Calcium antagonists in the treatment of hypertension. An overview

The availability of calcium antagonists has provided yet another therapeutic option in the management of hypertension. Calcium antagonists lower the blood pressure in hypertensive individuals while preserving the blood flow at the microcirculatory level. While all the available calcium antagonists are effective in the treatment of hypertension, they differ in their hemodynamic and pharmacologic actions. Nifedipine appears to be suitable for immediate treatment of severe hypertension and for chronic treatment of uncomplicated or refractory hypertension. In some but not all patients, co-administration of a beta-blocker is necessary to blunt reflex tachycardia. This problem is less likely with the tablet/long-acting formulation of nifedipine. Verapamil and diltiazem are useful as initial therapy for chronic mild-to-moderate hypertension. They are as effective as other first-line drugs in the treatment of uncomplicated hypertension. The heart rate with verapamil or diltiazem does not change or is slightly reduced, thus contrasting with nifedipine. Experience to date suggests that calcium antagonists do not cause adverse biochemical effects and in this respect are superior to diuretics and certain beta-blockers. Currently, verapamil is available as a sustained release preparation. In the near future, nifedipine or diltiazem may also be available in the long acting formulation to permit simplicity and to enhance patient compliance in the treatment of hypertension.     

Medical therapy of pulmonary hypertension. An overview of treatment and goals

Therapeutic medical advances over the past two decades have resulted in significant improvements in the outcome for patients with various forms of pulmonary arterial hypertension. As the current understanding of the pathology and pathobiology of pulmonary arterial hypertension has moved forward, rationale for additional therapeutic modalities with novel therapeutic agents has led to increased clinical investigations. A brief overview of the pathology and pathobiology is presented as background for an introduction to the current medical therapy for pulmonary arterial hypertension as well as the goals for future treatment.     

Calcium channel blockers in hypertension: reappraisal after new trials and major meta-analyses.

This review evaluates the current position of calcium channel blockers (CCB) in antihypertensive treatment in the light of three major comparative studies and two extensive meta-analyses. The latter both show that CCB are equivalent to conventional (initial beta-blocker or diuretic therapy) when total and cardiovascular mortality are the end points. Divergent points between the meta-analyses include stroke and myocardial infarction (MI). One meta-analysis compared CCB with conventional therapy, to find a small 13% reduction in stroke and a small, nonsignificant 12% increase in MI. The other meta-analysis found a 26% increase in MI when CCB were compared with all other therapies including the angiotensin converting enzyme (ACE) inhibitors. This increase was most robust (P < .001) when comparing CCB with ACE inhibitors, consonant with proposed protective effects of ACE inhibitors on cardiovascular risk. At present, only the comparison of CCB with conventional therapy, and not that with ACE inhibitors, rests on secure comparative data. When cost is compelling, conventional therapy is less expensive. For the individual patient, issues of quality of life (for example, impotence with diuretics and beta-blockers) might be decisive. Nonetheless, beta-blockers are preferred in postinfarct patients or in those with heart failure or unstable angina (a contraindication to dihydropyridines in the absence of beta-blockade). In others, the benefits of only a borderline stroke reduction with CCB versus an equally borderline increase in MI should be evaluated for each individual patient, taking into account the age group and the patient's preferences. In conclusion, overall CCB are neither better nor worse than conventional therapy, allowing for possible small differences in stroke and MI. The ACE inhibitors may protect better, although data are incomplete.     

Exercise hypertension in the perspective of systemic arterial hypertension. An overview

Systemic arterial hypertension is one of the most wide-spread diseases in the world. It is a chronic disease with a very long asymptomatic phase. At an estimated prevalence in the developed countries of 15 to 20%, it can be assumed that approximately 80% of men and 60% of women with hypertension are either unaware of their condition or are not treated adequately. These figures show that reliable diagnostic measures are needed to provide efficient detection of high blood pressure in a given population. In this regard, exercise testing has proven particularly well-suited. Using standardized ergometry, patients with latent, borderline or manifest hypertension can be identified. Exercise hypertension is defined on the basis of an abnormal blood pressure increase during physical exercise in persons with normal blood pressure at rest. Because of marked interindividual fluctuation in blood pressure, values measured at rest may be of only limited usefulness in the diagnosis of hypertension. In contrast, the blood pressure during dynamic exercise may be particularly informative with respect to probability of future development of manifest hypertension and treatment of high blood pressure. Long-term studies have shown that within five years up to one-third of patients with exercise hypertension develop manifest hypertension at rest. Based on the Canada Fitness Survey data indicating that about 2% of the population demonstrate exercise hypertension, it can be estimated that approximately 200,000 Canadians will develop manifest hypertension within five years. Similar statistics are also applicable for most of the developed countries of the world.(ABSTRACT TRUNCATED AT 250 WORDS)     

