Joint National Committee VI: individualized versus indiscriminate therapy for hypertension.

The treatment of hypertension has progressed from a few nontoxic choices to the close to 60 individual drugs listed in the recommendations of the Sixth Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Many combination drugs are also listed for use. The JNC documents have suggested initial therapy with diuretic or beta-blocker since 1993. Practitioners have followed these suggestions or not followed them on the basis of their personal bias. Since the 1997 JNC VI report, several studies that seem to support an individualistic approach to treatment have been reported. This is an exciting time in hypertension research. Clinicians who treat this common disorder will continue to line up as indiscriminate or individualistic prescribers, depending on their interpretation of the available data. We expect the hypertensive patient to be the winner of this increased attention.

Are some antihypertensive therapies more efficacious than others in preventing complications and prolonging life?

Antihypertensive therapy has been used for almost 35 years to reduce blood pressure and prevent morbidity and mortality related to the hypertensive state. Malignant, severe, and moderate hypertension have all been shown to be worthy of drug treatment, but controversy remains as to the degree of benefit that is achievable by treating milder hypertension. A variety of clinical trials have demonstrated that antihypertensive therapy reduces the incidence of stroke, congestive heart failure, and left ventricular hypertrophy and the progression in severity of hypertension. The benefits with respect to prevention of coronary heart disease (CHD) have been much less impressive. Thiazide diuretics have been the base therapy for the bulk of the hypertensive subjects studied to date who have not demonstrated reduced incidence of CHD. Therapy with beta-blockers has the potential for reducing CHD, but an analysis of four studies finds only two with positive results. On the other hand, since that study found reduced total mortality as well as CHD compared with thiazide diuretic, its findings cannot be ignored. Other questions deserving further investigation include how other antihypertensive therapies compare with respect to the risk reduction found with thiazide diuretics and beta-blockers, the optimal posttreatment blood pressure, whether persons with mild hypertension benefit from therapy, whether women should be treated differently, and whether atherosclerosis may be affected by specific antihypertensive therapies.

Treatment considerations for the hypertensive patient over age 55.

The prevalence of hypertension increases with age. The majority of the hypertensive population is over age 55. Although the treatment of systolic hypertension remains incompletely understood, the reduction of diastolic hypertension with pharmacotherapy has been shown to reduce complications from hypertension in persons over age 55. The older hypertensive patient is at risk for the same complications as the younger patient: angina, myocardial infarction, arteriosclerosis obliterans, stroke, myocardial hypertrophy, congestive heart failure, and renal failure; the risk of sudden death and multi-infarct dementia in the older patient may be somewhat higher. The older hypertensive individual may have reduced plasma volume and defective salt and water conservation, reduced renal function, impairment of baroreceptor reflexes and sympathetic reactivity, and altered drug pharmacokinetics, or may have arteriosclerosis leading to pseudohypertension. Many circumstances interfere with adequate compliance with therapeutic regimens among the elderly. Concomitant medical conditions increase the possibility of drug interactions and require that the practitioner be able to adjust the antihypertensive program to the patient.

Effects of a novel renin inhibitor in patients with essential hypertension.

The effects of A-64662, a new specific renin inhibitor, on plasma renin activity (PRA) and blood pressure (BP) were studied for the first time in patients with essential hypertension. A single intravenous bolus of vehicle, 0.001, 0.003, 0.01, 0.03, and 0.1 mg/kg was given to the first four patients, maintained on a constant 100 mEq Na diet. PRA was promptly reduced from 3.4 +/- 2.9 (mean +/- SEM) to 0.2 +/- 0.06 ng/ml/h, a 94% inhibition with the smallest dose, and to undetectable levels (less than 0.1 ng/ml/h) with the larger ones. However, BP did not change within this dose range. The subsequent seven patients received larger doses ranging from 0.2 to 1.0 mg/kg. In three cases, there was reduction in BP on the second dosing day, at doses of 0.4, 0.7, and 1 mg/kg. All responses were late (at 110 min after the injection), transient, and unrelated to baseline PRA. These results strongly suggest that there is a dissociation between the effectiveness of A-64662 in inhibiting PRA and its blood pressure lowering effect in hypertensive patients.

