Antihypertensive drugs: diuretics and betablockers are the best assessed

(1) In trials involving hypertensive non diabetic patients under 65, some diuretics and betablockers have prevented strokes, without conferring protection from coronary events or death. In one trial captopril had an effect comparable to that of diuretics or betablockers in terms of overall cardiovascular prevention, but was a little less effective in preventing strokes. (2) In trials involving hypertensive subjects over 65, some diuretics and betablockers have reduced the risk of stroke, coronary events, heart failure, and death. In one trial a diuretic was superior to a betablocker in terms of preventive efficacy and adverse effects. Nitrendipine, in combination with other antihypertensive drugs, prevented strokes in one trial. (3) In a trial involving hypertensive diabetic patients, captopril and atenolol reduced the risk of stroke, heart failure and worsening of retinal disease, without preventing coronary events or death. In two trials coronary events were more frequent on dihydropyridine than on an angiotensin-coverting-enzyme (ACE) inhibitor. (4) In one trial a diuretic reduced the risk of relapse after stroke, even in patients without severe hypertension.     

Arterial hypertension: second-line treatment. Try other single-agent treatments

(1) Reliable evidence supports the use of thiazide diuretics (chlortalidone or hydrochlorothiazide) as first-line treatment for uncomplicated arterial hypertension. (2) When patients fail to reach blood pressure targets with well-conducted treatment with thiazide diuretics, or this treatment is poorly tolerated, what are the best second-line options? To answer this question, we reviewed the available evidence, based on our standard in-house methodology. (3) We found no published trials specifically designed to evaluate second-line antihypertensive treatments in cardiovascular prevention. There were no available trials of dual- versus single-agent therapy after failure of a thiazide diuretic. (4) When the blood pressure target is not reached, inadequate drug efficacy is only one of several possible causes. Various other factors affecting blood pressure should also be investigated. (5) Dual-agent therapy carries an increased risk of adverse effects and drug interactions compared to monotherapy. (6) There is no consensus among clinical practice guidelines on second-line antihypertensive therapy. However, to minimise the risk of adverse effects, it is clearly better to select single-agent therapy with a drug that has been shown to prevent cardiovascular events in first-line treatment of otherwise healthy hypertensive patients. Possible options include: angiotensin-converting-enzyme inhibitors, angiotensin II antagonists, calcium channel blockers or betablockers. In patients over the age of 60, betablockers seem less effective that the other drugs in preventing strokes. (7) There is too little evidence to choose a specific third-line combination rather than another. However, any adverse effects that the patient experienced during prior treatments should be taken into account.     

The Effect of Antihypertensive Agents on New-Onset Diabetes Mellitus

Recent large hypertension trials have shown great differences in incidence of new-onset diabetes mellitus among patients receiving different antihypertensive drug therapies. The incidence of diabetes is unchanged or increased by the use of thiazide diuretics and beta-adrenoceptor antagonists (beta-blockers) and unchanged or decreased by ACE inhibitors, calcium channel blockers (CCBs), and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers). Recent results from ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) showed superiority of the 'new' combination of CCBs and ACE inhibitors over the 'old' or 'conventional' combination of beta-blockers and diuretics. In this review, the results from some of the large hypertension trials are discussed, and the hypotheses on how different antihypertensive drug regimens can affect glucose homeostasis are considered. The question now is whether the results from these recent trials should affect the choice of antihypertensive treatment, particularly for special groups. However, the key goal is still to reduce BP, and this usually requires combinations of drugs.     

Antihypertensive therapy in the prevention of stroke: what, when and for whom?

