Department of Cardiovascular Disease, Faculty of Medicine, Hypertension and Cardiovascular Rehabilitation Unit, KU Leuven University, Leuven, Belgium
Correspondence to Robert H. Fagard, MD, PhD, Professor of Medicine, Hypertension and Cardiovascular Rehabilitation Unit, UZ Gasthuisberg-Hypertensie, Herestraat 49, B-3000 Leuven, Belgium Tel: +32 16 34 87 07; fax: +32 16 34 37 66; e-mail: email@example.com
The primary objective of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)  was to test the hypothesis in a PROBE design that a newer antihypertensive treatment regimen [calcium channel blocker ± an angiotensin-converting enzyme (ACE) inhibitor] is more effective than an older regimen (beta-blocker ± a diuretic) in the primary prevention of coronary heart disease, which is the composite of nonfatal myocardial infarction, including silent myocardial infarction, and fatal coronary heart disease. A total of 19257 patients with hypertension, either untreated or previously treated (the majority), who were aged 40–79 years and with no history of coronary heart disease but with three additional cardiovascular risk factors, were assigned either amlodipine 5–10 mg adding perindopril 4–8 mg as required or atenolol 50–100 mg adding bendroflumethiazide 1.25–2.5 mg and potassium as required. The study was stopped prematurely after 5.5 years of median follow-up due to a significant mortality benefit of amlodipine-based therapy. Whereas the primary endpoint was not significantly different between the two treatment regimens at that time, at least partly explained by the premature termination of the trial, the incidence of most of the seven secondary endpoints was significantly lower on the amlodipine-based regimen than on the atenolol-based regimen. For example, the hazard ratio for total cardiovascular events and procedures was 0.84 [95% confidence interval (CI) 0.78–0.90; P < 0.001]. In the main publication, the authors reported that the effect on this composite endpoint was similar in prespecified subgroups, including subgroups according to age . In individuals older than 60 years, the hazard ratio was 0.83 (P < 0.001) and in those 60 years or younger, the hazard ratio was 0.85 (P = 0.0227), with no evidence of significant heterogeneity (P = 0.78).
In the current issue of the Journal, the authors report a more extensive evaluation of the efficacy and safety of the amlodipine-based versus atenolol-based regimen in older and younger participants . In these post-hoc analyses, the cut-off for age was different from the cut-off in the original publication , that is, 65 years instead of 60 years; 8137 patients were 65 years or older and 11 020 patients were less than 65 years. The age groups were separated by an average of 14 years (71 versus 57 years).
In the overall analysis of the ASCOT trial, the blood pressure reduction throughout the trial was more pronounced on amlodipine-based treatment by 2.7/1.9 mmHg . According to the current publication , this blood pressure difference was larger in the older age group (4.2/2.2 mmHg) than in the younger age group (1.7/1.7 mmHg). In addition, the number of antihypertensive medications used to help patients achieve the blood pressure targets was larger in the atenolol-based regimen compared with the amlodipine-based regimen in both age groups. The primary endpoint of the trial was not significantly reduced with amlodipine-based versus atenolol-based treatment in any of the age groups. The results on total cardiovascular events and procedures were similar to those in the original report, that is, significant reductions of, respectively, 17% in favor of amlodipine treatment in older individuals and 15% in younger individuals (P for heterogeneity = 0.69). In general, all of the predefined cardiovascular endpoints evaluated favored the amlodipine-based regimen and were statistically significant in seven of the 16 age-stratified endpoints. Whereas none of the tests for heterogeneity between age groups was significant, the incidence of nonfatal myocardial infarction (excluding silent myocardial infarction) and fatal coronary heart disease was only significantly reduced in younger patients, and fatal and nonfatal stroke was only significantly reduced in older patients. The overall conclusion of the authors was that an amlodipine-based regimen reduces the relative risk of cardiovascular events more effectively than an atenolol-based regimen in both older and younger patients.
In a companion article of the main publication , the ASCOT investigators reported on the role of blood pressure and other variables during follow-up in the differential cardiovascular event rates in the trial and concluded that residual differences were no longer significant after multivariate adjustment, with significant contributions of blood pressure and high-density lipoprotein (HDL) cholesterol. Such analyses were not presented for the two age groups in the current manuscript , whereas many of the baseline characteristics differed significantly between the two groups, such as blood pressure, heart rate, BMI, blood lipids, history of stroke or transient ischaemic attack, smoking habits and use of antihypertensive drugs, aspirin and alcohol, with possible differential changes during the trial. It is not known whether the development of diabetes, which was lower by 30% with the amlodipine-based regimen in the overall analysis , was different according to age. In addition, the percentage of time on perindropril was 58.5% in the amlodipine group and the time on bendroflumethiazide was 65.7% in the atenolol group, but details on the add-on therapy are not reported in the two age groups. It has also been shown that the atenolol ± thiazide-based treatment was much less effective than amlodipine ± perindopril-based treatment at lowering central aortic pressures  and it is known that the difference between central aortic pressure and brachial artery pressure becomes attenuated at an older age . Therefore, comparison between the two age groups is potentially hampered by the many intergroup differences. On the other hand, the additional analyses of the ASCOT trial  have been severely criticized  and it may not be warranted to perform these and other analyses separately in the two age groups. Anyhow, whatever the explanation, the results favor the amlodipine-based treatment regimen in both the older and the younger participants. In addition, whereas discontinuation rates due to serious adverse events were low in both age groups, they also favored the amlodipine-based regimen.
