Interpretation of prospective trials in hypertension: do treatment guidelines accurately reflect current evidence?

OBJECTIVE: To review the findings of prospective controlled trials of antihypertensive treatment and determine whether the evidence they have provided is embodied satisfactorily in current national and international guidelines for hypertension management. MANAGEMENT GUIDELINES: Conventional guidelines all advise prompt treatment of moderate-to-severe hypertension and treatment of even mild hypertension in subjects with cardiovascular disease, target organ damage or diabetes, and in the elderly; and treatment of isolated systolic hypertension in the elderly. All acknowledge that evidence for efficacy and safety of treatment is strongest for thiazide diuretics and beta-blockers. UNCOMPLICATED MILD HYPERTENSION: Conventional guidelines all emphasize the importance of long-term blood pressure, measured over some months, for treatment decisions. However the blood pressure for routine treatment varies from 160/100 mmHg (British Hypertension Society) to 140/90 mmHg (Joint National Committee V). This dictates very large differences in the number of patients to be treated to prevent a cardiovascular disease event and in the proportion of the population to be treated, yet the reasons for these differences are not explicit. None of the conventional guidelines is entirely satisfactory. The more conservative British Hypertension Society policy may leave untreated some middle-aged men who ought to be treated. The more aggressive Joint National Committee V policy will lead to treatment of some young subjects who have only a remote chance of benefit, at very high cost, and possibly with adverse harm-benefit consequences. RISK-BASED GUIDELINES: Guidelines developed in New Zealand target absolute cardiovascular disease risk in mild hypertension and have the potential to correct this shortcoming of conventional guidelines. However they require further consideration as regards the number needed to treat which is acceptable to well-informed patients, the appropriate estimate of relative cardiovascular disease risk reduction by treatment in mild hypertension, the pattern of treatment which will emerge and their acceptability in ordinary practice. CONCLUSION: Comparative evaluation will be needed to determine whether the outcome is better with conventional guidelines, which are simple but at the expense of accuracy, or with risk-targeted guidelines, which are more accurate but at the expense of simplicity.     

Lesion-induced plasticity as a potential mechanism for recovery and rehabilitative training

OBJECTIVES: To compare the potential years of life saved (YOLS) associated with risk factor modification in the primary and secondary prevention of cardiovascular disease (CVD). METHODS: The CVD life expectancy model estimates the risk of death due to coronary disease, stroke, and other causes based on the levels of independent risk factors (such as age, blood pressure, and blood lipid levels) found in the cohort of the Lipid Research Clinics. The model was validated by comparing its predictions with the observed fatal outcomes of 9 randomized clinical trials. We then estimated the YOLS associated with treating hyperlipidemia or hypertension among hypothetical patient groups with and without CVD at baseline. We defined high-risk patients as those with 3 risk factors (hyperlipidemia, cigarette smoking, and hypertension) and low-risk patients as those with isolated hypertension or hyperlipidemia. RESULTS: The fatal events predicted by the model were consistent with the clinical trial results. Among men and women with hyperlipidemia without CVD, the forecasted benefits of lipid therapy were substantially greater among high-risk groups vs low-risk groups (4.74-0.78 YOLS vs 2.50-0.25 YOLS, respectively). Among those with CVD, the forecasted benefits of treatment were similar for both high-risk and low-risk groups (4.65-0.65 YOLS vs 3.84-0.58 YOLS, respectively). The results for hypertension therapy also demonstrated greater benefits for high-risk vs low-risk patients undergoing primary prevention therapy (1.34-0.29 YOLS vs 0.85-0.13 YOLS, respectively), and the forecasted benefits in secondary prevention were similar (1.26-0.23 YOLS vs 1.00-0.23 YOLS, respectively). CONCLUSIONS: The clinical approach to risk factor modification in primary prevention should be different from that in secondary prevention. The forecasted benefits of therapy among patients without CVD are greatest in the presence of other risk factors. Among those with CVD, the benefits of therapy are equivalent, thereby obviating the need to target high-risk patients.     

