International Prospective Primary Prevention Study Research Articles

Smoking, Antihypertensive Treatment Benefit, and Comprehensive Antihypertensive Treatment Approach

Several major studies investigated the possibility of a primary preventive effect of beta-blockers. The International Prospective Primary Prevention Study in Hypertension (IPPPSH) compared a beta-blocker-containing vs. a non-beta-blocker-containing antihypertensive regimen in 6,357 moderate-severe hypertensive men and women treated over 3-5 years. Blood pressure (BP) control was comparable with either regimen. beta-Blocker treatment was associated with less hypokalemia, earlier electrocardiogram normalization, and fewer withdrawals for uncontrolled hypertension. In agreement with the Medical Research Council (MRC) trial on mild hypertension and the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, but at variance with the Primary Prevention Metoprolol in Patients with Hypertension (MAPHY) study, cardiac event rates were similar in beta-blocker- and non-beta-blocker-treated patients. With either regimen, in-study BP reduction was associated with a lower rate of stroke as well as of cardiac events. In a subgroup analysis, nonsmokers appeared to derive beta-blocker benefit, the results being similar to those of the MRC. Smokers required higher doses of drugs to achieve diastolic target pressure, had a higher heart rate and hematocrit, and a higher cardiac event rate than nonsmokers at any given level of diastolic pressure. Except for the MAPHY trial, these primary prevention studies do not support the concept of a cardiac primary preventive effect of antihypertensive beta-blockade but stress the importance of good BP control and a comprehensive risk factor prevention approach in the management of hypertensive patients.

Smoking, Antihypertensive Treatment Benefit, and Comprehensive Antihypertensive Treatment Approach

Several major studies investigated the possibility of a primary preventive effect of β-blockers. The International Prospective Primary Prevention Study in Hypertension (IPPPSH) compared a β-blocker-containing vs. a non-β-blocker-containing antihypertensive regimen in 6,357 moderate-severe hypertensive men and women treated over 3–5 years. Blood pressure (BP) control was comparable with either regimen. β-Blocker treatment was associated with less hypokalemia, earlier electrocardiogram normalization, and fewer withdrawals for uncontrolled hypertension. In agreement with the Medical Research Council (MRC) trial on mild hypertension and the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, but at variance with the Primary Prevention Metoprolol in Patients with Hypertension (MAPHY) study, cardiac event rates were similar in β-blocker- and non-β-blocker-treated patients. With either regimen, in-study BP reduction was associated with a lower rate of stroke as well as of cardiac events. In a subgroup analysis, nonsmokers appeared to derive β-blocker benefit, the results being similar to those of the MRC. Smokers required higher doses of drugs to achieve diastolic target pressure, had a higher heart rate and hematocrit, and a higher cardiac event rate than nonsmokers at any given level of diastolic pressure. Except for the MAPHY trial, these primary prevention studies do not support the concept of a cardiac primary preventive effect of antihypertensive β-blockade but stress the importance of good BP control and a comprehensive risk factor prevention approach in the management of hypertensive patients.

MAPHY and the Two Arms of HAPPHY

To the Editor.— JAMA recently published comments on the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) Study, together with a response from the authors. 1 I have some additional remarks. Although the Heart Attack Primary Prevention in Hypertension (HAPPHY) and MAPHY trials are judged as different by the Steering Committee of the HAPPHY trial, the MAPHY trial cannot be interpreted independently of the HAPPHY trial findings because all patients in the MAPHY Study are in the HAPPHY trial. Therefore, the meta-analysis presented by Staessen et al cannot be used for comparison of the MAPHY Study with previous trials. 1 The only valid way the comparison could be done would be to make a meta-analysis of the Medical Research Council trial and the International Prospective Primary Prevention Study in Hypertension and the atenolol part of the HAPPHY trial. The Steering Committee of the HAPPHY trial, therefore, should publish the results in the

Discussion of the Paper by Jennison and Turnbull

Discussion of the Paper by Jennison and Turnbull

Analysis of patient self‐assessment visual analogue scales

AbstractThe present paper describes an example of practical analysis of data from an application of visual analogue scales. Potentially useful and simple methods for analysing visual analogue scales are described for effective handling of complex data when the desire is to compare two or more groups of patients. Visual analogue scales were used to assess subjective tolerability in the International Prospective Primary Prevention Study in Hypertension, a large scale clinical trial. The methods are illustrated on the IPPPSH data.

Diuretic agents and beta-blockers in the treatment of hypertension.

