics were well controlled on monotherapy, whereas less than a third of the patients assigned to beta-blockers were well controlled on monotherapy. Diuretic therapy was superior to beta-blockade with regard to all end points and was effective in preventing cerebrovascular events (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.51-0.72), fatal stroke (OR, 0.67; 95% CI, 0.49-0.90), coronary heart disease (OR, 0.74; 95% CI, 0.64-0.85), cardiovascular mortality (OR, 0.75; 95% CI, 0.64-0.87), and all-cause mortality (OR, 0.86; 95% CI, 0.77-0.96). In contrast, beta-blocker therapy only reduced the odds for cerebrovascular events (OR, 0.75; 95% CI, 0.57-0.98) but was ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality (ORs, 1.01, 0.98, and 1.05, respectively)., Conclusions: In contrast to diuretics, which remain the standard first-line therapy, beta-blockers, until proven otherwise, should no longer be considered appropriate first-line therapy of uncomplicated hypertension in the elderly hypertensive patient.

The combination of an angiotensin converting enzyme inhibitor with a calcium antagonist has become a common way of treating patients with essential hypertension who respond insufficiently to monotherapy. This double-blind, randomized, parallel, placebo-controlled, multicenter, outpatient study evaluated the antihypertensive efficacy and safety of a calcium antagonist (verapamil SR) and an angiotensin converting enzyme inhibitor (trandolapril) in patients with mild-to-moderate (stages I and II) essential hypertension. Six hundred thirty-one patients were enrolled in this 10-week study. After a 4-week single-blind placebo phase, patients received one of the following daily dosage regimens in a double-blind fashion for 6 weeks: placebo, 4 mg of trandolapril, 240 mg of verapamil SR, or a combination of 4 mg of trandolapril and 240 mg of verapamil SR. Trough sitting diastolic blood pressure was lowered by 4.5 mm Hg, 4.3 mm Hg, and 8.1 mm Hg more than placebo in the trandolapril, verapamil SR, and combination groups, respectively. In the combination group, sitting diastolic blood pressure was significantly lowered (P < .01) by 3.6 mm Hg more than in the trandolapril group and by 3.8 mm Hg more than in the verapamil SR group. An analysis of the trough-to-peak ratio for sitting diastolic blood pressure revealed values of 0.75 and 0.67, for the 4-mg trandolapril and the combination groups, respectively, at end point. The overall incidence of adverse reactions was similar for all treatment groups. In this study the combination of an angiotensin converting enzyme inhibitor and calcium antagonist was well tolerated and more effective than either agent administered alone for the treatment of mild-to-moderate essential hypertension.

RATIONALE FOR DRUG COMBINATIONS: The most common reason for combining different drugs is to achieve an additional fall in arterial pressure. It therefore seems reasonable to combine drugs with different mechanisms of actions. NEED FOR CLINICAL TRIALS: However, the effects of combination therapy on the heart and other target organs remains poorly documented. Most of what we know with regard to combination therapy on hypertensive heart disease is based on extrapolation from monotherapy. The fact that two drugs when used separately are beneficial in a disorder does not necessarily imply that their combination is equally or more beneficial in the same disorder. Thus, it will become important to establish efficacy and safety of new drug combinations on hypertensive target organs and on morbidity and mortality by performing carefully designed clinical trials.

Essential hypertension is a common disorder, and a variety of antihypertensive drugs are available to lower blood pressure in the normal range. Identifying special subpopulations by differences in age, gender, race, and body weight has taught clinicians to be more selective in antihypertensive therapy. The rationale for this selectivity is often speculative and has not been corroborated by any hard data. It is hoped that some of the prospective, randomized trials currently in progress will throw some light on this question.

