The primary objective of the report is to assess the scientific basis for treatment of mild and moderate hypertension, up to a diastolic pressure of 105mmHg. This included evaluating the effects of pharmacologic and non-pharmacologic treatments. A secondary objective was to evaluate studies on the effects of antihypertensive treatments on left ventricular hypertophy (LVH), blood lipids, glucose metabolism and renal function.

For studies on pharmacologic interventions, MEDLINE was searched from 1967 to 1993 for controlled trials and up to 1992 for meta analyses. References of literature located by MEDLINE search were also sought.

For studies on non-pharmacologic interventions, MEDLINE was searched from 1970 to 1992 and a review of the references in the meta-analyses was undertaken.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were included. However, other treatment allocation methods were also allowed (e.g. alternate allocation). Blinding or placebo were not required. Duration of follow up was 6 months or more. The purpose of the study had to be stated as treating essential hypertension (excluding alternative uses of antihypertensive drugs). Meta-analyses were also included. Trials reviewed in the secondary objective were only included if follow up was one year or longer.

Specific interventions included in the review

Alpha methyldopa, acebutolol, amiloride, amlodipine, atenolol, clonidine, bendrofluthiazide, clorthalidone, doxazosin, enalapril, guanethidine, hydrochlorothiazide, hydralazine, metoprolol, nifedipine, oxprenolol, pindolol, propranolol, reserpine, spironolactone, triampterene, nutritional interventions (weight loss, sodium restriction, reduced alcohol intake, smoking cessation, lipid-lowering therapy), stress management and relaxation programme.

For some studies, treatments are simply categorised as beta-adrenoreceptor blockade based or non-beta-adrenoreceptor blockade based.

Participants included in the review

Patients with one of the following:

Mild hypertension: initial diastolic blood pressure (DBP) 90-104 mmHg.

Moderate hypertension: initial DBP 105-115 mmHg.

Isolated systolic hypertension: initial systolic blood pressure (SBP) >160mmHg with DBP <90mmHg.

Pregnancy-related hypertension was excluded.

Outcomes assessed in the review

Mortality (cardiac, stroke, total cardiovascular, non-cardiovascular, total death) or non-fatal events (cardiac, stroke, all cardiovascular). Adverse effects and quality of life were also considered.

How were decisions on the relevance of primary studies made?

The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.

An 8-item inventory, adapted from Fowkes & Fulton (see Other Publications of Related Interest ). Each item was given a score of acceptable, acceptable with reservations and not acceptable. These scores were totalled. In addition, an overall score (1-5, 1=poor, 5=excellent) was given. The specific criteria assessed were: study design, study sample, control group, quality of measurements and outcomes, completeness, distorting influences, strategy for data analysis and strategy for treatment. All 13 authors reviewed and scored each study individually. The 8-point score and overall scores from all reviewers were averaged. Studies with an average score of 8 or more on the 8-point protocol and those with an average overall score of 2 or more were included.

The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.

How were the studies combined?

A narrative synthesis was undertaken.

How were differences between studies investigated?

Although a statistical test for heterogeneity was not performed, each study is described in detail through the use of multiple tables highlighting specific points of comparison. Different interventions (drug versus placebo, drug versus drug, etc.) were analysed separately.

A total of 22 studies were included in the review. 14 drug versus placebo or no therapy, 4 drug versus drug, 2 multi-factorial risk reduction plus drug therapy, 2 non-pharmacologic interventions. Of these, 9 were double blinded, 3 single blinded and 10 were open-labelled. In the studies that involved screening, more than 2,059,161 people were screened. 42,442 patients were enrolled into treatment arms, and 41,236 were enrolled into control arms, a total of 83,678 patients. Of patients enrolled into treatment arms, approximately 36,646 (86%) were included in follow up. Of patients enrolled into control arms, approximately 35,855 (87%) were available at follow up.

Primary objective.

Most of the 22 studies had a follow up period of 4-7 years, except for 3 that were stopped early due to significant treatment effects and 2 that had shorter follow up periods (2.3 and 1.5 years).

Significant reductions in incidence of stroke were found in 10 of the 22 studies (none of which were in the non-pharmacologic studies). Incidence of coronary heart disease (CHD) was significantly reduced in 5 out of 22 studies (1 of which was in a non-pharmacologic study). Two of the studies indicating significant benefit were of elderly patients. Total mortality was significantly reduced in 5 out of 22 studies (none of which were in the non-pharmacologic studies). Based on a previous meta-analysis, it is concluded that the morbidity and mortality risk reduction for CHD is 16% and for stroke 38%.

