Per Lund-Johansen

MORTALITY AND MORBIDITY RESULTS FROM THE EUROPEAN WORKING PARTY ON HIGH BLOOD PRESSURE IN THE ELDERLY TRIAL

The latter was due to a reduction in cardiac mortality (−38%, p=0.036) and a nonsignificant decrease in cerebrovascular mortality (−32%, p=0.16). In the double-blind part of the trial, the total mortality rate was not significantly reduced (−26%, p=0.077). However, cardiovascular mortality was reduced in the actively treated group (−38%, p=0.023), owing to a reduction in cardiac deaths (−47%, p=0.048) and a non-significant decrease in cerebrovascular mortality (−43%, p=0.15). Deaths from myocardial infarction were reduced (−60%, p=0.043), and study-terminating morbid cardiovascular events were significantly reduced by active treatment (−60%, p=0.0064). Non-terminating cerebrovascular events were reduced (−52%, p=0.026), but the non-terminating cardiac events were not (+ 3%, p=0.98). In the patients randomised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial.

EFFICACY OF ANTIHYPERTENSIVE DRUG TREATMENT ACCORDING TO AGE, SEX, BLOOD PRESSURE, AND PREVIOUS CARDIOVASCULAR DISEASE IN PATIENTS OVER THE AGE OF 60

Results of the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial have been analysed in relation to age, sex, blood pressure, and previous cardiovascular disease. Cardiovascular mortality and the cardiovascular study-terminating events were significantly and independently related to treatment, age, cardiovascular complications at randomisation, and systolic but not diastolic blood pressure. The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry. There was some evidence that treatment effect decreases with advancing age. Little or no benefit from treatment could be demonstrated in patients over the age of 80 years, the great majority of whom were women.

Clinical evaluation of the Colin Abpm 630 at rest and during exercise: an ambulatory blood pressure monitor with gas-powered cuff inflation

The Colin ABPM 630 is a silent, gas-powered (CO2) ambulatory blood pressure monitor which uses both ausculatory and/or oscillometric methods to measure blood pressure. We compared simultaneous, same-arm blood pressures obtained with the monitor with those made by two blinded, skilled clinicians using a mercury column and teaching stethoscope. In a second study, the monitor readings were also compared with opposite-arm intra-arterial recordings of blood pressure. The group mean systolic blood pressures obtained by the Colin monitor via the Korotkoff mode were almost identical to the mercury column readings (127.8 +/- 19.4 versus 128.1 +/- 19.3 mmHg, P = NS) and the limit of agreement (2 standard deviations) for the differences in the two methods was +/- 9 mmHg. The diastolic blood pressure obtained by the Colin monitor was significantly lower than the clinicians readings (-6.0 +/- 5.9 mmHg, P less than 0.0001). Similar findings were obtained with the oscillometric mode, however, the mean systolic blood pressure given by the monitor was slightly higher than that given by the mercury column (1.9 +/- 4.5 mmHg, P less than 0.001). In contrast to the mercury column comparisons, the mean diastolic blood pressure obtained with the monitor was nearly the same as the mean intra-arterial diastolic blood pressure for both the Korotkoff (0.1 +/- 5.6 mmHg) and the oscillometric modes (1.2 +/- 6.3 mmHg). During 100-watt bicycle exercise, there was a considerably greater scatter in the individual comparisons of the monitor and intra-arterial blood pressure than that seen in the measurements at rest, but the group means were again similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Unattended Blood Pressure Measurements in the Systolic Blood Pressure Intervention Trial : Implications for Entry and Achieved Blood Pressure Values Compared With Other Trials