Cardiovascular risks of hypertension: lessons from observational studies

Hypertension is an acknowledged major risk factor for cardiovascular disease and death in both men and women. Despite a historical focus by clinicians on the importance of diastolic blood pressure (DBP) risks, epidemiologic data from numerous large-scale studies have clearly demonstrated that both systolic blood pressure (SBP) and DBP are important determinants of cardiovascular risk. Recent analyses have described notable risks associated with isolated and borderline elevations of SBP, which predominate in the elderly, emphasizing the independent contribution of elevated SBP in determining overall risk. Overviews of large-scale treatment trials show that antihypertensive drug treatment confers a favorable net clinical benefit in patients with diastolic and isolated systolic hypertension, and the magnitude of risk reduction is comparable to that expected from the observational data. However, at any level of SBP or DBP, the absolute magnitude of risk varies widely depending on the burden of coexisting risk factors present. Therefore, it is essential that decisions regarding the urgency, risks and benefits of antihypertensive drug treatments be informed by accurate determinations of overall cardiovascular risk.     

A general practice-based study examining the absolute risk of cardiovascular disease in treated hypertensive patients

BACKGROUND: When managing hypertension, the assessment of the absolute risk of a cardiovascular' event is now advocated as the most accurate way in which the risks and benefits of anti-hypertensive therapy should be judged. Most studies that have examined control of hypertension have relied solely on the blood pressure level attained after treatment, with no measurement of the likely absolute risk in individual patients. AIM: To assess control of hypertension by quantifying the 10-year absolute risk of cardiovascular disease in patients treated by their general practitioners, and to assess which risk factors are associated with uncontrolled hypertension in this group of patients. METHOD: A cross-sectional study was made of patients on drug treatment for hypertension in 18 Oxfordshire general practices subscribing to the VAMP (value-added medical products) computer system. The absolute risk of suffering a cardiovascular event in the following 10 years was measured according to each individual's risk factor profile. Factors associated with uncontrolled hypertension were ascertained using multiple logistic regression analysis. RESULTS: Overall, 40.9% (37.6% to 44.1%) of the hypertensive population had an absolute risk exceeding 20% of having a cardiovascular event in the following 10 years. The distribution of risk factors varies throughout the population. A higher blood pressure reading was strongly associated with an increased likelihood of high absolute risk, but high blood pressure readings in individual patients did not necessarily equate to a high absolute risk. The factors independently associated with uncontrolled hypertension were age, sex, past history of stroke, ischaemic heart disease and transient ischaemic attack, a body mass index greater than 30, diabetes, and current smoking. CONCLUSIONS: Absolute risk assessment maximizes the risk-benefit ratio in treated hypertensive patients. Individual control and management requires multifactorial assessment and management. Treatment of hypertension according to blood pressure reading alone is not a reliable way of reducing the absolute risk of cardiovascular disease.     

Heart protection: controlling risk factors for cardiovascular disease

Cardiovascular disease is the leading cause of illness and death in the United States. Clinical data continue to support primary prevention through the aggressive treatment of well-defined cardiovascular risk factors. Three risk factors that can be modified to lower the risk of cardiovascular disease and death are hypercholesterolemia, hypertension, and cigarette smoking. Even patients with asymptomatic cardiovascular disease have been shown to benefit from aggressive cholesterol-lowering therapy. New JNC-VI guidelines for managing hypertensive disease recommend that treatment decisions be based on level of blood pressure plus presence or absence of target organ damage or other risk factors. The risk of myocardial infarction in former smokers approaches that of nonsmokers after 3 years.     

New guidelines for prevention, detection, evaluation and treatment of high blood pressure

New guidelines for the management of patients at risk of developing hypertension and associated conditions have recently been published. These guidelines include a new risk stratification and blood pressure classification, as well as an altered approach to drug therapy. This article describes the major changes from previous recommendations, highlights the role of oral health care providers and emphasizes the dental implications of caring for patients with blood pressure conditions.     

Longer femoral necks in the young: a predictor of further increases in hip fracture incidence?

AIMS: To determine whether femoral neck length, a risk factor for hip fracture, is likely to increase in the coming decades in normal elderly New Zealand women. METHODS: Femoral neck length was measured from dual-energy x-ray absorptiometry scans of the proximal femur in white women aged 19-88 years (n = 211). Since this length remains constant throughout adult life, it is possible to predict future trends in this index in the elderly, from its measurement at the present time in younger adults. RESULTS: Femoral neck length was inversely related to age (p = 0.018) such that a 3.7 mm (5.7%) difference occurred over the age-range of this sample. CONCLUSIONS: Femoral neck length in elderly New Zealand women is likely to increase in the coming decades. As a result of the dependence of hip fracture risk on femoral neck length, future age-adjusted hip fracture incidence will increase by about 50% over the next 50 years unless significant public health initiatives are taken, either to increase bone density or to reduce fall frequency.     

