Stewart Mann

DOES PLACEBO LOWER BLOOD-PRESSURE?

The effect of placebo on blood-pressure levels in 20 hypertensive patients was examined as part of a double-blind randomised controlled trial with indoramin. Blood-pressure was measured by both standard sphygmomanometry and ambulant intra-arterial monitoring. Blood-pressure reduction during the placebo phase, as measured by sphygmomanometry in the outpatient clinic, was highly significant for both systolic and diastolic pressures. In the same subjects, concomitant assessment by ambulatory monitoring showed no significant effect of placebo on intra-arterial pressure. After indoramin treatment blood-pressures measured in the clinic showed a mean reduction of 6/8 mm Hg whereas intra-arterial monitoring showed mean reductions of 18/13 mm Hg. The placebo response, therefore, appears to be an artifact of clinic blood-pressure measurement and its use as a control value in pharmacological trials may lead to serious underestimation of the efficacy of the active drug.

SUPERIORITY OF 24-HOUR MEASUREMENT OF BLOOD PRESSURE OVER CLINIC VALUES IN DETERMINING PROGNOSIS IN HYPERTENSION

Long-term recordings of blood pressure in an individual could logically be expected to have greater prognostic power than values recorded in the clinic in view of the known inaccuracies and variability of the latter. This feature has been shown to be true in a large series investigated by Perloff and colleagues1. Specific components of the 24h profile may have greater prognostic power than others, ‘basal’ blood pressure (generally equated with night-time resting values) has been thought by some2 to have greater predictive value than that recorded during less standardised activity at other times of day. A further hypothesis is that high intrinsic blood pressure variability may play an independent role in determining cardiovascular pathology when measured either as a global index3 or as a specific component such as the slope of the early morning rise in pressure4.

Effect of labetalol on continuous ambulatory blood pressure.

1 The hypotensive action of labetalol was evaluated during 24 h by continuous intra-arterial ambulatory monitoring in 14 patients. The dose used ranged from 300-1800 mg daily. 2 The drug caused a significant reduction of systolic BP in 19 and diastolic BP in 20 of the 24 h of monitoring. Heart rate was also reduced but less markedly than BP. 3 The rapid early morning increase in BP was also effectively controlled. 4 The mild pre-waking increase in BP was not significantly reduced. 5 Labetalol treatment reduced the variation in systolic BP from the lowest observed quarter-hourly mean as compared with pre- treatment values. 6 The quarter hourly mean values were consistently smooth and revealed no sudden variations which might have resulted from postural hypotension.

Use of graded exercise testing in assessing the hypertensive patient

Twenty‐five patients with suspected hypertension were studied using the “Oxford” continuous intra‐arterial blood pressure recording technique. Each patient carried out graded exercise on a bicycle ergometer, using a standard protocol, and then underwent a fully ambulatory 24‐h outpatient blood pressure recording. Using computer analysis, ambulatory blood pressure in each patient was characterised by measuring the mean daytime systolic and diastolic pressures. Exercise was found to be associated with a characteristic increase in systolic and diastolic blood pressure. Submaximal and maximal exercise blood pressures were shown to correlate strongly with ambulatory blood pressure. A much weaker correlation was found between clinic and ambulatory blood pressure. These findings suggest that the blood pressure response to exercise may be a better indicator of elevated blood pressure than a casual clinic blood pressure in individual borderline subjects.

Once-daily pindolol in hypertension: An ambulatory assessment

Ambulatory monitoring of intra-arterial blood pressure was used to assess patterns of circadian blood pressure in 12 hypertensive patients who were treated with pindolol in either a once- or twice-daily dosage regimen. Neither once-daily nor twice-daily pindolol had much effect during the latter part of the night and early morning. In the six patients who agreed to further crossover studies, the hypotensive effects of once-daily therapy were not significantly different from those produced by a twice-daily regimen. While confirming the effectiveness of once-daily beta blockade in hypertension, we deduce that failure to affect nighttime blood pressure substantially is a feature independent of the dosage regimen and also, probably, of the individual beta blocker used.

Effect of labetalol in hypertension during exercise and postural changes.