The Systolic Blood Pressure Intervention Trial (SPRINT) enrolled 9361 participants aged ≥50 years in ≈100 expert medical centers and clinical practices throughout the United States.1 SPRINT excluded patients with diabetes mellitus and stroke survivors since previous clinical trials included those populations.2,3 Between 2010 and 2013, the SPRINT investigators randomly allocated the study participants into a standard treatment group receiving an average of 2 different blood pressure (BP) medications to achieve a systolic BP (SBP) target <140 mm Hg and into an intensive treatment group receiving an average of 3 BP medications to achieve a SBP target <120 mm Hg. The Director of the National Heart, Lung, and Blood Institute stopped SPRINT early because of a positive effect. The significant preliminary results of SPRINT were announced on September 11, 20154 and the study results were quickly and favorably commented on by the New York Times5 and the Washington Post.6 The target SBP <120 mm Hg had reduced rates of the composite primary outcome that included myocardial infarction (MI), other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes by 25% and the risk of death from all causes by 27%, when compared with the target SBP of <140 mm Hg. The primary results of the trial were presented at the Scientific Sessions of the American Heart Association in Orlando on November 9, 2015 and published on the same day.7 The SPRINT study was published with an accompanying statement from the Editor of New England Journal of Medicine 8 saying that “This clinical trial will change practice, and we are proud to publish it and to defend the importance of the expedited peer-review and publication process that it has undergone. The report is now in the public domain, and the investigators’ data …

Clinical evaluation of the Accutracker II ambulatory blood pressure monitor: assessment of performance in two countries and comparison with sphygmomanometry and intra-arterial blood pressure at rest and during exercise.

In order to assess the Accutracker II (Suntech Medical Instruments, Raleigh, North Carolina, USA), a relatively new ambulatory blood pressure (BP) monitor, versus standard forms of BP measurement, we compared same- and contralateral-arm measurements made, via a t-tube connected to a mercury column sphygmomanometer, by two clinicians using a teaching stethoscope and by intra-arterial recordings. Average systolic BP values obtained using the Accutracker II were similar to both the mercury column and intra-arterial determinations, but average diastolic BP values were lower than both the average mercury column (2.8 ± 4.2 mmHg, P < 0.001) and intra-arterial measurements (2.0 ± 4.7 mmHg, P < 0.02). During isometric exercise and 100-watt bicycle exercise, there were greater limits of agreement for the differences in BP between the Accutracker II and the intra-arterial transducer than were observed for the resting measurements, but these differences were no greater than those observed between intra-arterial and clinician-determined BP measurements. The clinical performance of the Accutracker II was assessed using 119 hypertensive subjects (84 in Norway and 35 in the USA) who wore the monitor for 24 h. While there was good-to-excellent data return in both countries, there were significantly less error codes secondary to excessive arm motion observed in Norway. Our data demonstrate that the Accutracker II is quite accurate compared with both the mercury column and intra-arterial methods of measuring BP, and performs well during 24 h outpatient activities. Our findings also indicate certain geographical differences which may be important in the performance of ambulatory BP-monitoring studies.

