François Gueyffier

Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials

BACKGROUND Previous meta-analysis of outcome trials in hypertension have not specifically focused on isolated systolic hypertension or they have explained treatment benefit mainly in function of the achieved diastolic blood pressure reduction. We therefore undertook a quantitative overview of the trials to further evaluate the risks associated with systolic blood pressure in treated and untreated older patients with isolated systolic hypertension METHODS Patients were 60 years old or more. Systolic blood pressure was 160 mm Hg or greater and diastolic blood pressure was less than 95 mm Hg. We used non-parametric methods and Cox regression to model the risks associated with blood pressure and to correct for regression dilution bias. We calculated pooled effects of treatment from stratified 2 x 2 contingency tables after application of Zelens test of heterogeneity. FINDINGS In eight trials 15 693 patients with isolated systolic hypertension were followed up for 3.8 years (median). After correction for regression dilution bias, sex, age, and diastolic blood pressure, the relative hazard rates associated with a 10 mm Hg higher initial systolic blood pressure were 1.26 (p=0.0001) for total mortality, 1.22 (p=0.02) for stroke, but only 1.07 (p=0.37) for coronary events. Independent of systolic blood pressure, diastolic blood pressure was inversely correlated with total mortality, highlighting the role of pulse pressure as risk factor. Active treatment reduced total mortality by 13% (95% CI 2-22, p=0.02), cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30%, and coronary events by 23%. The number of patients to treat for 5 years to prevent one major cardiovascular event was lower in men (18 vs 38), at or above age 70 (19 vs 39), and in patients with previous cardiovascular complications (16 vs 37). INTERPRETATION Drug treatment is justified in older patients with isolated systolic hypertension whose systolic blood pressure is 160 mm Hg or higher. Absolute benefit is larger in men, in patients aged 70 or more and in those with previous cardiovascular complications or wider pulse pressure. Treatment prevented stroke more effectively than coronary events. However, the absence of a relation between coronary events and systolic blood pressure in untreated patients suggests that the coronary protection may have been underestimated.

Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised controlled trials

BACKGROUND Beneficial clinical effects of treatment with antihypertensive drugs have been shown in middle-aged patients and in those hypertensive patients over 60 years old, but whether treatment is beneficial in patients over 80 years old is not known. METHODS We collected data from all participants aged 80 years and over in randomised controlled trials of antihypertensive drugs through direct contact with study investigators. Our primary outcome was fatal and non-fatal stroke. Secondary outcomes were death from all causes, cardiovascular death, fatal and non-fatal major coronary and cardiovascular events, and heart failure. FINDINGS There were 57 strokes and 34 deaths among 874 actively treated patients, compared with 77 strokes and 28 stroke deaths among 796 controls, representing 1 non-fatal stroke prevented for about 100 patients treated each year. The meta-analysis of data from 1670 participants aged 80 years or older suggested that treatment prevented 34% (95% CI 8-52) of strokes. Rates of major cardiovascular events and heart failure were significantly decreased, by 22% and 39%, respectively. However, there was no treatment benefit for cardiovascular death, and a non-significant 6% (-5 to 18) relative excess of death from all causes. INTERPRETATIONS The inconclusive findings for mortality contrast with the benefit of treatment for non-fatal events. Results of a large-scale specific trial are needed for definite conclusion that antihypertensive treatment is beneficial in very elderly hypertensive patients. Meanwhile, an age threshold beyond which hypertension should not be treated cannot be justified.

Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials

Objective To determine all cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes. Design Meta-analysis of randomised controlled trials. Data sources Medline, Embase, and the Cochrane database of systematic reviews. Study selection Randomised controlled trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (≥18 years) with type 2 diabetes. Data extraction Primary end points were all cause mortality and death from cardiovascular causes. Secondary end points were severe hypoglycaemia and macrovascular and microvascular events. Synthesis of results Results are reported as risk ratios with 99% confidence intervals. Statistical heterogeneity between trials was assessed with χ², τ², and I2 statistics. A fixed effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score. Results 13 studies were included. Of 34 533 patients, 18 315 received intensive glucose lowering treatment and 16 218 standard treatment. Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or cardiovascular death (1.11, 0.86 to 1.43). Intensive therapy was, however, associated with reductions in the risk of non-fatal myocardial infarction (0.85, 0.74 to 0.96, P<0.001), and microalbuminuria (0.90, 0.85 to 0.96, P<0.001) but a more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001). Over a treatment period of five years, 117 to 150 patients would need to be treated to avoid one myocardial infarction and 32 to 142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycaemia would occur for every 15 to 52 patients. In analysis restricted to high quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions but resulted in a 47% increase in risk of congestive heart failure (P<0.001). Conclusions The overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death. The benefit:risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remains uncertain. The harm associated with severe hypoglycaemia might counterbalance the potential benefit of intensive glucose lowering treatment. More double blind randomised controlled trials are needed to establish the best therapeutic approach in people with type 2 diabetes.

