Prof. Michael Bohm
Dr. Nicolas Werner
ACE-inhibition is an efficient and important therapeutic concept for the treatment of CVD in elderly patients. There is increasing evidence that especially old and very old patients benefit from a blockade of the RAS due to a reduced cardiovascular morbidity and mortality. Unless proven otherwise ACE-I therapy should be continued lifelong.
The incidence and prevalence of cardiovascular disease (CVD) is increased in elderly patients. Physiological, age-related structural alterations of the heart and the vasculature reduce the threshold for the development of CVD. The underlying molecular mechanisms include oxidative stress, non-enzymatic glucosylation, inflammation and changes in gene expression. Angiotensin II induces cell growth of vascular smooth muscle cells and cardiac myocytes, acts as a pro-inflammatory agent, shows pro-fibrotic potential, induces oxidative stress and endothelial dysfunction and has been implicated in the pathogenesis of atherosclerotic plaque instability. Interestingly, this angiotensin II mediated effects which are e.g. present in patients with arterial hypertension resemble the molecular mechanisms associated with physiological aging and the concomitant contribution might therefore explain the increased incidence of CVD in the elderly. Inhibition of the renin-angiotensin system (RAS) by ACE-inhibitors (ACE-I) or angiotensin II type 1 receptor antagonists (ARB) is an important tool for the treatment of hypertension, post-myocardial infarction and heart failure. In addition ACE-inhibition can reduce the progression of atherosclerosis, diabetic nephropathy, regresses left ventricular hypertrophy and might influence retinopathy (HOPE, CONSENSUS, RENAAL). These observations seem to request a lifelong inhibition of the RAS for all patients with CVD. However, elderly patients who might in particular benefit of a RAS inhibition due to a reduced threshold for the development of CVD are under-represented in most of the published studies and often suffer from concomitant renal insufficiency, stenosis of the renal arteries or aortic valve stenosis, all conditions which might question the use of ACE-I. In the following review we will focus on the role of ACE-I in old and very old patients with arterial hypertension, congestive heart failure, dementia and stroke.
Various studies have demonstrated that an effective reduction of blood pressure results in a significant reduction of cardiovascular events in patients <80 years old. In contrast, this relation between blood pressure and cardiovascular mortality is reduced or even reversed in old patients 1. A metaanalysis of interventional studies in patients >80 years old and the results of the pilot trial of the “Hypertension in the Very Elderly Trial” showed a beneficial effect of blood pressure reduction in terms of reduction of stroke, however, there was a trend towards an increased total mortality 2. Therefore, the randomised, placebo-controlled, double-blind “Hypertension in the Very Elderly Trial” currently investigates the role of indapamide plus optional perindopril (if blood pressure regulation can not be achieved with diuretics alone) in 2100 patients >80 years of age. Primary endpoints include lethal and non-lethal stroke. Secondary endpoints are total mortality, cardiovascular mortality, cardiac mortality, mortality due to stroke and skeletal fractures. First results are expected in 2006. Besides the lack of clinical data, there is good evidence from experimental studies that an ongoing ACE-I therapy has beneficial effects 3. Spontaneously hypertensive rats die within 15 months when treated with placebo while ramipril treatment was associated with a doubled lifespan (30 month, comparable to wildtype rats). This was mainly due to a preserved left ventricular function and the lack of an endothelial dysfunction.
A minority of elderly patients with CHF fulfill the inclusion criteria for major heart failure studies. With increasing age the probability to accomplish inclusion criteria becomes more and more unlikely. A subanalysis of the “Heart Outcomes Prevention Evaluation Study” (HOPE) in high risk patients >65 years old without clinical signs of CHF showed a more pronounced reduction of the relative risk compared to younger patients. Similar results were obtained in the subgroup analysis of the AIRE and CHARM-Study. Besides the fact that there is only very few data available concerning ACE-I in old and very old patients there is no data available investigating a continuous, lifelong therapy with ACE-I. For the SOLVD and AIRE Study post-observational studies are available which have investigated the influence of the study medication on survival 9-12 years (SOLVD and 3 years (AIREX) after completion of the study. The treatment with enalapril for 3-4 years was thereby associated with a significantly increased survival benefit compared to placebo 12 years after finalisation of the trial (HR 0.9; CI 0.84-0.95, p=0.0003). Similar results were obtained in the AIREX Study which demonstrated an absolute reduction of mortality of 11.4% 3 years after the completion of a 15 month therapy with ramipril.
The prevention of dementia by antihypertensive treatment was evaluated in the Syst-Eur-Study. Patients with arterial hypertension and no signs of dementia were treated with a Ca2+ channel blocker. Therapy was extended to ACE-I and/or diuretics when insufficient blood pressure regulation was achieved. Compared to control patients the incidence for dementia was reduced by 55% (3.9 years follow-up; 7.4 vs. 3.3 cases per 1000 patient years; p<0.001). It is unclear whether the observed effects are due to blood pressure reduction alone or ACE-I therapy. However, experimental data has shown an increased presence of ACE in the temporal cortex of patients with dementia suggesting an important role of the RAS 4. In patients with stroke the placebo controlled PROGRESS Study in 6105 patients showed a reduced incidence of 28% (CI 17-38%) and reduced rate of vascular events of 26% (CI 16-34) in the perindopril based regimen arm. Interestingly, these results were also achieved in patients without any signs of arterial hypertension.
The currently available data underlines that ACE-inhibition is an efficient and important therapeutic concept for the treatment of CVD in elderly patients. There is increasing evidence that especially old and very old patients benefit from a blockade of the RAS due to a reduced cardiovascular morbidity and mortality. However, until today clinical studies have only investigated the influence of ACE-I therapy over a time period of 5 years. Further insights into the role of RAS inhibition in elderly patients will be available from The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) program which currently compares the efficacy of an angiotensin II receptor blocker, an ACE-I, and the combination therapy for reducing cardiovascular risk5. Primary end points include cardiovascular death, acute myocardial infarction, stroke, and hospitalisation due to congestive heart failure. Secondary end points include newly diagnosed heart failure, revascularisation as well as new-onset of type 2 diabetes mellitus, nephropathy, dementia, and newly diagnosed atrial fibrillation all conditions which have a high incidence and prevalence in old and very old patients. Until randomised, placebo-controlled studies are available the results of the published, placebo-controlled ACE-inhibitor studies can be extrapolated to old and very old patients. Unless proven otherwise ACE-I therapy should be continued lifelong.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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4. Barnes NM, Cheng CH, Costall B, Naylor RJ, Williams TJ, Wischik CM. Angiotensin converting enzyme density is increased in temporal cortex from patients with Alzheimer's disease. Eur J Pharmacol. 1991;200:289-292. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1664329
5. Unger T. The ongoing telmisartan alone and in combination with ramipril global endpoint trial program. Am J Cardiol. 2003;91:28G-34G. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12781906
Dr N. Werner and Prof. M. Böhm Homburg-Saar, Germany Nucleus member of the ESC Working Group on Heart Failure
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