Renin inhibition with A-64662: effect on blood pressure and hormonal response in man.

We studied the effects of intravenous injections of the renin inhibitor A-64662 on blood pressure, plasma renin activity (PRA), angiotensin II (Ang II) and aldosterone levels in patients with essential hypertension. While PRA was completely suppressed with doses as small as 0.001 microgram/kg, blood pressure was affected only in a few instances in doses of 0.4-1.0 mg/kg. In the six patients in whom Ang II and aldosterone results were available these hormones were concomitantly reduced with PRA, although the PRA inhibition lasted much longer (up to 24 h). There was little relationship between the blood pressure changes and plasma levels of renin activity, Ang II and aldosterone, suggesting that the plasma pool of these variables may not be the crucial factor determining blood pressure responses in patients with essential hypertension.

The hypertensive patient with concomitant cardiovascular disease.

Many drugs for the treatment of hypertension are available in the United States today. Of the various factors that determine the appropriate treatment for a particular patient, the presence of concomitant heart disease requires specific tailoring of the antihypertensive therapy. Coronary artery disease, aortic insufficiency, congestive heart failure, left ventricular hypertrophy, premature ventricular contractions, supraventricular arrhythmias, mitral valve prolapse, orthostatic hypotension, and aortic dissection are some of the conditions that influence the choice of treatment. Diabetes places hypertensive patients at increased risk of heart disease, and exercise and sexual function are other considerations that govern the selection of treatment for the hypertensive person. For all of these conditions, more than one drug choice is often possible, but usually hypertensive patients can be treated with a beta-blocker or a calcium channel blocker in these special circumstances.

The relationship of various indices of heart size on chest x-ray to the 10-year incidence of hypertension. The Normative Aging Study.

A total of 598 males (aged 30-74 years) who had baseline (1961-1970) chest radiography and baseline blood pressure less than 140/90 mmHg were observed prospectively for 10 years. Subjects were participants of the Normative Aging Study, a longitudinal study on aging initiated in 1961 at the Veterans Administration Outpatient Clinic in Boston, Massachusetts. Blood pressures were taken at five- and 10-year follow-up examinations. Multiple logistic regression analysis indicated that the long diameter of the heart (on posteroanterior film) and the cardiac depth (on lateral film) were statistically significant predictors of subsequent hypertension after controlling for baseline body mass index, systolic pressure, and diastolic pressure. A similar model considering various composite indices of heart size indicated that the heart volume was a statistically significant and independent predictor of hypertension. Thus, increases in heart size may precede and predict the development of sustained hypertension.

High Blood Pressure in the Competitive Athlete: Guidelines and Recommendations.

In brief: Since short-term adverse effects of hypertension in competitive athletes have not been reported, it seems reasonable to permit most athletes with mild to moderate hypertension to participate in organized sports, Mild hypertension may be managed by restricting sodium intake, controlling weight, and using relaxation techniques. Some sympathetic inhibiting agents are preferable as first-step drugs because they lower arterial pressure at rest and during exercise. Occasionally small-dose diuretics may be added, usually with potassium supplements. Long-term observation of hypertensive athletes is needed to determine the presence or absence of late harmful effects of increased arterial pressure and exercise.

Renal revascularization in the azotemic hypertensive patient resistant to therapy.

We undertook this study to assess the frequency of renovascular hypertension in patients with azotemia and hypertension refractory to drug therapy and to determine the effects of renal revascularization on blood pressure and renal function in these subjects. Thirty-nine of 106 consecutive patients admitted for diagnostic evaluation of severe hypertension proved to have renovascular hypertension. Of 21 hypertensive patients with renal insufficiency, 10 appeared to have renovascular hypertension with either bilateral atherosclerotic renovascular disease or unilateral renal arterial stenosis in a solitary functioning kidney. Medical therapy in the hospital often induced further deterioration of renal function despite enhanced blood-pressure control. However, surgical revascularization or percutaneous transluminal angioplasty produced improvement or stabilization of renal function and control of blood pressure in all patients with azotemia who were treated in this manner, despite longstanding hypertension. The benefits of therapy have persisted for 10 to 42 months of follow-up. These studies indicate that refractory hypertension in association with renal insufficiency is a relatively common clinical presentation for renovascular hypertension and bilateral renal-artery disease. Diagnostic evaluation and consideration of renal revascularization appear warranted in such patients, both for the control of the hypertension and for improvement in renal function.