Control of hypertension and treatment of concomitant pathophysiologic conditions require use of multiple drugs. Unfortunately, most studies regarding hypertensive disease have focused on monotherapy. Thus, our knowledge of combination therapy in the treatment of hypertension is, to a great extent, extrapolation from monotherapy. Angiotensin converting enzyme (ACE) inhibitors in combination with calcium antagonists should be particularly efficacious in reducing left ventricular hypertrophy (LVH). Drug classes that either stimulate the renin-angiotensin system or the sympathetic nervous system are less likely to reduce LVH and should be avoided. In hypertensive patients with congestive heart failure, amlodipine should be added to triple therapy with an ACE inhibitor, whereas in the postmyocardial ischemia patient, verapamil may exert some additional beneficial effects with regard to reinfarction rates. Given that two drugs when used separately are beneficial in a disorder does not necessarily mean that their combination is equally or even more beneficial. Thus, combination therapy should primarily be used for lowering arterial pressure and only secondarily to possibly improve concomitant pathophysiologic conditions associated with hypertensive heart disease.

The Joint National Committee V suggested that combination therapy can provide effective blood pressure control in patients with stage I-IV hypertension. This 4 x 4 factorial trial design assessed the efficacy of monotherapy with trandolapril-an ACE inhibitor, and verapamil SR-a calcium antagonist, each in a range of 3 doses as monotherapy, and in combination therapy in patients with stage I-III diastolic hypertension. After a 4-week, single-blind placebo treatment period, 746 patients in 39 study centers were randomized to 1 of the 16 double-blind treatments for 6 weeks (placebo, verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono and combination therapies achieved the primary efficacy parameters: lowered diastolic blood pressure (at trough) more than placebo, p < 01 (except the 120 mg verapamil SR, NS, 0.5 mg trandolapril, 0.5/180 and 2/120 combinations, p < 05), yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo. Combination therapy was more effective than monotherapy for sitting diastolic blood pressure 2/180, p < 01; 2/240 and 8/240, p < 05. There were no differences between active treatment groups and placebo as a percentage of patients having adverse reactions. Trandolapril, 2 and 8 mg, appeared to have a greater incremental effect on the systolic blood pressure reduction of the combination than verapamil SR 180 and 240 mg.

The cardiovascular effects of a combination of trandolapril and verapamil were evaluated in 14 patients with mild to moderate essential hypertension. This combination therapy decreased arterial pressure mainly through a decrease in total peripheral resistance without causing an increase in heart rate or cardiac output: left ventricular mass was significantly reduced, cardiac systolic function improved, and plasma volume and renal blood flow remained unchanged.

The presence of left ventricular hypertrophy (LVH) usually indicates that hypertension is moderately severe and that combination therapy will be required to control blood pressure (BP). Unfortunately, most studies on the reduction of LVH have been done with monotherapy. Our knowledge of combination therapy in the treatment of hypertensive heart disease is to a great extent extrapolation from monotherapy. Angiotensin-converting enzyme (ACE) inhibitors in combination with calcium antagonists ought to be particularly efficacious in reducing LVH. Drug classes that either stimulate the renin angiotensin system or the sympathetic nervous system are less likely to reduce LVH and should be avoided. In hypertensive patients with congestive heart failure, amlodipine should be added to triple therapy with an ACE inhibitor, whereas in the post myocardial ischemia patient, verapamil may exert some additional beneficial effects with regard to reinfarction rates. Of note, given that two drugs when used separately are beneficial in a disorder does not necessarily mean that their combination is equally or even more beneficial. Thus, combination therapy should primarily be used for lowering arterial pressure and only secondarily to possibly improve concomitant pathophysiologic conditions associated with hypertensive heart disease.

Over the past 2 decades, nifedipine in the form of capsules has become widely popular in the treatment of hypertensive emergencies. Unlike other agents, such as sodium nitroprusside, nicardipine hydrochloride, diazoxide, and nitroglycerin--which require intravenous administration and monitoring of blood pressure--nifedipine can be given orally, and close monitoring is said not to be necessary. Although administration of nifedipine capsules has been reported to be expedient and safe, it has not been approved by the Food and Drug Administration for labeling for treatment of hypertensive emergencies or of any other form of hypertension because of lack of outcome data. A review of the literature revealed reports of serious adverse effects such as cerebrovascular ischemia, stroke, numerous instances of severe hypotension, acute myocardial infarction, conduction disturbances, fetal distress, and death. Sublingual absorption of nifedipine has been found to be poor; most of the drug is absorbed by the intestinal mucosa. Given the seriousness of the reported adverse events and the lack of any clinical documentation attesting to a benefit, the use of nifedipine capsules for hypertensive emergencies and pseudoemergencies should be abandoned.

