A truncated erythropoietin receptor EPOR-T is associated with hypertension susceptibility.

Erythropoietin (EPO) and its analogs increase blood pressure (BP) in susceptible patients. The ratio of truncated to full EPO receptors (EPORs) in endothelial progenitor cells harvested from anemic patients receiving EPO while undergoing hemodialysis is related to the increased BP observed in these patients. Truncated EPORs exert a hypertensive effect by opposing full EPOR stimulation that augments cyclic guanosine monophosphate (GMP) in vascular endothelium. The contribution of this discovery to clinical practice is debatable.

The diabetic hypertensive (or hypertensive diabetic)--a compelling need to optimize blood pressure.

In summary, the present information on treating hypertension in the diabetic overwhelmingly indicates a compelling need to lower BP to target diastolic BP of 80 mmHg or less, to be less concerned about the types of drugs used than the blood pressures achieved and the concordance with therapy and to rely on two or more antihypertensive drugs in the majority of cases. Management of the hypertensive diabetic is very cost-effective. It is clear that we must engage in total cardiovascular risk management if we are to prevent the microvascular and macrovascular complications in the hypertensive diabetic (or the diabetic hypertensive).

Grapefruit juice--felodipine interaction in the elderly.

BACKGROUND: Grapefruit juice can increase the oral bioavailability of a broad range of medications. This interaction has not been assessed in the elderly. METHODS: Twelve healthy elderly people (70 to 83 years of age) were administered 5 mg felodipine extended release with 250 mL grapefruit juice or water in a single-dose study. Subsequently, 6 of these people received 2.5 mg felodipine for 2 days, followed by 5 mg felodipine for 6 days with 250 mL grapefruit juice or water in a steady-state study. Plasma concentrations of felodipine and dehydrofelodipine metabolite, blood pressure, and heart rate were measured over 24 hours after single and final steady-state dose. RESULTS: Mean felodipine area under the curve and maximum concentration were 2.9-fold and 4.0-fold greater, respectively, with grapefruit juice in both studies. Interindividual variability in the extent of the interaction was high. Felodipine apparent elimination half-life was not altered. Dehydrofelodipine area under the curve and maximum concentration were increased and dehydrofelodipine/felodipine area under the curve ratio was reduced. Systolic and diastolic blood pressures were lower with grapefruit juice in the single-dose study, whereas they were not different between treatments in the steady-state study. Curvilinear relationships existed between plasma felodipine concentration and changes in systolic and diastolic blood pressures. Heart rates were higher with grapefruit juice in both studies; however, this effect was greater and more prolonged at steady state. CONCLUSIONS: A normal dietary amount of grapefruit juice produced a pronounced, unpredictable, and sustained pharmacokinetic interaction with felodipine by reducing its presystemic metabolism in the elderly. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and felodipine ingestion.

Assimilating new therapeutic interventions into clinical practice: how does hypertension compare with other therapeutic areas?

Medical research has helped to clarify the benefits of some therapies for improving the treatment or outcome associated with cardiovascular disease. However, the adoption of these approaches into routine clinical practice is, in many cases, inadequate. Consequently, there are many missed opportunities to reduce the burden of morbidity and mortality from cardiovascular disease. This review summarizes the factors that may prevent modified behavior in medical practice and the effectiveness of interventions that influence change. There are many barriers that may prevent or slow the adoption of new therapeutic advances into routine clinical practice. As a result, the use of well-proven, efficacious therapy can be suboptimal. Because of this underuse, the realized benefits of treatment are below the potential benefits. Adoption of new therapies is highly dependent on the use of interventions to promote clinical change. However, the effectiveness of different types of interventions varies greatly. Nevertheless, there is a wide range of strategies available that can be used to induce real changes in practice performance and potentially improve patient outcomes. It is essential that future intervention strategies focus on improving adoption of new therapies into clinical practice. The physician must be encouraged to prescribe proven treatments to those patients who stand to benefit most. In addition, better systems of care should be developed that improve the identification of patients as suitable candidates for proven treatments and sustain their long-term commitment to therapy.

A novel formulary: collaboration between health care professionals, seniors, private sector and government in Nova Scotia.

A novel formulary has been developed in Nova Scotia with the objective of providing quality treatment with needed medications at affordable cost. Creation of the formulary has involved collaboration among health care professionals, seniors, the Department of Health and pharmaceutical companies. This is the first Canadian formulary to use the Anatomic, Therapeutic, Chemical system. Drug listing is comprehensive rather than exclusive. Colour-coded recommendations on use assist physicians with drug choice. Relative costs are indicated within each therapeutic grouping. Listings indicate drugs approved for reimbursement, interchangeable medications, maximum allowable cost, drug identification number and manufacturer code. Treatment summaries provide brief overviews of therapeutic advice. Updates on new products and new or modified treatment summaries are provided every 6 months. The formulary will be the focus of coordinated educational activities on treatment for seniors and health care professionals.