Postural changes in diastolic blood pressure and the risk of myocardial infarction: the Normative Aging Study.

To assess the relationship of postural changes in blood pressure to risk of myocardial infarction, 1359 men were followed for an average of 8.7 years. The men were participants in the Normative Aging Study, a longitudinal study of aging initiated in 1963 at the Veterans Administration Outpatient Clinic in Boston. It was found that the relationship of sitting blood pressure to the subsequent incidence of myocardial infarction was modified by a variable formed by subtracting supine from standing diastolic blood pressure (delta DBP). The effect of sitting diastolic blood pressure on risk of myocardial infarction was confined primarily to men with a delta DBP of 10 mm Hg or more. The effect of sitting systolic blood pressure on risk of myocardial infarction was apparent in all categories of delta DBP (less than 1, 1 to 9, greater than or equal to 10 mm Hg), but the gradient of risk became stronger with increasing levels of delta DBP. The modifying influence of delta DBP remained even when standard coronary risk factors were included in multivariate analyses. These findings suggest a relationship of vascular responsiveness to risk of subsequent myocardial infarction and may have clinical utility.

Treatment of chronic orthostatic hypotension with ergotamine.

The acute and chronic effects of ergotamine were examined in four patients with chronic orthostatic hypotension. Chronic oral administration of ergotamine tartrate produced significant increases in standing blood pressure and marked clinical improvement, without appreciable recumbent hypertension. The blood pressure increases were not associated with significant changes in plasma norepinephrine or plasma renin activity. No major toxicity was observed at doses of 2-6 mg/day over treatment periods of 3-18 months. Hemodynamic studies on the effects of i.v. ergotamine tartrate (0.25-0.50 mg) revealed that the ergotamine-induced increase in blood pressure in the supine position was associated with an increase in total peripheral resistance (from 1616 +/- 165 to 2574 +/- 583 U) without a change in cardiac output. During 45-60 degrees upright tilt, ergotamine increased both total peripheral resistance (1801 +/- 296 to 3262 +/- 1107 U) and cardiac output (2.42 +/- 0.46 to 3.34 +/- 0.54 l/min). Forearm plethysmographic studies revealed decreased forearm blood flow and venous volume and increased vascular resistance with ergotamine. The orthostatic hypotensives had more platelet alpha-receptors (390 +/- 31 receptors/cell) than the control subjects (234 +/- 17 receptors/cell). The increased receptor level was associated with abnormally low circulating levels of norepinephrine and increased pressor responsiveness to infused norepinephrine in three of the four patients. Chronic ergotamine therapy appeared to reduce platelet alpha-receptor number to normal. The results indicate that ergotamine is of value in certain patients with chronic orthostatic hypotension and that the blood pressure effects are related to vasoconstriction in both arterial and venous beds.

Continuing medical education: 1960s to the present.

Since the 1960s, continuing medical education (CME) has undergone a period of reappraisal of its effectiveness and consideration of alternatives to the traditional teaching model. In this paper the authors discuss three proposals that were developed out of these concerns: the establishment of a national plan, a process program model based on the identified needs of physicians, and the use of mandatory continuing education as part of a relicensing/recertification procedure. The problems and controversies in each of these areas are explored. Recommendations for changes in CME are discussed and summarized into three areas: organizational needs, programmatic needs, and physician needs. The authors attempt to point out the general agreement in these recommendations as well as the difficulty of achieving any uniform or orderly change in the future.

Hypertension and age: clinical and biochemical correlates.

Plasma renin activity, aldosterone and norepinephrine levels were determined in 247 ambulatory hypertensive patients divided into young, middle aged, and old groups. PRA and the increase of PRA after furosemide were higher in the younger; NE was higher in the old group. Some relationships may be inherent in aging and not necessarily confined to hypertensives. This may explain discrepancies between reports by investigators who studied homogenous groups classified in different ways.