It is of interest to consider the results of the ASCOT trial in a more general perspective. Whereas several individual studies have reported on the effect of age, the Blood Pressure Lowering Treatment Trialists' Collaboration  quantified the effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults (≥65 years versus <65 years) in a comprehensive meta-analysis, including 31 trials and 190 606 participants. The meta-analysis showed no clear difference between the effects of various drug classes on major cardiovascular events, neither was there any significant interaction between age and treatment when age was fitted as a continuous variable. The authors concluded that reduction of blood pressure produces benefits in younger and older adults, with no strong evidence that protection against major cardiovascular events afforded by different drug classes varied substantially with age. At first sight, the results of the meta-analysis seem to be at variance with the results of the ASCOT trial, but important differences between the two approaches should be considered. First, ASCOT compares two treatment regimens, whereas the meta-analysis compares different first-line treatments. Second, the first-line treatments in ASCOT, that is a calcium channel blocker versus a beta-blocker, were not directly compared in the meta-analysis, in which calcium channel blockers were compared to treatment with a beta-blocker or a diuretic. Third, there may be differences among beta-blockers and it has been suggested that atenolol is less effective in preventing cardiovascular events, particularly stroke. Finally, it is of note that the ASCOT trial compares two treatment strategies without control group, so that the changes in blood pressure are not corrected for a possible placebo effect and that the true effect of the two treatment strategies on outcome remains unknown. However, meta-analyses and individual studies have convincingly shown that antihypertensive treatment is beneficial in elderly individuals with systolic-diastolic hypertension  or isolated systolic hypertension , and in the very elderly [10,11].
A second aim of the ASCOT trial was to assess the relative risk reduction due to antihypertensive treatment in older and younger patients. Observational studies have shown less strong proportional associations of blood pressure levels with risk in older compared with younger adults . In the ASCOT trial, compared with the atenolol-based regimen, the amlodipine-based regimen reduced the risk of cardiovascular events and procedures by 17% in older and by 15% in younger patients . A larger relative risk reduction might have been expected in the older age group because of the somewhat greater blood pressure reduction, but this may be difficult to prove because of insufficient statistical power. In the comprehensive meta-analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration , there was no difference in the risk reduction achieved per unit reduction in blood pressure for individuals aged less than 65 years compared with individuals aged at least 65 years for the primary outcome of total major cardiovascular events nor for any of the secondary outcomes. However, because event rates are higher among older patients, the absolute benefits are greater for older compared with younger patients with hypertension.
Finally, the question arises what these analyses according to age contribute to guidelines for the management of hypertension and clinical practice. First of all, any advantage or disadvantage in the ASCOT study should be attributed to the strategy and not to any individual drugs . The finding that the beneficial effect on the incidence of cardiovascular events is less with the beta-blocker ± diuretic strategy is compatible with the recommendations of the European Society of Hypertension/European Society of Cardiology  and their reappraisal by the European Society of Hypertension , that this combination is not among the favored ones, particularly in hypertensive patients with metabolic risk factors. Such caution appears to be valid in older and younger patients according to the ASCOT results , although it may not apply to newer vasodilator beta-blockers. Next it is of interest that the beneficial effect of the calcium channel blocker ± ACE inhibitor combination on outcome is similar in older and younger patients . Therefore, initiation of antihypertensive treatment with a calcium channel blocker, with addition of an ACE inhibitor for better blood pressure control, should be considered a valid strategy not only in older but also in younger patients. This contrasts with some current guidelines, such as the British NICE Clinical Guideline on management of hypertension in adults in primary care , in which the first choice for initial therapy should be an ACE inhibitor in younger patients, with the possible addition of a calcium channel blocker if required. Admittedly, the cut-off age between older and younger patients was 55 years in these recommendations, but it is likely that the results of the ASCOT trial also apply to patients younger than 55 years because the results were similar for patients below the age of 60 years  and below the age of 65 . It is probably prudent to leave the choice of antihypertensive drugs flexible for the individual patient, taking into account specific indications, additional risk factors, target organ damage and associated clinical conditions, and contraindications for specific drugs or drug classes, to achieve optimal blood pressure control and maximal overall benefit [14,15].
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