Effect of Antihypertensive Drug Treatment on Cardiovascular Outcomes in Women and Men: A Meta-Analysis of Individual Patient Data from Randomized, Controlled Trials

The effectiveness of antihypertensive drug treatment is well established and has been quantified in terms of overall reduction in the relative risk for stroke and other cardiovascular disease events [1, 2]. Risk for cardiovascular events (especially myocardial infarction) differs greatly between men and women, and these differences are not explained by other risk factors [3]. It remains unclear, however, whether the effect of antihypertensive treatment in reducing cardiovascular risk is dependent on sex. In a 1986 review, MacMahon and colleagues [4] stated that event rates, particularly those for fatal events and nonfatal myocardial infarction, were substantially lower in women than in men. The striking benefits of study treatments for the risk of fatal and non-fatal stroke were evident for both men and women. A reduction in total mortality could not be demonstrated for women, but the treatment effect for women was not significantly different from that in men, among whom there was an important and statistically significant reduction in mortality. This comment was based on the results of two trials: the Hypertension Detection and Follow-up Program (HDFP) [5] and the Medical Research Council trial of treatment of mild hypertension (MRC35-64) [6]. In their 1991 analysis of data from these trials plus data from the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial [7] and the Australian therapeutic trial in mild hypertension [8], Anastos and colleagues [9] concluded that the few data that do exist suggest that gender, like race and age, significantly influences the natural course of hypertension and the response to treatment . The data regarding aggressive treatment of white women are equivocal; there is concern that such treatment may actually be harmful. Since these reviews were published, reports of three additional trials of antihypertensive treatment in older hypertensive men and women have appeared in print: the Medical Research Council trial of treatment of hypertension in older adults (MRC 65-74) [10], the Systolic Hypertension in the Elderly Program (SHEP) [11], and the Swedish Trial in Old Patients with Hypertension (STOP) [12]. More recently, other reviewers have stated that antihypertensive medications do not appear to be as effective in women as in men [13] and that when treated, women often achieve less benefit than do men [14]. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project [15] offers the opportunity to provide more evidence on the effects of antihypertensive treatment in women; results are based on individual patient data from all of the randomized, controlled trials mentioned in the preceding paragraphs. The two main objectives of the current study are to quantify the average treatment effect in each sex separately and to determine whether treatment effect differs significantly between women and men. Methods The INDANA project (whose rationale, objectives, and methods are described in detail elsewhere [15]) is a collaboration of representatives from most of the large randomized, controlled trials of antihypertensive drug treatment. Its results are derived from centralized files of the baseline and follow-up data available for all patients enrolled in the trials. The Trials Our report is based on seven trials [5-710-12, 16] (Table 1) in which both men and women were enrolled. The inclusion criteria for the trials in the INDANA project are discussed elsewhere [15]. In summary, the steering group of the project made the following decisions: The data from the Australian trial [8] were not included in the analysis because separate outcomes are not available without censoring bias; the EWPHE trial [7] data were included only for the analysis of mortality end points (separate nonfatal outcomes are not available without censoring bias); and the data from HDFP [5] were considered in a sensitivity analysis (analysis was done with and without these data because of the originality of the trial design, which compared specific antihypertensive care systems with usual care). The data from the Veterans Administration and National Heart, Lung, and Blood Institute feasibility trial [17] are available in the INDANA database but have not yet been submitted to control and extraction procedures. Thus, these data were not used in our analysis. Because this trial has only a small weight in terms of patient-years and observed events, its exclusion is unlikely to change the results presented here. Table 1. Main Characteristics of the Seven Antihypertensive Drug Trials That Enrolled Men and Women* Outcomes According to the INDANA protocol, seven outcomes were analyzed: 1) fatal strokes; 2) fatal and nonfatal strokes, excluding transient ischemic attacks; 3) fatal coronary events [including sudden death, which was defined as unexpected and unexplained death occurring within a maximal interval of 24 hours after symptom onset]; 4) fatal and nonfatal major coronary events (using criteria for major coronary heart disease obtained from patient histories in HDFP) [1]; 5) cardiovascular-related mortality, including death from pulmonary thromboembolism; 6) major cardiovascular events [combining the second, fourth, and fifth outcomes and excluding such minor cardiovascular events as angina pectoris, intermittent claudication, or nonfatal congestive heart failure]; and 7) total mortality. Statistical Analysis Summarized data (number of patients and number of events) were extracted from the INDANA database by sex and by trial according to the intention-to-treat principle. For the group assigned to receive active treatment, the odds ratio compared with controls was estimated by sex for each outcome according to the Peto method [18]. The odds ratio in women was compared with the odds ratio in men by determining whether the ratio was different from 1. This interaction between sex and treatment effect was checked after adjustment for the main baseline risk factors (age, baseline smoking habits, systolic blood pressure, serum cholesterol level, presence of diabetes, and history of stroke or myocardial infarction) in a multivariate logistic model [19] fitted by outcome. For HDFP [5], we censored data at the date of the end of the trial intervention. Two deaths in the trial by Coope and Warrender [16] that were caused by pulmonary embolism were included with cardiovascular-related mortality in our analysis; one early cancer-related death in this trial was included in the analyses of total mortality because of the intention-to-treat principle. To illustrate the difference in the treatment effect between men and women, we applied two graphical approaches to the second and fourth outcomes (all strokes and all coronary events). First, each trial was represented by sex in a treatment-effect graph [20] in which the x-axis is the risk observed in the control group (Rc) and the y-axis is the risk observed in the treated group (Rt) (Figure 1). The odds ratio line, with a slope equal to the odds ratio and a null intercept, indicates the treatment effect by sex. The principal diagonal of the plane Rt x Rc represents the absence of treatment effect (Rt = Rc; odds ratio, 1). The vertical distance between the odds ratio line and the principal diagonal indicates the absolute risk reduction for a given untreated risk. Second, the absolute risk reduction attributable to treatment and its CI were computed by tertiles of individually predicted risk for each sex and were plotted against the average predicted risk in each tertile (Figure 2). The predicted risk was derived from individual scoring built on the results of a multivariate logistic model, including the major risk factors mentioned above. Tertiles were computed to contain similar numbers of events. Figure 1. Effect of antihypertensive treatment on absolute risk for fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right). Figure 2. Absolute risk reduction of fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right) by untreated risk level and sex. Meta-analysis computations were done using Easy-MA software [21]; data management and logistic regression were done using SAS software [22]. Results The key features of the seven trials are presented in Table 1. Five of the trials addressed hypertension in older persons, and two studied mild to moderate hypertension in younger persons. The drugs used in the trials were primarily thiazide diuretics, -blockers, or both. The data for these seven trials contained in the INDANA database represent 97.5% of all existing data from all applicable trials in terms of patient-years of follow-up during the active phase of the trials. The combined trial data on risk factors by sex (Table 2) show that, on average, women were older; had a higher baseline cholesterol level, a higher systolic blood pressure, and a lower smoking rate; and less frequently had a history of myocardial infarction. Because these baseline characteristics were similar for the active treatment and control groups, these groups are combined in Table 2. Table 2. Main Cardiovascular Risk Factors by Sex* For each of the seven outcomes, Table 3 and Table 5 shows the number of events in the active treatment and control groups that occurred in men and women, both within each trial and in all trials combined. Table 3. Events by Trial and Sex* Table 5. Table 3. Continued The exclusion of the HDFP data from the analysis changes neither the direction nor the magnitude of the odds ratio for either sex and does not affect the differences between men and women. These data are therefore included in the results presented. In Table 4, the combined odds ratios for all trials are shown separately for men and women; these odds ratios were estimated using a fixed-effects method. In women, odds ratios favoring treatment were statistically significant for strokes (both fatal and either fatal or nonfatal) and major car