Lifestyle modifications to prevent and control hypertension. 3. Recommendations on alcohol consumption. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada.

OBJECTIVE: To provide updated, evidence-based recommendations concerning the effects of alcohol consumption on the prevention and control of hypertension in otherwise healthy adults (except pregnant women). OPTIONS: There are 2 main options for those at risk for hypertension: avert the condition by limiting alcohol consumption or by using other nonpharmacologic methods, or maintain or increase the risk of hypertension by making no change in alcohol consumption. The options for those who already have hypertension include decreasing alcohol consumption or using another nonpharmacologic method to reduce hypertension; commencing, continuing or intensifying antihypertensive medication; or taking no action and remaining at increased risk of cardiovascular disease. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996 with the terms ethyl alcohol and hypertension. Other relevant evidence was obtained from the reference lists of articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design, and graded according to the level of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: A reduction in alcohol consumption from more than 2 standard drinks per day reduces the blood pressure of both hypertensive and normotensive people. The lowest overall mortality rates in observational studies were associated with drinking habits that were within these guidelines. Side effects and costs were not measured in any of the studies. RECOMMENDATIONS: (1) It is recommended that health care professionals determine how much alcohol their patients consume. (2) To reduce blood pressure in the population at large, it is recommended that alcohol consumption be in accordance with Canadian low-risk drinking guidelines (i.e., healthy adults who choose to drink should limit alcohol consumption to 2 or fewer standard drinks per day, with consumption not exceeding 14 standard drinks per week for men and 9 standard drinks per week for women). (3) Hypertensive patients should also be advised to limit alcohol consumption to the levels set out in the Canadian low-risk drinking guidelines. VALIDATION: These recommendations are similar to those of the World Hypertension League, the National High Blood Pressure Education Program Working Group on Primary Prevention of Hypertension and the previous recommendations of the Canadian Coalition for High Blood Pressure Prevention and Control and the Canadian Hypertension Society. They have not been clinically tested. The low-risk drinking guidelines are those of the Addiction Research Foundation of Ontario and the Canadian Centre on Substance Abuse. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada. The low-risk drinking guidelines have been endorsed by the College of Family Physicians of Canada and several provincial organizations.

1999 Canadian recommendations for the management of hypertension. Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension.

OBJECTIVE: To provide updated, evidence-based recommendations for health care professionals on the management of hypertension in adults. OPTIONS: For patients with hypertension, there are both lifestyle options and pharmacological therapy options that may control blood pressure. For those patients who are using pharmacological therapy, a range of antihypertensive drugs is available. The choice of a specific antihypertensive drug is dependent upon the severity of the hypertension and the presence of other cardiovascular risk factors and concurrent diseases. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: MEDLINE searches were conducted from the period of the last revision of the Canadian Recommendations for the Management of Hypertension (January 1993 to May 1998). Reference lists were scanned, experts were polled and the personal files of the authors were used to identify other studies. All relevant articles were reviewed, classified according to study design and graded according to levels of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS: Harms and costs: The diagnosis and treatment of hypertension with pharmacological therapy will reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and mortality. RECOMMENDATIONS: This document contains detailed recommendations pertaining to all aspects of the diagnosis and pharmacological therapy of hypertensive patients. With respect to diagnosis, the recommendations endorse the greater use of non-office-based measures of blood pressure control (i.e., using home blood pressure and automatic ambulatory blood pressure monitoring equipment) and greater emphasis on the identification of other cardiovascular risk factors, both in the assessment of prognosis in hypertension and in the choice of therapy. On the treatment side, lower targets for blood pressure control are advocated for some subgroups of hypertensive patients, in particular, those with diabetes and renal disease. Implicit in the recommendations for therapy is the principle that for the vast majority of hypertensive patients treated pharmacologically, practitioners should not follow a stepped-care approach. Instead, therapy should be individualized, based on consideration of concurrent diseases, both cardiovascular and noncardiovascular. VALIDATION: All recommendations were graded according to the strength of the evidence and the consensus of all relevant stakeholders. SPONSORS: The Canadian Hypertension Society and the Canadian Coalition for High Blood Pressure Prevention and Control.

Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.

BACKGROUND: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. METHODS: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. FINDINGS: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001). INTERPRETATION: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

Familial studies of heritability of alpha1-adrenergic receptor responsiveness in superficial veins.