The therapeutic approach to the control of hypertension. Its impact on health policy

The pharmacologic approach to the control of hypertension must consider both the clinical perspective and the Public Health approach policy in which social costs have to be balanced against benefits to the entire population. Cost-effectiveness analysis are at the core of decisions taken within this frame of reference. The issue of cost-effectiveness of preventive and therapeutic measures are crucial in the case of less developed countries. An analysis of studies undertaken in Mexico leads to the conclusion that, from a Public Health perspective, a program for the control of hypertension with a strong emphasis on drug therapy is likely to require a significant proportion of the health budget. Therefore, more emphasis must be placed on primary prevention based on modifications of life style.     

Antihypertensive treatment in the elderly

Drug treatment with beta-blockers and diuretics in hypertensive men and women aged 70 and above confers highly significant and clinically relevant reductions in cardiovascular (especially stroke) morbidity and mortality. This satisfactory effect is not impaired by a low tolerability of the drugs used. Furthermore, treatment of elderly hypertensives with beta-receptor blockers and/or diuretics is cost-effective. In STOP-Hypertension the cost-effectiveness ratios were low and of the same magnitude for both men and women. The clinical implication of this is that blood pressure lowering therapy should be considered in elderly hypertensives, at least up until they are 80 years old. It should also be remembered that elderly patients often have other diseases than hypertension and that the drug treatment should be adjusted accordingly, e.g. by using a calcium antagonist or an ACE inhibitor, when indicated.     

National guidelines for clinical decisions, a methodological view

Medical guidelines used to be based mostly on expertise and experience. Since the eighties they are increasingly scientifically founded. In recent years results of possible treatments have been estimated quantitatively and compared. In drawing up the consensus text 'Antithrombotic prophylaxis of vascular events in patients with manifest atherosclerotic vasculopathy' the preparatory committee, after systematic arrangement of the relevant literature, made maximal use of the results of randomized prospective clinical trials of good quality and sufficient magnitude, published in peer-reviewed journals. For most indications, the pathophysiological reasoning and the study results were in agreement. A demonstrated effect of a treatment was evaluated on the basis of its magnitude and related to the associated costs and efforts. For the consensus 'Treatment and prevention of coronary heart disease by lowering the serum cholesterol level' use was made of estimates of effects of treatment with statins versus placebo. For prevention of total mortality and non-fatal myocardial infarctions and strokes, the relative risk reduction was 30-35%. The decrease of the absolute risk depended on the initial risk. The committee was of the opinion that treatment would be useful given an absolute risk of 25% of a (subsequent) manifestation of cardiovascular disease within 10 years. This would cost Dfl. 40,000.-per year of life gained, which the committee considered acceptable. In the argumentation of guidelines there is a trend to systematic evaluation and quantitative application of the research data. Subjective assessments remain necessary, particularly the evaluation of clinical relevance of observed or assumed effects of treatments.     

The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives

Direct evidence about the effects of antihypertensive treatment on vascular disease in older patients is available from five randomized trials conducted exclusively in patients over the age of 60 years. These trials involved a total of 12,483 individuals with systolic or diastolic hypertension (mean age = 72 years, mean entry blood pressure = 181/88 mmHg). Over an average follow-up period of 4.7 years, a 15/6 mmHg difference in blood pressure between study and control groups was achieved. Among those patients assigned active treatment, stroke incidence was reduced by 34% SD6 and coronary heart disease incidence was reduced by 19% SD7. These proportional reductions were of similar size to those observed in trials in predominantly younger patients. However, the absolute benefits observed in older patients were more than twice as great as those observed in younger patients. The results suggest that over 10 years, treatment would prevent at least one major vascular event among every 10 elderly patients at similar risk to those enrolled in the trials.     