Pharmacology of Combined α-β-Blockade II

The cardinal haemodynamic disturbance in established hypertension is an increased total peripheral resistance and a subnormal blood flow, particularly during exercise. The spontaneously occurring changes in central haemodynamics have been followed in young males with essential hypertension over a 17-year period: a gradual increase in total peripheral resistance and blood pressure, and a gradual fall in cardiac output and stroke volume, have been demonstrated. Labetalol is a unique antihypertensive agent which induces both alpha- and beta-blockade. Numerous studies have shown that when labetalol is given intravenously to patients with mild to moderate essential hypertension, blood pressure falls within a few minutes-partly due to reduction in cardiac output and heart rate and partly due to reduction in total peripheral resistance. In most series the average reduction in blood pressure was 17 to 22%, the reduction in total peripheral resistance 11 to 14%, and the reduction in cardiac output 2 to 10%. Thus, the reduction in cardiac output with labetalol is less than that seen after single-dose injection of beta-blockers without intrinsic sympathomimetic activity. After intravenous injection, the blood pressure-lowering effect is most marked in the upright position and during muscular exercise when cardiac output is usually significantly reduced. Labetalol reduces blood pressure in severe hypertension. Intravenous doses of 0.2 to 0.8 mg/kg bodyweight reduce blood pressure by approximately 20%. This hypotensive effect is partly due to a reduction in total peripheral resistance and partly due to a fall in cardiac index. When the reduction in blood pressure is gradual and moderate (less than 20%), it is mainly produced by a reduction in total peripheral resistance. During long term use labetalol induces haemodynamic changes rather similar to those seen after bolus injection. However, during prolonged use there is a tendency to normalisation in cardiac output and stroke volume; the sustained decrease in blood pressure is mainly due to a reduction in total peripheral resistance. In a recent 6-year follow-up study where 15 patients were studied before treatment and after 1 and 6 years on long term labetalol treatment, a tendency to normalisation of central haemodynamics was found. Over the years total peripheral resistance was gradually reduced by 15 to 20% at rest as well as during exercise. Stroke volume gradually increased and after 6 years of treatment was approximately 10% higher than the pretreatment value. This compensated for the reduced heart rate and no significant reduction in cardiac output was seen either during exercise or at rest.(ABSTRACT TRUNCATED AT 400 WORDS)SummaryThe cardinal haemodynamic disturbance in established hypertension is an increased total peripheral resistance and a subnormal blood flow, particularly during exercise. The spontaneously occurring changes in central haemodynamics have been followed in young males with essential hypertension over a 17-year period: a gradual increase in total peripheral resistance and blood pressure, and a gradual fall in cardiac output and stroke volume, have been demonstrated.Labetalol is a unique antihypertensive agent which induces both α- and β-blockade. Numerous studies have shown that when labetalol is given intravenously to patients with mild to moderate essential hypertension, blood pressure falls within a few minutes — partly due to reduction in cardiac output and heart rate and partly due to reduction in total peripheral resistance. In most series the average reduction in blood pressure was 17 to 22%, the reduction in total peripheral resistance 11 to 14%, and the reduction in cardiac output 2 to 10%. Thus, the reduction in cardiac output with labetalol is less than that seen after single-dose injection of β-blockers without intrinsic sympathomimetic activity. After intravenous injection, the blood pressure-lowering effect is most marked in the upright position and during muscular exercise when cardiac output is usually significantly reduced.Labetalol reduces blood pressure in severe hypertension. Intravenous doses of 0.2 to 0.8 mg/kg bodyweight reduce blood pressure by approximately 20%. This hypotensive effect is partly due to a reduction in total peripheral resistance and partly due to a fall in cardiac index. When the reduction in blood pressure is gradual and moderate (< 20%), it is mainly produced by a reduction in total peripheral resistance.During long term use labetalol induces haemodynamic changes rather similar to those seen after bolus injection. However, during prolonged use there is a tendency to normalisation in cardiac output and stroke volume; the sustained decrease in blood pressure is mainly due to a reduction in total peripheral resistance.In a recent 6-year follow-up study where 15 patients were studied before treatment and after 1 and 6 years on long term labetalol treatment, a tendency to normalisation of central haemodynamics was found. Over the years total peripheral resistance was gradually reduced by 15 to 20% at rest as well as during exercise. Stroke volume gradually increased and after 6 years of treatment was approximately 10% higher than the pretreatment value. This compensated for the reduced heart rate and no significant reduction in cardiac output was seen either during exercise or at rest.Studies of the regional circulation have shown that labetalol reduces renal vascular resistance and forearm resistance. Coronary blood flow is slightly decreased but the reduction is less than that seen after conventional β-blockers. The effect on the pulmonary circulation is modest, and a significant reduction in pulmonary resistance is usually not seen.The responses to short and long term administration of labetalol differ from the responses to β-blockers, α-blockers and calcium antagonists. The long term responses resemble the effects of prolonged administration of prizidilol, a combined β-blocker and vasodilator. Prizidilol has been withdrawn from clinical trials and although several new compounds have been developed, labetalol is the only drug generally available for the treatment of hypertension which has both β-blocking and vasodilating or α-blocking properties.The haemodynamic effects of labetalol are well documented and would seem to make labetalol a particularly useful antihypertensive drug.

Haemodynamic effects of nifedipine in essential hypertension at rest and during exercise.

Fifteen males with previously untreated essential hypertension in WHO stage I, aged 20-64 years were studied on an outpatient basis. Oxygen consumption, heart rate, cardiac in a in a supine and sitting position and during steady state work at 50, 100 and 150 W. Following the haemodynamic study, nifedipine (long-acting form) 40-80 mg daily was given as the sole drug for 3-12 months (mean 11 months) whereupon the haemodynamic study was repeated. Systolic, diastolic and mean arterial pressures fell about 17% at rest supine and sitting and from 15 to 10% at the three different workloads (P less than 0.001). All but one patient demonstrated a fall in mean arterial pressure of 10 mmHg or more. The fall in pressure was associated with a statistically significant (P less than 0.05) reduction in total peripheral resistance (17% during rest and 10 to 16% during exercise). There were no statistically significant changes in oxygen consumption, heart rate, cardiac index or stroke index.