BACKGROUND: Studies of monozygotic and dizygotic twins indicate an important genetic influence on the variability of responsiveness to norepinephrine in superficial human vein. OBJECTIVES: Genetic aspects of variability of alpha1-adrenergic receptor responsiveness to norepinephrine in superficial veins were further investigated by studying the response to norepinephrine in the dorsal hand veins of parents and their children. METHODS: Subjects were healthy nonsmoking adults (n = 24; age range, 40 to 52 years) and their biological children (n = 20; age range, 15 to 26 years) who were free from medications likely to modify vascular tone. Superficial vein responsiveness to norepinephrine was assessed by the linear variable differential transformer technique. The dose of norepinephrine required to constrict superficial vein diameter by 50% from baseline (ED50) was calculated for each subject. Heritability was estimated by standard techniques of regression of mid-parent/child (natural logarithm) ED50 values. RESULTS: ED50 ranged from 5.6 to 254.6 ng/min in the parents and from 7.8 to 242.3 ng/min in the children. Heritability was calculated at 0.88. CONCLUSIONS: These data confirm wide variability in superficial vein responsiveness to norepinephrine. The results confirm a major genetic influence in biological responsiveness of superficial vein to norepinephrine in healthy humans. Heritability of vascular alpha-adrenergic receptor responsiveness may influence vascular regulation during sympathetic stimulation and blockade.

Variability in prescription drug utilization: issues for research.

The authors report the results of a literature review to identify research issues relating to physician prescribing practices and evaluate the potential for existing Canadian databases to support initiatives to improve prescribing practices. Methodologies such as small-area variation analysis and drug utilization reviews are discussed, and Canadian data sources relating to drug prescribing are assessed. The authors conclude that small-area variation analysis can be used to identify differences in drug utilization rates. A ranking method to identify drugs with the greatest variability in utilization can then be used to establish priorities for further analysis. After statistically significant factors associated with prescribing patterns are identified, intervention and policy formation will be possible. This will involve a more sophisticated integration of existing provincial information sources and the adoption of uniform guidelines to promote rational prescribing practices.

Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study.

A randomized double-blind trial comparing the alpha-adrenergic blocker doxazosin and the beta-adrenergic blocker atenolol was completed by 131 patients with mild to moderate hypertension. Blood pressure and fasting blood lipids were determined at baseline and 4, 12, and 24 weeks of treatment. At entry, plasma lipids and lipoproteins were similar in those patients randomized to doxazosin or atenolol. After 24 weeks of treatment with atenolol, there were significant (P < .05) decreases in high-density lipoprotein cholesterol (HDL-C) and increases in triglycerides and very-low-density triglycerides (VLDL-T). In contrast, doxazosin was associated with significant (P < .05) increases in HDL-C and decreases in triglycerides and VLDL-T. There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002). Neither apoA-I nor apoB concentration at baseline nor apoE phenotype was predictive of the lipid responses during antihypertensive treatment with either drug. Thus, there are significant favorable changes in HDL-C, total triglycerides, and VLDL-T between patients with mild to moderate hypertension and normal plasma lipids when treated with the alpha-blocker doxazosin compared with the beta-blocker atenolol. Plasma lipid or apo concentrations were not predictive of their lipid response during antihypertensive therapy with either of these agents.

Adverse effects of alpha 1-adrenergic blocking drugs.

Earlier nonselective alpha 1-adrenergic blocking drugs such as phentolamine and phenoxybenzamine are now restricted to the pharmacological management of alpha 1-adrenergic crisis and phaeochromocytoma. Prazosin, the first selective alpha 1-blocker approved for the treatment of hypertension, became available in the mid-1970s. Additional alpha 1-blockers such as doxazosin and terazosin have been introduced during recent years. The undesirable effects of all members of this class are similar. Most adverse events can be attributed to reversible competitive antagonism of postsynaptic alpha 1-adrenergic receptors in tissues that sustain high levels of alpha-adrenergic sympathetic tone, e.g. resistance arteries, capacitance veins and the urinary bladder outflow tract. Orthostatic hypotension with a sensation of intense faintness and occasional syncope, can occur shortly after the initial dose. Aggravating factors include upright posture, intravascular volume depletion and concurrent administration of other medications that lower blood pressure, including all other classes of antihypertensive drugs. The problem is reduced or avoided by the choice of low starting doses, beginning treatment at bedtime and by minimising other risks. Among overall adverse effects, asthenia, dizziness, faintness and syncope predominate and occur in 10 to 20% of patients, leading to discontinuation of therapy in about half that number. Infrequent adverse events include headache, drowsiness, palpitations, urinary incontinence and priapism. Some patients experience a 1 to 2kg bodyweight gain which may be associated with secondary hyperaldosteronism. Tolerance appears to develop to the benefits of alpha 1-blockade in patients with congestive heart failure, but not in hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Early effects of cardiovascular drugs--do they predict clinical outcomes?