Treatment benefits are greater with greater reduction in blood pressure, including patients with only mild hypertension. Benefits are also seen in patients with reductions in SBP, DBP or Isolated systolic hypertension (particularly the elderly). Risk reduction in women is equal to that of men, although younger women are less likely to have hypertension. Benefits are also seen in the elderly, up to 75-80 years. The greatest treatment benefits over a 5 year period are seen in elderly patients and those with existing cardiovascular disease. Benefits of reducing blood pressure in patients with elevated cholesterol, obesity or in smokers are minor.

Secondary objective.

The results of the review of trials measuring changes in left ventricular hypertrophy (LVH) indicate that, based on ECG findings, reduction in blood pressure using a diuretic has a benefit for patients with pronounced LVH. Studies based on echocardiographic evidence of LVH are less clear, due to problems with study design. Differences between antihypertensive drugs were not clearly shown, although ACE-Inhibitors may also have an effect in patients with pronounced LVH. Data on the effects of lowering blood pressure on preventing renal damage are unclear, primarily because the incidence is much lower than cardiovascular complications. The effects of antihypertensive medications on metabolic risk factors are unclear. Glucose levels or the incidence of diabetes mellitus have not shown any significant changes in long-term antihypertensive studies. Changes in total cholesterol appear to be small, 3-6%, and vary even within a single drug class. Changes in low-density lipoprotein or triglycerides appear to be minor, and inconsistent.

Adverse effects and quality of life.

Drug intervention has shown adverse effects in 10-20% of patients treated. In some cases, side effects were so severe that treatment was discontinued. No substantial differences in quality of life between different forms of treatment were found.

A full economic analysis was performed, and is reviewed in the NHS Economic Evaluation Database. Cost per life-year gained was calculated in 1992 Swedish costs (Swedish krone, SEK). The cost per life-year gained, was based on a 5% discount rate, a treatment period of 1 year, assuming a risk reduction of 16% for CHD and 38% for stroke, and treatment costs of 3000 SEK per year. Cost per life-year gained ranged from 440-947 SEK for men <45, depending on initial DBP (90-94 at the low end, and > 105 at the high end). Women in this age group had a cost per life-year gained of 746 - 2506 SEK. Figures for men 45-69 years were 68 SEK on the high end, and a cost saving on the low end. Women age 45-69 had a high of 215 SEK at the mild hypertension end and a cost saving at the high hypertension end. For persons > 70 the cost per life-year gained ranged from 25 SEK at the mild hypertension end to cost saving at the high end. Cost saving was also seen for women > 70 with DBP's in the 100-104 range (high moderate).

The positive effects of drug therapy are documented at a stable diastolic blood pressure of 95mmHg or above. The positive effects of drug therapy are clearly demonstrated in older individuals with a stable systolic blood pressure of 160 mmHg or above. The absolute benefits from treating persons with DBP's in the 90-99 mmHg range over a 5-year period are small, and the patient's total risk factor profile must be taken into account. Persons with borderline hypertension should be monitored without treatment for 3-6 months, minimum. While other anti-hypertensive drugs reduce blood pressure as well, only treatment based on diuretics and/or beta-blockers has been studied (at the date of this review) in relation to morbidity or mortality, with more data available on diuretics. Therefore, these two groups of drugs are considered first-line therapy. Lifestyle-related therapies demonstrate the ability to reduce blood pressure for a limited time, but no studies have shown an effect on morbidity or mortality.

This was an extensive review of the literature, with a well-defined study question and a scoring system to evaluate each study for validity. Inclusion criteria were used. The search strategy could have been described in more detail, i.e. by providing the search terms. Individual studies were described to some extent in the text, with further information provided in tables. The synthesis of study outcomes was performed narratively, with reference to a previously published meta-analysis which included some, but not all, of the studies reviewed here. The method of arriving at results and conclusions (i.e. weighting of studies based on validity score) was not discussed.

Deficiencies in patient groups included in the studies are addressed, as is the lack of studies using newer drugs. At the time of this review, there were no large, well-controlled trials of sufficient duration to assess newer drugs. However, as results from such trials become available, these conclusions may need to be updated.

A review of studies which include mild to moderate hypertension completed since 1992, particularly using newer drugs, is warranted at this time. The findings of this review are quite impressive with respect to the elderly. Studies which would explore and improve the rate of adequately treated mild to moderate hypertension in the elderly are needed.

Fowkes FGR, Fulton PM. Critical appraisal of published research: introductory guidelines. BMJ 1991;302:1136-40.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.