Angiotensin II receptor antagonists represent a new class of drugs that provide a site-specific blockade of the effects of angiotensin II. Losartan potassium, the first compound of this drug class, has recently become available in the United States. The clinical experience with angiotensin II receptor antagonists has demonstrated that these drugs are safe and efficacious for the treatment of hypertension and, possibly, congestive heart failure. Unlike with angiotensin-converting enzyme inhibitors, the incidence of cough observed with angiotensin receptor antagonists is similar to that with placebo. Although several angiotensin receptors have been characterized, the effects of losartan and other angiotensin receptor antagonists under development are selective for the angiotensin II type 1 receptor. Unlike angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists do not inhibit bradykinin metabolism or enhance prostaglandin synthesis. The antihypertensive efficacy of the angiotensin receptor antagonists has been documented to be similar to that of angiotensin-converting enzyme inhibitors. If the findings of clinical studies corroborate the initial reports on efficacy and safety, it seems likely that the angiotensin receptor antagonists will be added to the list of drugs that have been deemed suitable for first-line therapy in the treatment of hypertension and congestive heart failure.

Left ventricular hypertrophy (LVH), an increase in the muscle mass of the left ventricle, has been identified as a powerful risk factor for future cardiovascular morbidity and mortality. The risk of acute myocardial infarction, congestive heart failure, sudden death, and other cardiovascular events increases sixfold to eightfold with the occurrence of LVH. The increase in myocardial mass lowers coronary reserve and enhances cardiac oxygen requirements, gives rise to ventricular ectopy, and impairs left ventricular filling and contractility. Hypertension, obesity, advanced age, valvular heart disease, and other pathologic disorders that cause an increase in the hemodynamic burden can lead to LVH. LVH and its sequelae can be reduced by specific antihypertensive therapy, but despite these promising findings, future epidemiologic studies are necessary to document the clinical benefits of a reduction in LVH.

In patients in whom monotherapy does not control blood pressure a second agent is required. Common combinations in clinical practice are a beta-blocker plus a diuretic, an angiotensin converting enzyme (ACE) inhibitor plus a diuretic, a beta-blocker plus a dihydropyridine calcium antagonist, and an ACE inhibitor plus a calcium antagonist. Since both ACE inhibitors and calcium antagonists are metabolically inert and exert favorable effects on target organ disease, their combination is of particular interest. When combined, these two drug classes have additive effects on antihypertensive efficacy, reduction of left ventricular hypertrophy, and protection of the renal circulation. However, whether or not these favorable pathophysiologic changes induced with combination therapy of ACE inhibitors and calcium antagonists will translate into a reduction of morbidity and mortality remains to be documented.

There are four possible pathophysiological mechanisms which may relate left ventricular hypertrophy (LVH) with cardiovascular morbidity and mortality: LVH diminishes left ventricular filling; LVH decreases coronary reserve and hampers myocardial oxygenation; LVH is commonly associated with ventricular arrhythmias, and with long-standing LVH, left ventricular contractility decreases. LVH can be reduced by a range of antihypertensive drugs, although not all drugs are equipotent in this regard. Two recent meta-analyses have indicated that ACE inhibitors are among the most powerful monotherapeutic modalities to reduce LVH. Calcium channel blockers are almost as effective, whereas beta-blockers and diuretics seem to have a lesser effect, despite equipotent antihypertensive properties. Reducing LVH with ACE inhibitors and calcium channel blockers has been shown to improve contractility and left ventricular filling, and diminish ventricular ectopy. A preliminary study also indicates that coronary reserve increases after reduction in LVH. Despite these promising pathophysiological signs, it remains unknown whether or not a reduction in LVH will reduce morbidity and mortality over and above the reduction achieved by a reduction in arterial pressure alone.