It is clear that antihypertensive regimens based on a low dose thiazide diuretic are effective for the primary prevention of stroke, particularly in older patients. In patients with diabetes mellitus who are at a higher risk of stroke, low dose thiazide diuretics and ACE inhibitors are of benefit. In those with isolated systolic hypertension, long-acting dihydropyridine calcium antagonists, in addition tolow dose thiazide diuretics, have also been shown to significantly reduce stroke risk. However, to attain sufficient lowering of blood pressure (BP) to most effectively reduce the risk of stroke (i.e. to levels of 140-150/80-85 mm Hg or lower and perhaps to <140/<80 mm Hg in patients with diabetes mellitus) combination therapy will be required. Immediately following stroke BP tends to fall spontaneously and therapy is probably not required in the great majority of patients during the first few days poststroke. If treatment is required shortly after this period, agents with a slow and gentle onset of action appear to be preferable; some preliminary data suggest that ACE inhibitors, despite lowering systemic BP, have no significant effect on cerebral blood flow. However, there is little clinical outcome data to clearly define the role of antihypertensive treatment in the early poststroke period. Whether existing antihypertensive therapy should be continued following stroke is also unclear, but such decisions may be influenced by factors such as the actual BP level, other indications for treatment (e.g. angina pectoris or cardiac failure) or the presence of dysphagia. There is more evidence to suggest that, some weeks to months following stroke (particularly a minor stroke), lower rather than higher BP is favourable, and better control of high BP with therapy reduces stroke recurrence.     

Antioxidative effects of thiazide diuretics in refractory hypertensive patients. A randomized crossover trial of chlortalidone and trichlormethiazide

Some thiazide diuretics seem to exert antioxidant effects, which may be beneficial in the management of hypertension. Although many large-scale clinical trials on hypertension have proved that thiazide diuretics confer significant reductions in stroke and cardiovascular events, most of these trials preferentially used chlortalidone. Therefore, the difference in antioxidant effects between chlortalidone (CAS 77-36-1; 12.5 mg/day) and another thiazide diuretic, trichlormethiazide (CAS 133-67-5; 1 mg/day) was studied. Forty patients with refractory hypertension even after treatment with a combination of a calcium channel blocker and an angiotensin II receptor blocker were randomly assigned to additionally receive either chlortalidone or trichlormethiazide for 6 months. Then, diuretics were switched in each patient and they were treated for another 6 months. Ambulatory blood pressure was monitored for 24 h and markers of inflammation (C-reactive protein) and oxidative stress (8-isoprostane, malondialdehyde-modified low-density lipoproteins) were measured before and after each treatment. Addition of chlortalidone resulted in a greater reduction of blood pressure (mean of 24 h; from 146.8 +/- 18.0/83.8 +/- 12.2 mmHg to 122 +/- 18/72 +/- 11 mmHg) than that of trichlormethiazide (134 +/- 18/ 78 +/- 11 mmHg, p < 0.001). The levels of C-reactive protein, malondialdehyde-modified low-density lipoproteins, and 8-isoprostane were lower after chlortalidone therapy than after trichlormethiazide therapy. These results suggest that chlortalidone is superior to trichlormethiazide in patients with essential hypertension.     

Calcium antagonists in the treatment of hypertension in patients with ischaemic heart disease

Are lives saved or heart attacks prevented by antihypertensive therapy, as a result of blood pressure reduction alone, or because of other properties of the antihypertensive medications which are independent of blood pressure lowering? Long-acting calcium antagonists seem to be as effective as thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors in preventing all-cause mortality and stroke in patients with hypertension, but are probably inferior to ACE inhibitors in preventing coronary artery disease. In patients with symptomatic coronary artery disease, calcium antagonists are generally as effective as β-blockers in relieving angina and improving exercise time-to-onset of angina or ischaemia. Unstable angina or myocardial infarction require treatment with a β-blocker, with an ACE inhibitor added when necessary for blood pressure control or if there is significant left ventricular (LV) dysfunction. If β-blockers are contraindicated and if there is no LV dysfunction, a non-dihydropyridine calcium antagonist can be substituted.     