Indicators such as lowering of blood pressure in hypertension, alleviation of chest pain in angina pectoris, improvement in rest or exertional dyspnea from congestive heart failure (CHF) and suppression of ventricular arrhythmia are widely used in the management of cardiovascular diseases. There are often strong associations between the physiological indicators and the long-term clinical outcomes of cardiovascular disease such as stroke, myocardial infarction, sudden death and all-cause mortality. Physicians have assumed reasonably that early improvements in physiological markers will lead invariably to better long-term clinical outcomes. In recent years, a number of large clinical trials have demonstrated that short-term physiological improvements are not necessarily linked to better long-term clinical outcomes, but may be associated with less benefit than expected or even with detrimental outcomes. Management of cardiovascular diseases is complicated by the possibility that beneficial effects of a particular drug may be offset by its negative actions on the cardiovascular system. Effective antihypertensives may depress cardiac contractility; inotropes enhance left ventricular contractility in CHF, but may increase the risk of serious ventricular dysrhythmia; drugs which suppress ventricular arrhythmia may precipitate CHF or even excite pro-arrhythmic effects. Physicians must be conscious of this interplay of potentially beneficial and deleterious effects when cardiovascular drugs are prescribed. It is important in the analysis of large clinical trials of cardiovascular drugs to identify those situations in which the drug exhibits more benefit than harm and to determine, if possible, those aspects of drug action, drug dosage and population characteristics which contribute to the beneficial and detrimental actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effect and tolerability of felodipine extended release (ER) tablets in comparison with felodipine plain tablets (PT) and placebo in hypertensives on a diuretic. Canadian Study Group.

Antihypertensive efficacy and tolerability of felodipine extended release (ER) (o.d.), felodipine plain tablet (PT) (b.i.d.), and placebo were compared in mild to moderate hypertensives whose seated diastolic blood pressure (DBP) was > or = 95 mm Hg while on hydrochlorothiazide 25 mg od. In addition to the diuretic, patients were randomised to felodipine ER 5 mg od (n = 50), PT 2.5 mg bid (n = 50), or placebo (n = 48) for 6 weeks, with clinic visits every 2 weeks. If seated DBP was > or = 90 mm Hg at any visit, daily dosage of felodipine was doubled to a maximum of 20 mg. The mean difference between ER and placebo was 5.1 mm Hg (p = 0.003); for PT vs. placebo the difference was 5.3 mm Hg (p = 0.002). Seated systolic blood pressure (SBP) was reduced by a mean difference of 6.8 mm Hg in the felodipine PT group compared with placebo (p = 0.03). Fourteen patients were withdrawn: 4 from the placebo group, 4 from the felodipine ER group, and 6 from the felodipine PT group. The most commonly reported adverse event was peripheral edema. In patients not adequately controlled on diuretic alone, felodipine ER o.d. and felodipine PT b.i.d. were superior to placebo in reducing seated DBP.

Creatinine elevation in patients receiving amiodarone correlates with serum amiodarone concentration.

Serum creatinine and drug concentrations were measured at 0, 1, 2, 3, 6, 9 and 12 months in 30 consecutive patients started on amiodarone. In 28 of these patients with no obvious cause for altered renal function, mean serum creatinine increased to 11% above baseline (P < 0.005). Rising creatinine concentrations correlated with amiodarone concentrations (y = 93.9 + 8.6x, r = 0.51, P < 0.0001). When assessing elevation of serum creatinine in a patient receiving amiodarone, physicians should be aware that it may be related to this drug.

Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.

The place of alpha blockers in the antihypertensive armamentarium.

Although beta-blockers and diuretics are presently the only medications shown to reduce morbidity and mortality in hypertensives in large clinical trials, these drugs have not exerted optimal expected benefits in reducing cardiac events. Alpha-1 selective blockers exhibit a favorable impact on lipids, particularly on HDL-cholesterol. Unlike beta-blockers, they do not increase triglycerides and they do not produce the increase in LDL-cholesterol observed with traditional doses of diuretics. Alpha-blockers should be considered in the treatment of hypertensives with lipid disorders or diabetes and in those who have contraindications, failure to respond or toxicity associated with diuretics and/or beta-blockade.

Cardiovascular risk factors in perspective.

Coronary heart disease and other manifestations of atherosclerosis are leading causes of morbidity and mortality in Canada. Despite favourable trends in recent years, we should try to reduce cardiovascular events further. Physicians must translate current knowledge into public health policies and management strategems for individual patients. Patients are best served by a comprehensive risk management approach, involving nonpharmacological (mainly lifestyle) changes and drug therapy.