Device-guided breathing exercises for the treatment of hypertension: An overview

The American Heart Association considers device-guided breathing as a reasonable treatment modality in their statement on non-pharmacological options for lowering blood pressure. This review discusses all randomized controlled trials that have investigated the effects of device-guided breathing on blood pressure in patients with hypertension. Thirteen studies were included in this review. In total, 627 patients were in-cluded, of which 365 patients were allocated to device-guided breathing. Only 6 studies used acceptable control groups: listening to music, meditative relaxa-tion exercises, or a sham-device. Two sponsored trials showed beneficial effects of device-guided breathing, both used listening to music as a control group. The remaining 4 studies, which had no employees of the manufacturer listed as co-author, observed no benefi-cial effects on blood pressure. There is only 1 study that used a sham device as a control group. All other studies were to some extend methodologically flawed. Based on the studies with an acceptable methodologi-cal quality, there is no clear evidence supporting a short-term beneficial effect on blood pressure by using device-guided breathing.     

Multicenter trials in the treatment of arterial hypertension. Socioeconomic repercussions

The various therapeutic trials conducted throughout the world demonstrate the benefit of treatment even for a moderate elevation of diastolic pressure (90 or 95 mmHg). At this level of hypertension, treatment is more preventative than curative. This article discusses the benefits and the costs on the individual and collective scale in the context of two opposed strategies: mass treatment after a certain level of blood pressure or treatment of subjects at high risk of cardio-vascular disease. To achieve a collective benefit, all of the hypertensives defined in this way need to be detected, treated and followed-up in the long-term. Stimulation of the present medical system would appear to be more effective and less costly than the creation of specialized structures.     

An overview of the safety and efficacy of nicardipine in clinical trials

Nicardipine is currently being evaluated in clinical trials as a treatment for angina and hypertension. Over 2,000 patients have received nicardipine, most at dosages of 20 to 40 mg 3 times daily. In 12 double-blind, parallel-group studies (4 of them placebo-controlled) the efficacy of nicardipine was evaluated in mild to moderate hypertension; supine systolic blood pressure was lowered by 10 to 15 mm Hg and supine diastolic blood pressure by 10 mm Hg. A clear dose response is present at dosages from 10 to 40 mg 3 times daily.

Patients with angina were treated in 9 double-blind, crossover design studies: 4 of these were placebo-controlled; 3 were comparison studies with β blockers; 2 were comparisons with nifedipine. Treadmill exercise tests were the major measure of efficacy. Results of these studies showed consistent, statistically significant improvement in exercise tolerance and time to onset of angina, and clinical improvement in patients with chronic stable angina. The effective dosages of nicardipine were 30 or 40 mg 3 times daily. A placebo-controlled study demonstrated remarkable efficacy in patients with vasospastic angina. No deaths or serious adverse reactions were attributed to nicardipine during clinical trials. The most common side effects reported were flushing, palpitations, headache and pedal edema. These appeared to be due to the drug's pharmacologic property of vasodilatation.     

Quality of life in treatment of hypertension. A metaanalysis of clinical trials.

A metaanalysis was performed to determine the effects on quality of life (QL) in hypertension as reported in published clinical trials of antihypertensive drug therapy. All studies included compared active treatment to baseline (placebo or no treatment) with the patients as their own control and used blinded, randomized trials. Change was measured by self and/or interviewer-assisted evaluation, standardized psychomotor/cognitive tests, or sleep laboratory observations. After an exhaustive literature search (1970 to 1990), nine published trials of 27 population groups (n = 1620) using 14 drugs from six pharmacological groups met selection criteria and were analyzed for five QL constructs: sexual function, sleep, psychomotor, general well-being, and mood. Small positive effect size (d) improvement with treatment was seen for sleep (d = 0.106), psychomotor (d = 0.283), general well-being (d = 0.139), and mood (d = 0.167) while no effect could be determined for sexual function (d = -0.030) based on 95% confidence intervals. Either a comparably small improvement with treatment or no effect was seen among various pharmacological drug groups; no negative effect with treatment was identified. A larger positive effect could be postulated if the drug choice was individualized to the patient rather than randomized as in clinical trial methodology. Although none of the drug groups had a clearly superior effect, a more frequent positive effect with angiotensin converting enzyme inhibitors and beta-blockers was seen for all constructs. Narrower demographics and smaller sample sizes may have biased similar positive effects in calcium-channel blockers and diuretics.     

The new clinical trials on pharmacological treatment in pulmonary arterial hypertension.