Calcium antagonists in the treatment of hypertension in patients with ischaemic heart disease

Are lives saved or heart attacks prevented by antihypertensive therapy, as a result of blood pressure reduction alone, or because of other properties of the antihypertensive medications which are independent of blood pressure lowering? Long-acting calcium antagonists seem to be as effective as thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors in preventing all-cause mortality and stroke in patients with hypertension, but are probably inferior to ACE inhibitors in preventing coronary artery disease. In patients with symptomatic coronary artery disease, calcium antagonists are generally as effective as beta-blockers in relieving angina and improving exercise time-to-onset of angina or ischaemia. Unstable angina or myocardial infarction require treatment with a beta-blocker, with an ACE inhibitor added when necessary for blood pressure control or if there is significant left ventricular (LV) dysfunction. If beta-blockers are contraindicated and if there is no LV dysfunction, a non-dihydropyridine calcium antagonist can be substituted.     

Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension.

Enalapril, an angiotensin converting enzyme (ACE) inhibitor usually administered orally once daily, decreases blood pressure by lowering peripheral vascular resistance without increasing heart rate or output. It is effective in lowering blood pressure in all grades of essential and renovascular hypertension. Patients not responding adequately to enalapril monotherapy usually respond with the addition of a thiazide diuretic (or a calcium antagonist or beta-blocker), and rarely require a third antihypertensive agent. Enalapril is at least as effective as other established and newer ACE inhibitors, and members of other antihypertensive drug classes including diuretics, beta-blockers, calcium antagonists and alpha-blockers, but therapy with enalapril may be less frequently limited by serious adverse effects or treatment contraindications than with other drug classes. The most frequent adverse effect limiting all ACE inhibitor therapy in clinical practice is cough. This favourable profile of efficacy and tolerability, and the substantial weight of clinical experience, explain the increasing acceptance of enalapril as a major antihypertensive treatment and supports its use as logical first-line therapeutic option.     

Enalapril and hydrochlorothiazide in hypertensive Africans

Summary The antihypertensive efficacy both of angiotensin converting enzyme (ACE) inhibitors and thiazide diuretics has been claimed to be influenced by plasma renin activity, which declines with age and is low in blacks. In a double-blind, placebo-controlled, double-dummy, randomized, parallel-group preliminary study, the antihypertensive efficacy and tolerability of the ACE inhibitor enalapril (20 mg day^–1) and hydrochlorothiazide (50 mg day^–1) were evaluated and compared for 4 weeks in 20 African patients with essential hypertension. The two groups had similar baseline clinical features and serum Na⁺ and K⁺ levels.Hydrochlorothiazide caused a significant and sustained fall in erect blood pressure with a reflex tachycardia. Enalapril exerted only a modest antihypertensive action, but significantly reduced erect heart rate.Direct comparison of hydrochlorothiazide — and enalapril — induced hypotension suggested a greater fall in subjects on the thiazide. The 95% confidence limits for the thiazide-enalapril difference in antihypertensive action at the end of the study was 39.5 to –7.5 mm Hg systolic and 22.0 to –6.6 mm Hg diastolic. The maximal blood pressure fall after hydrochlorothiazide was positively correlated with age (r=0.50;p<0.05), whilst that of enalapril was inversely related age to (r=–0.57,p<0.05).The results are compatible with the notion that ACE inhibitor monotherapy may be less effective than thiazide diuretic treatment in African and black patients with essential hypertension. The findings also support the concept that age and racial factors may influence the response to antihypertensive treatment.     

Valsartan: new preparation. Just a second-line antihypertensive drug

(1) Valsartan is a antihypertensive drug belonging to the family of angiotensin II receptor antagonists. (2) At a dose of 40 mg/day its antihypertensive effect is inconsistent. (3) At 80 mg/day its effect on blood pressure, its adverse effects and its contraindications (mainly pregnancy and renal artery stenosis) are similar to those of angiotensin-converting-enzyme (ACE) inhibitors, except that coughing is rarer with valsartan than with ACE inhibitors. (4) Valsartan has no demonstrated advantage over losartan, another angiotensin II antagonist. (5) Valsartan has not been shown to prevent the complications of arterial hypertension, and its use is therefore less well validated than that of diuretics and betablockers.     

Angiotensin-converting enzyme inhibitors and stroke risk: benefit beyond blood pressure reduction?