1 Fourteen hypertensive patients were studied by intra-arterial BP monitoring to quantify the effects of standardized physiological stresses: Valsalva manoeuvre, isometric, treadmill and bicycle exercise, and 60 degree tilting before and after labetalol treatment. 2 The dose of labetalol ranged from 100-600 mg three times daily and the response was judged on outpatient clinic recordings. 3 The drug produced a sustained reduction of BP and heart rate responses during dynamic exercise and the Valsalva manoeuvre, but the degree of change from the lowered baseline were not changed by labetalol. The fall in BP on cessation of exercise was decreased rather than increased. 4 The response to controlled isometric muscle contraction was affected in a similar fashion. 5 Tilting produced a fall in BP after treatment, and this was most marked in those patients on the highest doses. However, compensatory increases in diastolic BP were observed.

Circadian rhythms in hypertension.

Continuous intra-arterial blood pressure recordings have been performed in 37 untreated ambulatory hypertensive subjects, who were investigated on an outpatient basis. Hourly data analysis demonstrated a circadian variation of both blood pressure and heart rate which were highest during the morning and fell during the late afternoon to reach a nadir during sleep. Prior to waking there was an increase in blood pressure, but not heart rate; however both blood pressure and heart rate increased briskly shortly after waking. Chronic therapy with oxprenolol (in 10patients) reduced daytime blood pressure, but had little effect during the night-time or early morning.

Alpha-adrenoreceptor blockade with indoramin in hypertension.

We have evaluated the effects of indoramin, an alpha-adrenoreceptor blocking drug, used as sole therapy in a group of 27 patients with essential hypertension. Blood pressure and heart rate were measured continuously over prolonged ambulatory periods using an established invasive technique before and after six weeks of therapy. The protocol was randomised, double-blind, and with double-dummy placebo control. A standardised programme of physiological stress testing was also performed during each study. Placebo produced no appreciable change in the levels or patterns of blood pressure over 24-h periods, but indoramin produced a significant reduction, which was particularly marked during the night. Physiological testing did not reveal any postural hypotension, and the response to dynamic and isometric exercise was modified in level but not in degree of change. There were many unwanted effects, which may limit the clinical value of this drug.

Effects of oxprenolol on the intra-arterial blood pressure response to dynamic exercise in hypertensive men.

Summary The intra-arterial blood pressure of 20 male patients with essential hypertension was continuously recorded during dynamic exercise. Graded exercise testing on a bicycle ergometer and a stair-climbing test were performed prior to and during treatment with oxprenolol. Acute oxprenolol therapy was associated with a reduction in heart rate but little reduction in blood pressure. Chronic treatment for 14.3 weeks with oxprenolol (mean daily dose, 344 mg) was associated with a substantial reduction of blood pressure at rest and at each level of bicycle exercise. A similar antihypertensive effect was demonstrated during stair climbing. The normal blood pressure response to exercise as assessed by the relative (percentage) increase in pressure above the pre-exercise level and the rate of increase in blood pressure (per unit of work), as well as exercise tolerance, were unchanged by chronic β-blockade with oxprenolol.

Intra-arterial ambulatory blood pressure monitoring in the assessment of antihypertensive drugs

Direct measurement of blood pressure in ambulatory patients was performed with the intra-arterial “Oxford System” to assess the effectiveness of differing antihypertensive agents. The betablocker, metoprolol (200 mg daily), decreased daytimed blood pressure from 174/95 mmHg to 158/85 mmHg; the combination of metoprolol and chlorthalidone (25 mg daily) further decreased the mean daytime pressure to 143/78 mmHg (p < 0.001 systolic, p < 0.005 diastolic). The calcium channel blockers, nifedipine (20–40 mg twice daily) and verapamil (120–160 mg three times daily), each significantly decreased the nifedipine, but decreased significantly with verapamil. The angiotensin converting enzyme inhibitor, enalopril (20–40 mg daily), significantly decreased blood pressure for 18 of 24 hours, the antihypertensive effect being most pronounced during the daytime period. These experiences indicate that the technique of direct ambulatory blood pressure monitoring is of value in studying both the efficacy and the duration of antihypertensive treatment.mean hourly blood pressure during most of the day (23 of 24 hours with nifedipine, 15 of 24 hours of verapamil). Heart rate did not change with nifedipine, but decreased significantly with verapamil. The angiotensin converting enzyme inhibitor, enalopril (20–40 mg daily), significantly decreased blood pressure for 18 of 24 hours, the antihypertensive effect being most pronounced during the daytime period. These experiences indicate that the technique of direct ambulatory blood pressure monitoring is of value in studying both the efficacy and the duration of antihypertensive treatment.