Adult hypertension: reducing cardiovascular morbidity and mortality

(1) Since our last review of treatments for arterial hypertension in 1999 (Prescrire International no.41), many new data have been published and new antihypertensive drugs have appeared on the market. (2) The working definition of hypertension is unchanged, namely blood pressure of at least 160/95 mm Hg in the general population, and at least 140/80 mm Hg in patients with diabetes and a history of stroke; these figures must be found on several occasions using a standardised method, with the patient at rest. (3) The goals of antihypertensive therapy are to reduce mortality and cardiovascular events, and not simply to drive blood pressure below a fixed (and often controversial) threshold. (4) Some drug and non drug interventions have a positive risk-benefit balance in the long term. (5) When antihypertensive drug therapy is needed, trials based on clinical endpoints show that it is best to start treatment with a single drug. (6) New data support the use of certain thiazide diuretics (chlortalidone, or hydrochlorothiazide if chlortalidone is not available) as first line treatment for most hypertensive patients, including non diabetic adults, diabetic adults, elderly subjects (over 65 years), and stroke patients. Some betablockers and angiotensin-converting-enzyme inhibitors (ACE inhibitor) are second-line alternatives. (7) Assessment of other antihypertensive drugs has also progressed since 1999, including indapamide (thiazide-like diuretic), amlodipine, diltiazem and verapamil (calcium channel blockers), lisinopril (ACE inhibitor), and losartan and valsartan (angiotensin II antagonists). However, these drugs are not as thoroughly evaluated as thiazide diuretics, betablockers and some ACE inhibitors.     

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.     

Hypertension and diabetes mellitus: the critical role of evidence based decision making in patient management

Many diabetic hypertensives are inadequately managed because of the doctor's misplaced emphasis on possible differences in efficacy and risk profile of antihypertensive drugs. These patients are at higher risk of various cardiovascular events, and evidence shows they experience greater reduction in adverse clinical outcomes as a result of tight control of blood pressure than do nondiabetic hypertensives. It is, therefore, critically important that such patients be identified and that the blood pressure is tightly treated. Several drugs often have to be used in combination in order to achieve adequate blood pressure control. Nonpharmacologic measures, such as exercise, have been shown to reduce blood pressure and to reduce the rate complications in diabetic patients. All classes of antihypertensives have been shown to be equivalent in reducing all adverse cardiovascular events in diabetic hypertensives. Although there is nothing to choose between diuretics, calcium channel blockers, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, the choice of drug should be tailored for the individual patient. Drug selection should be based on the complication that is most likely in the given patient. Available data suggests that the lower the blood pressure the better the prognoses, with no threshold of the lower limit of the ideal value. Many professional associations advise that a target blood pressure in the diabetic hypertensive under treatment should be below 130/80 mm Hg. There is no evidence to support the avoidance of thiazide diuretics in these patients, and indeed some patients derive specific benefits from the use of these drugs. Tight control of blood pressure is the overriding priority, and this takes precedence over the theoretical debate of which drug is the best choice or concern over possible adverse reactions.     

Benefits of anti-hypertensive therapy in the elderly

Hypertension is common in the elderly, up to half of the population over the age of 65 years can be so classified. Raised systolic and diastolic blood pressure levels increase the risk of cardiovascular morbidity and mortality in those aged up to 80 years. Recent intervention studies have shown that antihypertensive treatment reduces death from stroke and myocardial infarction, without producing intolerable side-effects. The benefits of treating isolated systolic hypertension and hypertension following stroke are, as yet, unproven. The therapeutic goals for treating hypertension in the elderly should be to lower blood pressure while keeping adverse reactions to a minimum and thereby not impairing the patient's quality of life. Non-pharmacological methods should be tried initially before resorting to drug therapy. Both thiazide diuretics and beta-adrenoceptor antagonists are of proven value as first line hypotensive agents in the elderly. Drug therapy should be tailored to the individual patient and increased slowly to reduce the incidence of side-effects.     

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.     