Hypertension, a leading cause of morbidity and mortality, accounts for 25-49% of all strokes. Randomized placebo-controlled trials primarily with diuretics and beta-blockers administered in patients with hypertension have demonstrated a 38% reduction in primary stroke. Placebo-controlled trials with angiotensin-converting enzyme (ACE) inhibitors have not been conducted in patients with hypertension. However, in a meta-analysis of four placebo-controlled trials of ACE inhibitors in patients with coronary heart disease and/or diabetes mellitus, the overall risk of primary stroke was significantly reduced. Results of the Heart Outcomes Prevention Evaluation trial, which produced a substantial reduction in stroke with an apparently small reduction in blood pressure, suggest that the benefit of ACE inhibitors may be related to their effects on the renin-angiotensin-aldosterone system more than on blood pressure reduction. In active-control comparisons in patients with hypertension, ACE inhibitors have demonstrated reductions in primary stroke risk similar to reductions with diuretics, beta-blockers, and calcium channel blockers. The data suggest that for primary prevention of stroke antihypertensive therapy should be individualized in patients. Relatively few data are available concerning the benefit of antihypertensive therapy in the secondary prevention of stroke. In patients who had experienced a stroke or transient ischemic attack, therapy with a diuretic or a combination of a diuretic plus an ACE inhibitor could be recommended based on available outcome studies conducted in this patient population. It is premature to conclude that the benefit of ACE inhibitor therapy in primary or secondary prevention of stroke is an effect independent of blood pressure reduction. Hypertension detection, treatment, and control in patients still must be the principal focus of clinicians for both primary and secondary prevention of stroke.     

Drug treatment for hypertension in Finnish primary health care

Objective: To analyse the prescribing patterns of antihypertensive drugs in Finnish primary health care and to describe the profiles of monotherapy and combination therapy in relation to the duration of high blood pressure. Methods: Thirty out of 250 primary health care centres were randomly selected for the study. All doctors (n?=?337) from the participating health centres recorded all hypertensive patients (n?=?4405) during a 2-week period in May 1995. Adequate information was obtained concerning 4294 hypertensives, of whom 65% were women with a mean age for the total study population of 64 years. 85% of the patients (n= 3638) had antihypertensive medication which was classified into five main categories: diuretics, beta blocking agents, calcium channel blockers, ACE inhibitors and hypotensives. Results: Of the patients using antihypertensive medication, 48% were undergoing monotherapy and 52% combination therapy. Beta blocking agents were the most frequently prescribed drugs for hypertension, being used by half of the patients. ACE inhibitors and diuretics were prescribed in a different manner for male and female hypertensives, with men receiving more ACE inhibitors and women more diuretics. The number of antihypertensive drugs increased with the duration of hypertension, though 38% of the patients having hypertension for over 10 years were still undergoing monotherapy. Among patients undergoing combination therapy, 75% received two different agents, most often a diuretic with a beta blocking agent. Conclusions: With increasing duration of hypertension, the number of antihypertensive drugs also increased. Beta blocking agents were the drug of choice for all patients. For women, combination therapy more frequently included diuretics, whereas ACE inhibitors were favoured for men.     

某高校社区门诊离退休教工抗高血压药的使用分析

目的了解和分析某社区门诊离退休教工抗高血压药的使用情况。方法抽查1 264例(2011年3月)门诊离退休高血压患者处方,详细统计及分析。结果 5大类抗高血压药中,钙拮抗药(CCB)使用率最高,达到51.91%,β-肾上腺素受体阻滞药(β-阻滞药)占14.49%,血管紧张素转化酶抑制药(ACEI)占9.22%,血管紧张素Ⅱ受体抑制药(ARB)占11.33%,利尿药占1.45%。采用单种抗高血压药治疗1 018例(占80.54%),联合使用2种或2种以上抗高血压药246例(占19.46%),利尿药联合使用率占13.82%。结论该社区门诊抗高血压药的种类及联合用药符合《中国高血压防治指南》的要求,基本合理规范,但抗高血压药物联合应用较少、利尿药的使用率偏低。     