Pharmaco-economics of anti-influenza vaccinations]

The types of pharmacoeconomic analysis performed in the assessment of influenza vaccination, including cost-benefit and cost-effectiveness analysis are presented in this study. The studies concerned working adults or high-risk elderly people who were selected from Medline and Embase databases. The primary difference between the two types of vaccination programmes is related to the major type of benefits: direct benefits related to averted hospitalizations for elderly versus indirect benefits of averted production losses for healthy working people. In the group of persons aged over 65 years the disease costs are influenced mainly by complications and hospitalizations. Vaccination is most cost-effective in influenza prophylaxis as compared with other strategies (chemoprophylaxis and treatment using neuraminidase or ion channel inhibitors) and may be recommended from the pharmacoeconomic point of view.     

Impact of major cardiovascular disease risk factors, particularly in combination, on 22-year mortality in women and men

BACKGROUND: The appropriateness of current cardiovascular disease (CVD) risk factor guidelines in women continues to be debated. OBJECTIVE: To present new data on the appropriateness of current CVD risk factor guidelines, for women and men, from long-term follow-up of a large population sample. METHODS: Cardiovascular disease risk factor status according to current clinical guidelines and long-term impact on mortality were determined in 8686 women and 10503 men aged 40 to 64 years at baseline from the Chicago Heart Association Detection Project in Industry; average follow-up was 22 years. RESULTS: At baseline, only 6.6% of women and 4.8% of men had desirable levels for all 3 major risk factors (cholesterol level, <5.20 mmol/L [<200 mg/dL]; systolic and diastolic blood pressure, <120 and <80 mm Hg, respectively; and nonsmoking). With control for age, race, and other risk factors, each major risk factor considered separately was associated with increased risk of death for women and men. In analyses of combinations of major risk factors, risk increased with number of risk factors. Relative risks (RRs) associated with any 2 or all 3 risk factors were similar: for coronary heart disease mortality in women, RR= 5.72 (95% confidence interval [CI], 2.35-13.93), and in men, RR = 5.51 (95% CI, 3.10-9.77); for CVD mortality in women, RR = 4.54 (95% CI, 2.33-8.84), and in men, RR = 4.12 (95% CI, 2.56-6.37); and for all-cause mortality in women, RR = 2.34 (95% CI, 1.73-3.15), and in men, RR = 3.20 (95% CI, 2.47-4.14). Absolute excess risks were high in women and men with any 2 or all 3 major risk factors. CONCLUSIONS: Combinations of major CVD risk factors place women and men at high relative, absolute, and absolute excess risk of coronary heart disease, CVD, and all-cause mortality. These findings support the value of (1) measurement of major CVD risk factors, especially in combination, for assessing long-term mortality risk and (2) current advice to match treatment intensity to the level of CVD risk in both women and men.     

Understanding the relationship between relative and absolute risk

BACKGROUND: Relative risks are the most common statistics used to quantify the risk of mortal or morbid outcomes associated with different patient groups and therapeutic interventions. However, absolute risks are of greater value of both patient and physician in making clinical decisions. METHODS: The relationship between relative and absolute risks is explained using graphical aids. A program to estimate absolute risks from relative risks is available on the internet (see ftp://ftp.vanderbilt.edu/pub/biostat/absrisk+ ++.txt). This program uses a competing hazards model of morbidity and mortality to derive these estimates. RESULTS: When a patient's absolute risk is low, it can be approximated by multiplying her relative risk by the absolute risk in the reference population. This approximation fails for higher absolute risks. The relationship between relative and absolute risk can vary dramatically for different diseases. This is illustrated by breast cancer morbidity and cardiovascular mortality in American women. The accuracy of absolute risk estimates will be affected by the accuracy of relative risk estimates, by the appropriateness of the reference groups used to calculate relative risks, by the stability of cross-sectional, age-specific morbidity and mortality rates over time, by the influence of individual risk factors on multiple causes of mortality, and by the extent to which relative risks may vary over time. CONCLUSIONS: Valid absolute risk estimates are valuable when making treatment decisions. They can often be obtained over time intervals of 10 to 20 years when the corresponding relative risk estimates have been accurately determined.     