Treatment of hypertension with calcium antagonists

Calcium antagonists are the latest addition to the antihypertensive armamentarium. The evidence available suggests that they lower blood pressure at least as effectively as diuretics, beta-receptor blockers and other vasodilators. Nifedipine is as effective as hydralazine as a third-line drug. Both nifedipine and verapamil may be used alone as first-line therapy, but they are more expensive and probably cause more symptomatic side-effects than diuretics or beta-receptor blockers.     

The management of hypertension in the overweight and obese patient: is weight reduction sufficient?

The management of hypertension in the overweight and obese patient is a frequently encountered but under investigated clinical problem. The conventional management of such patients involves weight reduction with dietary therapy or a combined approach with dietary and anti-obesity drug therapy. However, long-term weight reduction, which is necessary to sustain blood pressure (BP) control, is not feasible in over 80% of patients. Anti-obesity therapy with orlistat has inconsistent effects on BP and may benefit only patients who have uncontrolled or non-medicated hypertension. Anti-obesity therapy with sibutramine may be associated with a modest worsening of BP control. Consequently, antihypertensive drug therapy is often required to supplement a weight reduction programme, and also in patients with severe hypertension or hypertension-associated end-organ damage. Treatment with a thiazide diuretic should be considered as first-line antihypertensive drug therapy in overweight and obese patients. ACE inhibitors or non-dihydropyridine calcium channel antagonists are reasonable alternatives where clinically indicated, or they can be used in combination with a thiazide diuretic if treatment with the diuretic alone is insufficient. If such treatment is inadequate for BP control, the addition or substitution of an alpha- or beta-adrenoceptor antagonist may be considered, although the latter can be associated with weight gain. Concurrent disease is an important determinant of first-line and supplementary antihypertensive drug therapy. Additional studies are needed to determine the long-term (>1 year) efficacy and safety of antihypertensive and anti-obesity management strategies in the overweight and obese hypertensive patient.     

和尿剂在高血压治疗中的重要地位

本文采用文献综述的方法，确定利尿剂在高血压治疗中的地位。国际临床试验结果进行荟萃分析显示．小剂量利尿剂能减少心血管病事件的发生和死亡率；大规模临床试验证明利尿剂降压效果是肯定的，尤其对老年人、肥胖及高血压合并心力衰竭的患者效果更加明显；利尿剂除了具有显著的降压作用以外，还能起到良好的协同作用，是复方降压制剂中的主要成分；在应用利尿剂的同时，要正确处理好利尿剂引起的代谢障碍。事实证明小剂量利尿剂是预防心血管病发病和死亡的有效一线药物，在高血压治疗中占重要地位。     

Pinacidil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of hypertension

Pinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called 'potassium channel openers' which act via potassium efflux to hyperpolarize cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle. Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by beta-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension. Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or beta-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects. The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the overall incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy. Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.     

Initial treatment choices, second-line therapy, and reasons for stopping medication in the treatment of hypertension by general practitioners in England, Scotland and Wales: 1990-1995

Information on general practitioners' choices of initial and second-line antihypertensive treatment, and reasons for stopping therapy, are limited. We analysed data on the use of the four main classes of antihypertensive drugs (diuretics, beta-blockers, calcium antagonists and angiotensin-converting enzyme inhibitors) between 1990 and 1995 from an ongoing cross-sectional postal survey of general practitioners' prescribing activity (the New and Change Therapy Enquiry). There were 18,092 new courses and 9424 discontinuations between 1990 and 1995. Diuretics were the commonest first-line choice. Use of beta-blockers first-line decreased significantly in comparison with diuretics during the study period. Switches to calcium antagonists and angiotensin-converting enzyme inhibitors increased. The increased use of newer agents was not explained by increased use for concomitant conditions (diabetes or cardiovascular disease). Diuretics were most often discontinued because of poor efficacy (44% of diuretic stops). In contrast, most beta-blockers (55%), calcium antagonists (64%) and angiotensin-converting enzyme inhibitors (60%) were stopped because of side-effects. In conclusion, use of beta-blockers first-line decreased. Switches to calcium antagonists and angiotensin-converting enzyme inhibitors increased. The reasons may be due to greater perceived efficacy of newer agents rather than increased use for concomitant conditions.     