The cost effectiveness of ACE inhibitors as first-line antihypertensive therapy

BACKGROUND: Current hypertension guidelines differ in their recommendations for first-line antihypertensive therapy. OBJECTIVE: To evaluate the cost effectiveness of ACE inhibitor therapy as antihypertensive first-line therapy as compared with conventional antihypertensive therapy with beta-adrenoceptor antagonists or diuretics. STUDY DESIGN: Cost-effectiveness analysis based on data from randomised trials and observational studies comparing the effectiveness of ACE inhibitor and conventional antihypertensive therapy, we constructed a Markov model to compare four strategies in the management of uncomplicated hypertension: (i) prescribing ACE inhibitor therapy to all patients; (ii) prescribing conventional therapy to all patients; (iii) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on electrocardiography (ECG); or (iv) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on echocardiography. METHODS: Cost data were derived from the medical literature and focus groups, and utility values were derived from patients on antihypertensive monotherapy. All costs were calculated in 1999 Canadian dollars, but are reported in US dollars according to the 1999 purchasing power parity rate for medical and healthcare. The effectiveness of ACE inhibitor therapy in the presence of left ventricular hypertrophy was derived from observational studies. The time horizon was over a lifetime. PERSPECTIVE: Third-party payer. PATIENTS/PARTICIPANTS: A cohort of men aged 40 years without cardiovascular comorbidity requiring antihypertensive drug therapy. MAIN OUTCOME MEASURES AND RESULTS: In the baseline analysis, all four strategies resulted in expected discounted QALYs that differed from each other only at the third decimal point (i.e. less than 0.003). Given the uncertainties in the variable estimates and the small size of the differences, these differences are extremely small and unlikely to represent real differences. Even accepting the small gains as real, the resulting cost-effectiveness ratios are unattractively high: $US 200,000 per QALY gained for the echocardiography strategy (compared with ECG), and $US 700,000 for the "ACE inhibitor for all" strategy (compared with ECG). The incremental cost effectiveness of prescribing ACE inhibitor therapy to everybody was never less than $US 100,000/QALY in the sensitivity analysis. CONCLUSIONS: Prescribing ACE inhibitors as antihypertensive first-line therapy in patients without cardiovascular morbidity cannot be recommended at the present time unless the acquisition costs of ACE inhibitors become substantially more attractive.     

Renal protection and antihypertensive drugs: current status.

The renal protective effect of antihypertensive drugs is linked to 2 mechanisms. First, reduction in blood pressure (BP) is a fundamental prerequisite common to all antihypertensive drugs. The exact definition of the level to which BP should be reduced remains to be established, although there is some evidence that BP should be reduced below 130/85 mm Hg in patients with diabetic and nondiabetic nephropathies and below 125/75 mm Hg in patients with nondiabetic nephropathies and proteinuria >1 g/day. However, available data suggest that tight BP control (BP<140/80 mm Hg) can reduce the risk of cardiovascular complications in hypertensive patients with type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus; NIDDM). Secondly, intrarenal actions on mechanisms such as glomerular hypertension and hypertrophy, proteinuria, mesangial cell proliferation, mesangial matrix production and probably endothelial dysfunction, which can cause and/or worsen renal failure, are relevant for the renal protective action of some drug classes. ACE inhibitors possess such properties and also seem to lower proteinuria more than other antihypertensive drugs, despite a similar BP lowering effect. Calcium antagonists likewise exert beneficial intrarenal effects, but with some differences among subclasses. It remains to be evaluated whether angiotensin II-receptor antagonists can exert intrarenal effects and antiproteinuric actions similar to those of ACE inhibitors. While primary prevention of diabetic nephropathy is still an unsolved problem. there is convincing evidence that in patients with type 1 (insulin-dependent diabetes mellitus; IDDM) or 2 diabetes mellitus and incipient nephropathy ACE inhibitors reduce urinary albumin excretion and slow the progression to overt nephropathy. Similar effects have been reported with some long-acting dihydropyridine calcium antagonists, although less consistently than with ACE inhibitors. In patients with diabetic overt nephropathy, ACE inhibitors and nondihydropyridine calcium antagonists are particularly effective in reducing proteinuria and both drugs can slow the decline in glomerular filtration rate more successfully than other antihypertensive treatment. Available data in patients with nondiabetic nephropathies indicate that ACE inhibitors can be beneficial, principally in patients with significant proteinuria, in slowing the progression of renal failure. However, it is still unclear whether this beneficial effect of ACE inhibitors is particularly evident in patients with mild and/or more advanced renal failure and whether calcium antagonists possess a similar nephroprotective effect. Overall, data from clinical trials thus seem to indicate that ACE inhibitors and possibly calcium antagonists should be preferred in the treatment of patients with diabetic and nondiabetic nephropathies. However, further information is needed to understand renal protection.     