Past medical therapy for pulmonary arterial hypertension included the use of calcium-channel antagonists in acute vasoreactive subjects and oral anticoagulants and continuous intravenous administration of epoprostenol in the more severe cases. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in >1,100 patients. Except for terbogrel, all compounds improved the mean exercise capacity by different degrees, as assessed by the 6-min walk test. In the evaluation of the clinical relevance of exercise capacity improvements, additional elements need to be considered, such as baseline functional class and concomitant favourable effects on combined clinical events (including hospitalisations, mortality and rescue therapies), quality of life and haemodynamics. No trials have shown effects on mortality, as the study protocols were not designed for assessing this end-point. Each new compound presents side-effects that are unpredictable in the individual patient and require appropriate attention upon treatment initiation and maintenance. These new therapeutic options will be available in the near future and will allow tailoring of the most appropriate treatment to the single patient, according to an individualised benefit-to-risk ratio.     

An approach to the treatment of hypertension in the aged.

Because of the multiplicity of disease conditions and diminished tolerance for drugs in the aged, it is necessary to know concomitant pathologic conditions to determine which antihypertensive drug to use. In the Philadelphia Geriatric Center, there are about 1,000 residents, between 70 and 100 years of age. About 40% have hypertension; almost 50% have or once had depression; there are many cases of hiatal hernia and/or peptic ulcer; in one subdivision of residents, almost 40% have renal disease with BUN above 30 mg/100 ml. In antihypertensive treatment, some individuals respond fairly well to reassurance and weight reduction, when obese, even without drugs. All are given a low-salt diet. A diuretic is first used--thiazide in cases of good renal function, furosemide with impaired renal function. Liquid potassium supplements are given. If there is but little reduction in blood pressure in several weeks, methyldopa is added in ascending doses, in cases with or without renal impairment. In hypertension with impaired renal function, furosemide and/or methyldopa were especially valuable. Furosemide as an antihypertensive drug was also noted to delay the onset of congestive heart failure. Since reserpine can aggravate peptic ulcer and can precipitate or aggravate depression, it should seldom be used to treat hypertension in the aged. Guanethidine is rarely used, since it can cause cerebrovascular insufficiency and marked weakness. High blood pressure should be reduced slowly in the aged, to avoid untoward effects.     

Current overview of EORTC clinical trials with tamoxifen.

Based upon concepts derived from estrogen receptor studies, a phase II exploratory trial was conducted where tamoxifen (NSC-180973) was administered concomitantly with cytotoxic chemotherapy in postmenopausal patients with advanced breast cancer. Chemotherapy was composed of two 28-day cycles given alternatively. Cycle A consisted of adriamycin and vincristine, and cycle B consisted of cyclophosphamide, methotrexate, and 5-fluorouracil. Fifty-five patients were fully evaluable. Complete remissions were obtained in 13 (24%) and partial objective remissions in 27 (49%). The overall remission rate was 73%. Toxic side effects ranged from mild to severe. The most significant were nausea and vomiting (most patients), weakness and pain (two thirds of the patients), and hematologic changes (half of the patients). It is concluded that the present combination of endocrine and cytotoxic therapy represents one of the most effective currently available treatments of advanced breast cancer. In an early clinical trial of tamoxifen in premenopausal patients with advanced breast cancer, two objective remissions, lasting 5 and 9+ months respectively, were obtained in ten patients treated. Tamoxifen is worthy of further assessment in premenopausal patients.     

An overview of controlled studies of adolescent substance abuse treatment.

Although several treatments for adolescents with substance use disorders are available, there are few well-controlled studies in the extant literature that compare these treatments for efficacy. This paper provides an overview of controlled treatment studies for adolescents with substance use disorders. It focuses specifically on five main treatment modalities: family-based and multi-systemic interventions, behavioral therapy, cognitive behavioral therapy, pharmacotherapy, and twelve step approaches. Examples of adolescent-specific standardized assessment instruments are also provided, the inclusion of which may improve future treatment comparison studies. While the results look especially promising for cognitive behavioral therapy and family-based/multi-systemic therapies for adolescents with SUDs, most of the relevant studies fail to utilize validated outcome measures, making it difficult to conclude that one treatment approach is more effective than another.     

An overview of randomized trials of rehabilitation with exercise after myocardial infarction