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.     

Hypertension and diabetes

Hypertension is common in people with diabetes with an estimated prevalence using the new criteria (> or = 140/90) at 70%. The recent large randomized controlled studies in diabetic subjects has clearly shown the benefit of blood pressure lowering with reduction in cardiovascular endpoints and microvascular disease. ACE inhibitors, calcium antagonists, thiazide diuretics and beta-blocking agents have been the agents validated by the trials. The challenge now is to implement antihypertensive therapy to achieve tight blood pressure targets (< or = 140/80), usually requiring dual or even triple therapeutic regimens.     

Angiotensin II Receptor Antagonists Alone and Combined with Hydrochlorothiazide

Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.     

Pharmacotherapy of hypertension in patients with diabetes mellitus

The co-existence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Overwhelming evidence supports aggressive treatment of hypertension in diabetic patients. However, only a small percentage of diabetic hypertensive patients reach their treatment goal of blood pressure (BP) < 130/80 mmHg. Tight BP control is not only cost-effective but also more rewarding than glycaemic control. The optimal goal of BP control in diabetics should be 130/80 mmHg. In subjects with diabetes and renal insufficiency, the BP should be lowered to 125/75 mmHg to delay the progression of renal failure. The choice of an antihypertensive agent should be based on proven effects on morbidity and mortality rather than on surrogate parameters such as lipid or glucose. Limited data suggests that an angiotensin converting enzyme inhibitor (ACEI) is the agent of choice, especially in those with proteinuria or renal insufficiency. beta-blockers (betaBs) can be the first-line agent in diabetics with coronary heart disease, while thiazide diuretics (TD) and calcium-channel blockers (CCBs) are the second-line drugs. Angiotensin II-receptor blockers (ARBs) may be proven to be as effective as ACEIs in diabetics with hypertension. alpha-adrenergic antagonists (AAAs) should be avoided. Most hypertensive patients require more than one agent to control their BP. There is no evidence to support one combination regimen over others; nevertheless, a combination of an ACEI with a TD or a betaB may be the most cost-effective regimens compared to other combinations.     

Antihypertensive Drugs

For most patients with systemic hypertension, long-term drug treatment is indicated and is beneficial. There is overwhelming evidence to suggest that antihypertensive drugs offer protection against complications of hypertension. Whereas nondrug therapeutic options should be implemented in all patients, a vast majority will require pharmacological treatment to achieve goal blood pressure levels. Fortunately, a number of drugs are available to accomplish successful treatment of hypertensive disorders. While it is conventional to initiate treatment with a single drug, a suitable combination of drugs is often required to control the blood pressure effectively. Although diuretics and β-blockers are effective and well tolerated, other classes of drugs are being increasingly used as the initial choice of therapy for hypertension. Every class of antihypertensive drugs offer advantages and some disadvantage; the physician should weigh the benefits and risks in selecting one drug over another. While the clinical parameters are followed in the management of patients with hypertension, it is also necessary to monitor the patients’ biochemical profile periodically in order to modify and adjust the therapy accordingly. A careful selection of drug therapy along with close follow-up offers the best prospect to reduce the burden of morbidity and mortality in hypertension. This article provides an overview of drugs in the management of patients with hypertension.     