Hereditary macular dystrophies

BACKGROUND: Orthostatic hypotension is a common phenomenon in the elderly. Hormonal changes during orthostatic stress have been described in elderly normotensive people and in those with essential hypertension. However, the hormonal response in elderly people who have systolic hypertension during orthostasis has not yet been quantified. METHODS: In this study we investigated 14 non-diabetic men, aged 60 to 75 years, with untreated systolic hypertension who were subjected to 45 degrees passive head-up incline on a tilt table for 15 min. Their hormonal profile and hemodynamic changes were analyzed before and after the stress. RESULTS: In the supine position, plasma levels of norepinephrine, atrial natriuretic peptide and aldosterone were in the normal range, while the plasma renin activity was low. Immediately upon tilt the systolic blood pressure fell but it reverted to baseline values after 15 min of orthostasis. At that time the cardiac output decreased while the systemic vascular resistance and the plasma norepinephrine concentration rose. The atrial natriuretic peptide appeared to fall, and the renin-aldosterone level did not change. CONCLUSION: The physiologic response to orthostatic stress in elderly people with systolic hypertension is comparable to that of elderly normotensive people and those with essential hypertension, i.e. a decrease in cardiac output and an increase in plasma norepinephrine levels. The atrial natriuretic peptide appeared to fall appropriately. The response of the renin-aldosterone system mimicked that in elderly patients with low renin essential isolated hypertension. These observations may have a bearing on the management of elderly people with systolic hypertension who also have orthostatic symptoms; they may not require a different approach from that needed for others of the same age group.     

Should treatment of risk factors of cardiovascular diseases be directed only by absolute risk?

Consensus groups have recommended using the baseline absolute risk of disease over five to ten years rather than relative risk when treatment with lipid-lowering or antihypertensive drugs is considered. Targeting patients with a coronary event rate of 20% over ten years ensures that society's investment in drugs yields substantial benefits by reducing the incidence of premature disease. However, the use of absolute risk is most appropriate among the middle-aged. Because all elderly persons have a high absolute risk of disease, almost all may be eligible for drug treatment. The costs of postponing death after the age of 70 are therefore substantial. Among young persons with familial hypercholesterolemia on the other hand, the consequences of a death before middle-age are so enormous that most patients are treated with drugs even though absolute risk is very low. An additional problem with using absolute risk is that the risk of atherosclerotic disease accumulates over time. Calculation of benefit on the basis of short-term trials might underestimate long-term benefit. In the future, non-invasive measures of atherosclerosis and new markers of risk may provide valuable information on risk stratification in primary prevention.     

Restructuring long-term care and the geography of ageing: a view from rural New Zealand

This paper examines the major points of contact between the restructuring of long-term care and the evolving geography of the elderly in the Waikato, one of New Zealand's agricultural heartlands. The time frame of the study is 1981-91, a decade in which new Zealand embarked on a sweeping program of service restructuring and privatization. Comparative analysis of data on the evolving distribution of the elderly and on the shifting supply of long-term care beds reveals that restructuring has sharpened contrasts between urban and rural contexts for ageing. Almost all the urban centres in the Waikato benefited from an expansion of long-term care driven by private-sector initiatives, while rural communities suffered a broad-based depletion of services. However, the data indicate that, contrary to the trend in long-term care, more older elderly people (defined as those aged 80 or older) are "staying on' in rural communities. The paper concludes with a consideration of emergent policy issues; we speculate that it through the aggregate outcomes of decisions to "stay on' that the personal troubles of the elderly residents of service-depleted communities may yet become an important policy issue in rural New Zealand.     

Surgery for lung cancer: age alone is not a contraindication

A retrospective analysis of the clinical features, operative procedures, postoperative complications and subsequent survival of 70 (50 male) elderly patients undergoing surgery for lung cancer compared with 74 (53 male) younger patients treated at the same hospital during the same period was performed, to determine if elderly people with lung cancer are less likely to benefit from and/or tolerate surgery. The elderly group had to wait longer for operation (p = 0.001) and were more likely to have pre-existing disease (p = 0.019). In contrast, they had fewer recognised postoperative complications (p = 0.032) and there was no difference between the two groups in perioperative mortality and subsequent survival. Surgical treatment of localised lung cancer represents the best chance for cure and this study suggests that age should not be a consideration in the decision to operate or not. The patient's general state of health should be assessed and management decisions based on individual status rather than on age.     

Community-acquired pneumonia

This seminar reviews the aetiology, clinical presentation, approach to diagnosis, and management of immunocompetent adults with community-acquired pneumonia (CAP). Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of CAP is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumoniae, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America. These guidelines differ in their emphasis on empirical versus pathogenic-specific management.