A score for predicting risk of death from cardiovascular disease in adults with raised blood pressure, based on individual patient data from randomised controlled trials.

Abstract Objective: To create a risk score for death from cardiovascular disease that can be easily used. Design: Data from eight randomised controlled trials of antihypertensive treatment. Setting: Europe and North America. Participants: 47 088 men and women from trials that had differing age ranges and differing eligibility criteria for blood pressure. Main outcome measure: 1639 deaths from cardiovascular causes during a mean 5.2 years of follow up. Results: Baseline factors were related to risk of death from cardiovascular disease using a multivariate Cox model, adjusting for trial and treatment group (active versus control). A risk score was developed from 11 factors: age, sex, systolic blood pressure, serum total cholesterol concentration, height, serum creatinine concentration, cigarette smoking, diabetes, left ventricular hypertrophy, history of stroke, and history of myocardial infarction. The risk score is an integer, with points added for each factor according to its association with risk. Smoking contributed more in women and in younger age groups. In women total cholesterol concentration mattered less than in men, whereas diabetes had more of an effect. Antihypertensive treatment reduced the score. The five year risk of death from cardiovascular disease for scores of 10, 20, 30, 40, 50, and 60 was 0.1%, 0.3%, 0.8%, 2.3%, 6.1%, and 15.6%, respectively. Age and sex distributions of the score from the two UK trials enabled individual risk assessment to be age and sex specific. Risk prediction models are also presented for fatal coronary heart disease, fatal stroke, and all cause mortality. Conclusion: The risk score is an objective aid to assessing an individuals risk of cardiovascular disease, including stroke and coronary heart disease. It is useful for physicians when determining an individuals need for antihypertensive treatment and other management strategies for cardiovascular risk. What is already known on this topic Many other factors are known to affect the risk of cardiovascular disease in patients with raised blood pressure A patients overall risk should be taken into account when determining their need for antihypertensive drugs and other strategies for improving cardiovascular health What this study adds A new score uses 11 risk factors to quantify an adults risk of death from cardiovascular disease, including stroke and coronary heart disease The score is based on a large cohort of participants in controlled trials of antihypertensive drugs An individuals risk can be readily assessed as high or low compared with others of the same age and sex The website http://www.riskscore.org.uk/ is available for users of the risk score