Benzothiadiazine diuretic agents and beta-adrenergic receptor-blocking drugs are two of the main groups of drugs used to treat mild hypertension. Recently, questions have been raised about their relative efficacy in preventing morbidity and mortality from vascular disease in addition to their effect on lowering blood pressure. Attention has been focused on the unfavorable metabolic effects of diuretic drugs and the proven value of beta-adrenergic receptor blockade in secondary prevention after myocardial infarction. Four randomized controlled trials comparing drugs in these two classes have been published: the Medical Research Council trial, the International Prospective Primary Prevention Study in Hypertension, the Heart Attack Primary Prevention in Hypertension trial, and the Metoprolol Atherosclerosis Prevention in Hypertension study. These trials, especially that of the Medical Research Council, have raised some questions about the relative efficacy of these two classes of drugs in preventing stroke in smokers and nonsmokers. Overall, there is little evidence of a reduction in morbidity and mortality after myocardial infarction. The predicted advantage of beta-adrenergic receptor blockade over diuretic therapy has not been realized although there are sufficient hints of a differential benefit to encourage the performance of further trials.

Beta-Blockers and Diuretics the Happhy and Maphy Studies

The question whether initial antihypertensive treatment with a beta-blocker prevents hypertensive complications better than initial treatment with a non-betablocker, mainly diuretic based treatment, has been studied in recent large-scale studies like the Medical Research Council (MRC) trial, the International Prospective Primary Prevention Study in Hypertension (IPPPSH), the Heart Attack Primary Prevention in Hypertension (HAPPHY) study and the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study. The first three studies were unable to find a more beneficial effect of beta-blockers than of thiazide diuretics. The MAPHY study, however, found a lower total mortality, in the metoprolol treated group than in the diuretic treated. As the HAPPHY and MAPHY studies share a substantial part of patient-years and number of deaths, these diverging results have evoked confusion and debate. This paper presents the main results of both studies and discusses the possible reasons for the different outcome.

Impact of smoking on heart attacks, strokes, blood pressure control, drug dose, and quality of life aspects in the International Prospective Primary Prevention Study in Hypertension

Effects of smoking are highlighted in a posthoc analysis of this randomized, double-blind International Prospective Primary Prevention Study in Hypertension (IPPPSH). At the time of entry, 37% of the men and 23% of the women were smoking cigarettes, and only 537 patients changed their smoking status during the trial. In men and women, smoking doubled cardiac and cerebrovascular event rates. Nonsmoking men had fewer myocardial infarctions and sudden deaths when treated with oxprenolol. Smoking status did not affect in-study blood pressure control, the type of drugs, or the combinations used, but smokers were given higher doses of oxprenolol. For a given blood pressure during antihypertensive treatment, rates for cardiac and cerebrovascular events were higher in smokers. Heart rates were higher in both oxprenolol and non-beta-blocker-treated smokers. Smoking dose dependently increased hematocrit level. Among physician-elicited symptoms, dyspnea and cold extremities were more frequent in smokers, whereas dyspnea, headaches, impotence, dizziness, and anxiety states were common, with unsatisfactory blood pressure control (diastolic blood pressure > 95 mm Hg). Quality of life may be more jeopardized by smoking, poor blood pressure control, or diuretic use than by beta-blocker-based therapy. In the IPPPSH, the patient who smoked had double the cardiovascular complication rates without cardiac benefit from the beta-blocker despite higher doses given; the higher heart rate and hematocrit level may have been contributing factors.

Aims of Treatment of Hypertension

The major aim of treatment of arterial hypertension is to reduce the increased risks of cardio-cerebrovascular morbidity and mortality that are associated with elevated blood pressure (BP). A direct relationship can be found between the level of BP and risk, even down to what is normally considered to be the "normotensive range", i.e., diastolic BPs of 80 mm Hg. Moreover, when considering that the risk in treated hypertensive patients is more closely linked to the BP level achieved during treatment than to the initial untreated level, it becomes obvious that the aim should be to lower elevated arterial pressure to strictly "normotensive" levels. Recently, the results of several large-scale trials have shown that treated hypertensive patients still have an increased risk for morbidity and mortality, compared with normotensive subjects recruited from the same population and of the same sex and age. The main reason for this appears to be inadequate control of BP. Since mortality and morbidity from coronary heart disease (CHD) still constitute the major risk in hypertension, special efforts should be directed towards this problem. In addition to the obvious need for better control of BP, there appears to be a need also for direct measures against CHD. The beta-blockers are therefore of particular interest. Despite the fact that the large-scale Medical Research Council (MRC) and the International Prospective Primary Prevention Study in Hypertension (IPPPSH) studies only indicated that beta-blockers could have a primary preventive effect against CHD in nonsmoking male patients, the possibility that beta-blockers may in fact have a primary preventive effect against CHD in hypertension is still logical.