Combination Drug Therapy in Hypertension: A Rational Approach for the Pharmacist

ObjectiveTo review the use of combination therapy versus monotherapy in hypertension, and to review seven major antihypertensive combinations in regard to their pharmacologic actions and appropriateness.Data SourcesLiterature was identified through a MEDLINE search from January 1985 to December 1997. Search terms included hypertension, blood pressure, combination therapy, diuretics, beta-receptor antagonists, calcium channel antagonists, angiotensin-converting enzyme inhibitors (ACEls). Major hypertension texts were also reviewed for information on combination therapy.Study SelectionClinical studies focusing primarily on blood pressure control with combinations of antihypertensive medications.Data ExtractionData were evaluated with respect to study design, clinical outcomes, and use of antihypertensive classes commonly seen in practice.Data SynthesisCombination therapy in hypertension is often required because many patients cannot be controlled on one drug alone. Available data demonstrate that ACEIs plus diuretics or calcium channel blockers (CCBs) produce synergistic effects on blood pressure. Beta-blockers plus diuretics or CCBs produce additive effects, as does the rarer combination of diltiazem plus a dihydropyridine CCB. Ineffective combinations include betablockers plus ACEls and dihydropyridine CCBs plus diuretics, although there are specific clinical circumstances where these combinations may be used.ConclusionWhen used appropriately, certain combinations of antihypertensives can effectively control blood pressure and minimize side effects. The pharmacist who understands and applies the pharmacology of these antihypertensives can help prescribers make rational decisions in selecting combination therapy.     

Capecitabine: new indication. In breast cancer: inadequately assessed

There is no consensus on treatment of locally advanced or metastatic breast cancer after failure of first-line cytotoxic chemotherapy. Common options are continuous infusion of a taxane (docetaxel or paclitaxel), vinorelbine or fluorouracil. Capecitabine is now licensed for use in breast cancer, both in combination with IV docetaxel after anthracycline failure, and as single-agent therapy after failure of anthracyclines and taxanes. The clinical evaluation dossier on capecitabine fails to answer the most important questions about comparative efficacy and safety. In second-line treatment, after anthracycline failure, the only available comparative trial showed that the capecitabine + docetaxel combination increased median survival time by about three months relative to placebo + docetaxel, but caused more adverse events. There are no trials comparing capecitabine with other options. There is no evidence that capecitabine increases the length or quality of survival, relative to intravenous vinorelbine, in women with breast cancer that is resistant to both anthracyclines and taxanes. The classical adverse effects of capecitabine are also observed in women with breast cancer, namely palmoplantar erythrodysesthesia, diarrhoea, nausea and vomiting, and major hyperbilirubinemia. Capecitabine can be taken by mouth and this may be an advantage. However, current evidence is too limited to justify using capecitabine outside of clinical trials.     

Meta-analysis of the comparative effects of different classes of antihypertensive agents on brachial and central systolic blood pressure,and augmentation index

AIMS

Brachial systolic blood pressure (bSBP) exceeds aortic pressure by a variable amount, and estimated central systolic blood pressure (cSBP) may be a better indicator of cardiovascular risk than bSBP. We undertook a systematic review and meta-analysis to compare the effect of single and multiple antihypertensive agents on bSBP, cSBP and augmentation index (AIx).

Methods

A random effects meta-analysis was performed on 24 randomized controlled trials of antihypertensives with measurements of bSBP, cSBP and/or AIx. Separate analyses were performed for drug comparisons with or without placebo, and drug combinations.

Results

In the placebo vs. drug meta-analysis, antihypertensive therapy reduced bSBP more than cSBP and there was no statistically significant evidence of heterogeneity by drug class, although the number of individual studies was small. In placebo-adjusted drug vs. drug comparison, treatment with β-blockers, omapatrilat and thiazide diuretics lowered cSBP significantly less than bSBP (i.e. central to brachial amplification decreased), whereas other monotherapies lowered cSBP and bSBP to similar extents. Sample sizes were too small and effect estimates insufficiently precise to allow firm conclusions to be made regarding comparisons between individual drug classes. Antihypertensive combinations that included β-blockers decreased central to brachial amplification. β-Blockers increased AIx, whereas all other antihypertensive agents reduced AIx to similar extents.

CONCLUSIONS

A reduction in central to brachial amplification by some classes of antihypertensive drug will result in lesser reductions in cSBP despite achievement of target bSBP. This effect could contribute to differences in outcomes in randomized clinical trials when β-blocker- and/or diuretic-based antihypertensive therapy are compared with other regimens.