Of 22 randomized trials of rehabilitation with exercise after myocardial infarction (MI), one trial had results that achieved conventional statistical significance. To determine whether or not these studies, in the aggregate, show a significant benefit of rehabilitation after myocardial infarction, we performed an overview of all randomized trials, involving 4,554 patients; we evaluated total and cardiovascular mortality, sudden death, and fatal and nonfatal reinfarction. For each endpoint, we calculated an odds ratio (OR) and 95% confidence interval (95% CI) for the trials combined. After an average of 3 years of follow-up, the ORs were significantly lower in the rehabilitation than in the comparison group: specifically, total mortality (OR = 0.80 [0.66, 0.96]), cardiovascular mortality (OR = 0.78 [0.63, 0.96]), and fatal reinfarction (OR = 0.75 [0.59, 0.95]). The OR for sudden death was significantly lower in the rehabilitation than in the comparison group at 1 year (OR = 0.63 [0.41, 0.97]). The data were compatible with a benefit at 2 (OR = 0.76 [0.54, 1.06]) and 3 years (OR = 0.92 [0.69, 1.23]), but these findings were not statistically significant. For nonfatal reinfarction, there were no significant differences between the two groups after 1 (OR = 1.09 [0.76, 1.57]), 2 (OR = 1.10 [0.82, 1.47]), or 3 years (OR = 1.09 [0.88, 1.34]) of follow-up. The observed 20% reduction in overall mortality reflects a decreased risk of cardiovascular mortality and fatal reinfarction throughout at least 3 years and a reduction in sudden death during the 1st year after infarction and possibly for 2-3 years. With respect to the independent effects of the physical exercise component of cardiac rehabilitation, the relatively small number of "exercise only" trials, combined with the possibility that they may have had a formal or informal nonexercise component precludes the possibility of reaching any definitive conclusion. To do so would require a randomized trial of sufficient size to distinguish between no effect and the most plausible effect based on the results of this overview.     

Brivanib治疗肝癌的临床研究进展

Brivanib可同时抑制成纤维细胞生长因子受体(FGFR)-1、FGFR-2、FGFR-3、血管内皮细胞生长因子受体(VEGFR)-2和VEGFR-3,以达到抑制肿瘤新生血管形成及肿瘤细胞生长的作用。旨在总结Brivanib治疗肝癌的进展,已完成的Ⅰ和Ⅱ期临床试验结果均证实了Brivanib在肝癌治疗中的安全性和有效性。然而,1项已完成的Ⅲ期随机双盲安慰剂对照研究表明,Brivanib作为晚期肝癌二线治疗手段(即Sorafenib治疗失败者)并未显著改善患者的总体生存期。另1项Ⅲ期随机双盲对照试验结果也表明,Brivanib作为晚期肝癌一线治疗手段并未比Sorafenib显著改善患者的总体生存期。这2项临床试验的失败使得其他两项有关Brivanib治疗肝癌的临床试验提前终止。通过分析以上研究认为亚组分析以及事先筛选Brivanib可能获益的肝癌患者(即FGF信号途径激活的肝癌患者)也许对进一步探究Brivanib的在肝癌治疗中的角色是必要的。     

Beta blockade during and after myocardial infarction: An overview of the randomized trials

Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value, and for many such patients mortality reductions of about 25% can be achieved. No important differences are clearly apparent among the benefits of different beta blockers, although some are more convenient than others (or have slightly fewer side effects), and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit. If monitored, the side effects of long-term therapy are not a major problem, as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment. By contrast, although very early IV short-term beta blockade can definitely limit infarct size, more reliable information about the effects of such treatment on mortality will not be available until a large trial (ISIS) reports later this year, with data on some thousands of patients entered within less than 4 hours of the onset of pain. Our aim has been not only to review the 65-odd randomized beta blocker trials but also to demonstrate that when many randomized trials have all applied one general approach to treatment, it is often not appropriate to base inference on individual trial results. Although there will usually be important differences from one trial to another (in eligibility, treatment, end-point assessment, and so on), physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related randomized trials and not just a few particular trial results. Although most trials are too small to be individually reliable, this defect of size may be rectified by an overview of many trials, as long as appropriate statistical methods are used. Fortunately, robust statistical methods exist--based on direct, unweighted summation of one O-E value from each trial--that are simple for physicians to use and understand yet provide full statistical sensitivity. These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another. (Moreover, they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust.) Their robustness, sensitivity, and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews.     

Endocrine hypertension:An overview on the current etiopathogenesis and management options

Endocrine causes of secondary hypertension include primary aldosteronism,pheochromocytoma,cushing's syndrome,hyperparathyroidism and hypo-and hyperthyroidism.They comprise 5%-10% of the causes of secondary hypertension.Primary hyperaldosteronism,the most common of the endocrine cause of hypertension often presents with resistant or difficult to control hypertension associated with either normo-or hypokalemia.Pheochromocytoma,a great mimicker of many conditions,is associated with high morbidity and mortality if left untreated.A complete history including pertinent family history,physical examination along with a high index of suspicion with focused biochemical and radiological evaluation is important to diagnose and effectively treat these conditions.The cost effective targeted genetic screening for current known mutations associated with pheochromocytoma are important for early diagnosis and management in family members.The current review focuses on the most recent evidence regarding causes,clinical features,methods of diagnosis,and management of these conditions.A multidisciplinary approach involving internists,endocrinologists and surgeons is recommended in optimal management of these conditions.