Electrophysiologic effects of flecainide acetate in patients with sinus nodal dysfunction.

Flecainide acetate (R818) is a new antiarrhythmic agent for oral and intravenous use; it has predominantly class I properties and a long plasma half-life. Electrophysiologic effects were evaluated in 11 patients with sinus nodal dysfunction before administration of flecainide acetate and 15 to 60 minutes after intravenous administration of 1.5 mg/kg body weight of flecainide acetate given over 15 minutes. In 8 of 11 patients with maximal sinus nodal recovery time increased after flecainide acetate. However, the mean maximal sinus nodal recovery time was not statistically significantly increased from 1,929 +/- 184 (mean +/- standard error of the mean [SEM]) to 2,770 +/- 500 ms (p less than 0.10). The corrected sinus nodal recovery time increased from 875 +/- 181 before to 1,727 +/- 507 ms after administration of flecainide acetate (p less than 0.05). The sinus cycle length and sinoatrial conduction time were not significantly changed. Flecainide acetate induced a marked prolongation of the H-V interval (from 41 +/- 3 to 52 +/- 4 mg [p less than 0.01]) as well as a significant increase in the A-H interval, QRS duration, and QT100 interval. The effective and functional refractory periods of the atria increased by 12% (p less than 0.01) and 11% (p less than 0.01), respectively. The atrioventricular (AV) nodal functional refractory period increased significantly by 7% (p less than 0.01), whereas the 9% prolongation of the effective refractory period was not statistically significant. No side effects were observed. It is concluded that flecainide acetate prolongs atrial and ventricular conduction and refractoriness, and thus appears to be a potent antiarrhythmic agent. However, the sinus nodal function is depressed, and thus caution is advised in the use of flecainide acetate in patients with sinus nodal dysfunction.

Central haemodynamics in essential hypertension at rest and during exercise: a 20-year follow-up study.

Central haemodynamics were studied invasively at rest and during ergometer-bicycle exercise in 77 males with essential hypertension aged 17-66 years and in 33 age-matched normotensives. At the start of the study, resting cardiac index, the heart rate, oxygen consumption (VO2) and mean arterial blood pressure were about 15% higher in those hypertensive patients aged 17-29 years than in the normotensives while the total peripheral resistance index was similar in both groups. During exercise, the stroke index decreased significantly and the total peripheral resistance index increased in the hypertensive group. After 10, and then 20 years, central haemodynamics were restudied in the hypertensive patients. The initially high cardiac index-low total peripheral resistance index pattern was reversed after 10 years. At the 20-year follow-up there was a further fall in the cardiac index and a more marked increase in the total peripheral resistance index at rest as well as during exercise. The study has shown a progressively abnormal haemodynamic pattern over two decades in young subjects with essential hypertension, characterized by a reduced cardiac function and excessive systemic vascular resistance.

The hemodynamics of the aging cardiovascular system.

Our information on the hemodynamics of the aging cardiovascular system in normotensive and hypertensive subjects is mainly based on cross-sectional studies. In normotensive subjects with no indication of coronary heart disease, recent noninvasive studies seem to indicate that cardiac output at rest and during exercise does not decline with age. These results contrast with what has been found by invasive studies in unselected populations. In hypertensive subjects it is well established that the hemodynamics of young subjects at the early stage differ greatly from what is seen in elderly hypertensive subjects. In the early phase, a high resting cardiac output is typical, whereas in the elderly, cardiac output is very low and total peripheral resistance ITPRI very high. Echo studies have shown that left ventricular hypertrophy develops early in hypertension-together with increased stiffness and reduced left ventricular compliance. A subnormal stroke volume during exercise is seen early in the process of hypertension. Data from the 20-year follow-up study of the Bergen population demonstrate that in groups of young (17–29 years) versus elderly (60–69 years) patients with hypertension with the same mean arterial blood pressure. the hemodynamic mechanisms behind increased blood pressure were widely different. The increase in mean arterial blood pressure during exercise was much steeper in the older subjects than in the younger ones, and TPR was about twice as high during 150 W exercise. Cardiac index (Cl) in the oldest group was approximately half of that in the youngest group. The differing hemodynamic patterns in the young and elderly might have implications for when and how to start drug treatment. and also for what type of treatment to select.