Recent evidence has shown that a decrease in left ventricular hypertrophy (LVH) by antihypertensive agents suppresses ventricular ectopy, improves ventricular filling, and maintains or even enhances LV function. However, not all antihypertensive drugs reverse LVH or reduce ectopy in spite of their ability to lower blood pressure. Preliminary data suggest that the reversal of LVH is linked to a decrease in cardiovascular morbidity and mortality.

Left ventricular hypertrophy (LVH) is both a target organ response to chronic arterial hypertension and a disorder that may be responsible for cardiovascular events. Although an increase in ventricular wall thickness may initially be compensatory and decrease wall stress, numerous studies have indicated that LVH is associated with a reduction in coronary flow reserve, diastolic and systolic ventricular dysfunction, and ventricular arrhythmias, all of which predispose to morbid cardiovascular events, including acute coronary syndromes, congestive myocardial failure, and sudden death. Reduction in LVH has been accomplished with beneficial effects on diastolic function and ventricular arrhythmias, without pressure-induced deterioration in systolic or diastolic function. Although therapy with diuretics and vasodilators effectively lowers arterial pressure, these therapies are not usually associated with significant regression of LVH. Calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, beta-adrenergic blockers, central adrenergic blocking agents, and possibly alpha-adrenergic blockers and diuretics with vasodilatory properties are associated with reductions in LV mass. However, studies are still needed to determine the relative effects of various antihypertensive therapies on LVH regression, coronary flow reserve, ventricular function, ventricular ectopy, and most importantly, on protection against major cardiac morbidity and mortality inherent to LVH.

The immediate and short-term cardiovascular effects of oral isradipine therapy were evaluated in 11 patients with mild to moderate systemic hypertension. Isradipine, 5 mg administered orally, induced a significant reduction in arterial pressure from 165 +/- 6/88 +/- 3 mm Hg to 140 +/- 5/76 +/- 2 mm Hg (p less than 0.001) within 2.5 hours by a decrease in total peripheral resistance associated with an increase in heart rate and cardiac output. Contrary to the acute effect, oral therapy with isradipine for 3 months reduced arterial pressure through a decrease in total peripheral resistance but without causing an increase in heart rate or cardiac output or activation of the sympathetic nervous system. Isradipine slightly reduced left ventricular mass and improved cardiac systolic function and left ventricular filling. Renal blood flow increased, and renal vascular resistance (p less than 0.01) and total blood volume (p less than 0.002) decreased without a change in either sodium excretion or body weight. Thus, isradipine, when given for 3 months, decreased arterial pressure by reducing total peripheral resistance without activation of reflexive mechanisms. Its favorable effects on systemic hemodynamics, total blood volume, renal blood flow, and cardiac structure and function suggest isradipine to be an excellent choice for antihypertensive therapy.

The benefits of continuous antihypertensive therapy have been extensively documented. However, lack of compliance with the prescribed regimen, excessive cost, and troublesome adverse effects of some antihypertensive agents led to the consideration of intermittent therapy or even complete discontinuation of therapy as an effective alternative to lifelong medication. Prospective studies dealing with this subject reported inconsistent results. Nevertheless, they allowed us to identify selection criteria of candidates for step-down or discontinuation of antihypertensive therapy. Such candidates include patients with mild essential hypertension who have one or more of the following characteristics: young age, normal body weight, low salt intake, no alcohol consumption, low pretreatment blood pressure, successful therapy with one drug only, and no or only minimal signs of target organ damage. Stopping antihypertensive therapy without subsequent rise in arterial pressure was shown to be possible in a subset of patients with mild essential hypertension for a period of months to years. This approach appears to be safe, provided that blood pressure is monitored frequently, and may improve compliance, save treatment costs, and reduce adverse effects of certain drugs, although its long-term consequences for morbidity and mortality remain to be determined.

The development of left ventricular hypertrophy (LVH) is one way that the heart compensates for the hemodynamic burden of sustained hypertension. However, this adaptation itself contributes to increased cardiovascular morbidity and mortality. In this article, Dr Messerli describes the causes and consequences of LVH and discusses the current therapeutic approach to patients with the condition.