Treatment of hypertension in patients 80 years and older: the lower the better? A meta-analysis of randomized controlled trials.

Background Results of randomized controlled trials are consistent in showing reduced rates of stroke, heart failure and cardiovascular events in very old patients treated with antihypertensive drugs. However, inconsistencies exist with regard to the effect of these drugs on total mortality. Methods We performed a meta-analysis of available data on hypertensive patients 80 years and older by selecting total mortality as the main outcome. Secondary outcomes were coronary events, stroke, cardiovascular events, heart failure and cause-specific mortality. The common relative risk (RR) of active treatment versus placebo or no treatment was assessed using a random-effect model. Linear meta-regression was performed to explore the relationship between intensity of antihypertensive therapy and blood pressure (BP) reduction and the log-transformed value of total mortality odds ratios (ORs). Results The overall RR for total mortality was 1.06 (95% confidence interval 0.89–1.25), with significant heterogeneity between hypertension in the very elderly trial (HYVET) and the other trials. This heterogeneity was not explained by differences in the follow-up duration between trials. The meta-regression suggested that a reduction in mortality was achieved in trials with the least BP reductions and the lowest intensity of therapy. Antihypertensive therapy significantly reduced (P < 0.001) the risk of stroke (35%), cardiovascular events (27%) and heart failure (50%). Cause-specific mortality was not different between treated and untreated patients. Conclusion Treating hypertension in very old patients reduces stroke and heart failure with no effect on total mortality. The most reasonable strategy is the one associated with significant mortality reduction; thiazides as first-line drugs with a maximum of two drugs.

Pulsatile blood pressure component as predictor of mortality in hypertension: a meta-analysis of clinical trial control groups

Objective Although current guidelines rest exclusively on the measurement of systolic and diastolic blood pressures, the arterial pressure wave is more precisely described as consisting of a pulsatile (pulse pressure) and a steady (mean pressure) component. This study explored the independent roles of pulse pressure and mean pressure as predictors of mortality in a wide range of patients with hypertension. Design and methods This meta-analysis, based on individual patient data, has combined results from the control groups of seven randomized clinical trials conducted in patients with systolo-diastolic or isolated systolic hypertension. The relative hazard rates associated with pulse pressure and mean pressure were calculated using Coxs proportional hazard regression models with stratification for the seven trials and with adjustment for sex, age, smoking and the other pressure. Results A 10 mmHg wider pulse pressure at baseline, which corresponds to approximately one-half of its standard deviation, was independently associated with an increase in risk by 6% for total mortality (P = 0.001), 7% for cardiovascular mortality (P = 0.01), and 7% for fatal coronary accidents (P = 0.03).The corresponding increase in risk of fatal stroke was similar (+6%, P = 0.27) but there were too few strokes to reach statistical significance. In similar analyses, mean pressure was not identified as an independent predictor of these outcomes. Significant interactions of pulse pressure or mean pressure with age suggested that the prognostic power of pulse pressure for fatal stroke was more important at higher age (P = 0.04), whereas the prognostic power of mean pressure for coronary mortality was greatest in the young (P = 0.01). Conclusions In hypertensive patients pulse pressure, not mean pressure, is associated with an increased risk of fatal events. This appears to be true in a broad range of patients with hypertension.

Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials

Catherine Cornu and colleagues performed a meta-analysis of randomised controlled trials of metformin efficacy on cardiovascular morbidity or mortality in patients with type 2 diabetes and showed that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain.

Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data.

Severe myoclonic epilepsy in infancy (SMEI) is a rare, but severe disorder with seizures typically resistant to conventional antiepileptic drugs. The objective of the present study was to systematically review the literature on the available treatments for SMEI.

Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors

Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer’s disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. β-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating β-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Aβ42 into less toxic Aβ40. Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Aβ42 brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on β-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.