Angiotensin II-receptor blockers: clinical relevance and therapeutic role.

The limitations of angiotensin-converting-enzyme (ACE) inhibitors and the role of angiotensin II-receptor blockers (ARBs) in the treatment of hypertension, heart failure, and diabetic nephropathy are discussed. Although ACE inhibitors are generally well tolerated, two important class-related adverse effects are cough, which is common, and angioedema, which is rare but serious. Cough and angioedema appear to be less frequent with ARBs than with ACE inhibitors. ARBs seem to be as capable as ACE inhibitors of producing renal dysfunction. ARBs may offer more complete inhibition of angiotensin II than ACE inhibitors. The mechanism of action is based on selective binding to angiotensin type 1 receptors. Many clinical studies have shown that ARBs lower blood pressure as effectively as other antihypertensive agents, including ACE inhibitors. ARBs do not appear to have a greater clinical effect than ACE inhibitors in patients with heart failure. Some studies of combination ARB and ACE inhibitor therapy for heart failure indicate advantages of the combination over therapy with either class. ARBs may exert renal protective effects in diabetic nephropathy. ARBs offer an alternative to ACE inhibitors in the management of hypertension, especially for ACE-inhibitor-intolerant patients. ACE inhibitors remain the drugs of choice for patients with heart failure, left ventricular dysfunction after MI, and diabetic nephropathy; ARBs offer these patients an alternative when ACE inhibitor therapy is not tolerated.     

Antihypertensive drug therapy and the risk of lower extremity amputations in pharmacologically treated type 2 diabetes patients

PURPOSE: The objective of this study was to determine the association between different antihypertensive drug therapies and lower extremity amputations (LEAs) in type 2 diabetes patients. METHODS: Data were obtained from the PHARMO Record Linkage System comprising pharmacy records and data on hospitalisations for all 450,000 residents of eight Dutch cities. In a nested case-control study among 12,140 type 2 diabetes patients who used antihypertensive drugs, 26 cases with a first LEA and 94 controls without a LEA matched on age, sex and calendar time were identified. Logistic regression was used to estimate the relative risk of LEA and to adjust for potential confounding factors. RESULTS: Among type 2 diabetes patients who used antihypertensive drugs, subjects who used thiazide diuretics, alone or in combination, had a higher risk of LEA compared to subjects who used Angiotensin Converting Enzyme (ACE) inhibitor monotherapy (crude odds ratio (OR): 6.11 [95% confidence interval (CI): 1.32-28.27]). The use of thiazide diuretics was also associated with an increased risk of LEA when compared to the use of any non-thiazide antihypertensive drug (adjusted OR: 7.04 [1.10-45.30]). The increased risk of LEA associated with the use of thiazides compared to the use of non-thiazides depended on the duration of use (adjusted OR(< or = 365 days), 4.82 [0.61-38.34] and adjusted OR(>365 days), 26.16 [1.02-674.02], p-trend = 0.01). CONCLUSIONS: Treatment with thiazide diuretics compared to treatment with other antihypertensive drugs was associated with excess amputations in type 2 diabetes patients. Due to several limitations of this study, our findings do not preclude the use of thiazides in type 2 diabetes mellitus patients as yet.