Hope in Life and Value of blood pressure control

Two editorials were published in the August issue of Journal of Hypertension devoted to the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study [1,2]. Both articles conclude (and we do not disagree with them) that the results of the VALUE study come to confirm the supremacy of blood pressure control to prevent the development of cardiovascular events and death in hypertensive patients. However, Staessen and Birkenhäger [1] go further and conclude that VALUE ‘puts the concept of prognostic benefit beyond blood pressure-lowering to rest'. The conclusions of these two editorials deserve further comment regarding the conditions under which comparative studies of different antihypertensive monotherapies have been conducted. For their development, cardiovascular and renal disease require the presence of cardiovascular risk factors. This is followed by target organ damage development (including development of atherosclerosis in the arterial tree). Subsequently, established cardiovascular disease appears (including clinical manifestations of coronary, cerebrovascular or peripheral arterial disease and renal disease). Finally, disease progression can eventually lead to death. Blood pressure is among the most relevant risk factors for the development of cardiovascular and renal disease. In the general population, the risk appears to start at levels of 115/75 mmHg and rises continuously, with an approximately doubling of risk with each incremental increase in blood pressure of 20 mmHg systolic or 10 mmHg diastolic pressure [3]. A similar relationship between blood pressure and cardiovascular events or death appears to exist in treated hypertensives [4]. The absence of adequate blood pressure control in a relevant percentage of patients in most comparative studies of arterial hypertension impairs an adequate analysis of the data [5]. A particularly difficult blood pressure control is observed in patients with the highest level of global cardiovascular risk, such as diabetics, patients with associated clinical conditions and patients with advanced target organ damage [6,7]. Studies comparing two antihypertensive monotherapies are performed after calculating a sample size that presumably ensures a number of cardiovascular events and deaths sufficient to detect the hypothetical difference between the two therapies considered at baseline. In other words, the sample of patients recruited for the study must contain a number of patients who, despite treatment, will suffer an event or die within the next 3–5 years. For this reason, patient selection in the VALUE study was based on detection of very high cardiovascular risk [8]. According to their global cardiovascular risk, VALUE patients were nearer to those in the Heart Outcomes Prevention Evaluation (HOPE) study [9] than those in most other previous studies of antihypertensive treatment. This was later confirmed by the prevalence of events actually observed in the VALUE study, which was clearly above those found in previous comparative studies [10]. The absence of a washout period and the rollover design contemplated for the initiation of active therapy in the VALUE study [8] can, at least in part, explain the better results in blood pressure control observed under amlodipine during the first few months of the study. Calcium channel blockers are particularly effective in situations of high salt intake and have persistent natriuretic and diuretic properties that facilitate their antihypertensive capacity [11]. The difference in blood pressure control seen during the first 6 months appears to contribute importantly to the difference in events. As stated by Williams [2], this finding questions the real benefit attributed to angiotensin-converting enzyme-inhibitors in studies of high-risk patients in whom these drugs were compared with placebo [9], and suggests that in patients about to suffer an event or die, small changes in blood pressure are able to influence event appearance. In other words, in the presence of advanced vascular disease, events can be driven by small changes in blood pressure. Needless to say that, under the conditions of a clinical trial, a period of blood pressure differences similar to those seen during the first few months of the VALUE study can occur and account for events later attributed to a given therapy, but are really due to a relatively small and perhaps transient increase in blood pressure. The only comparative study in which a significant difference was found in favour of one of the drugs being compared is the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study [12]. The composite primary endpoint, including fatal and non-fatal myocardial infarction, stroke and heart failure, as well as sudden cardiac death, occurred significantly less in the group of patients who were treated with losartan than in those who were treated with atenolol. This result was largely driven by the improved prognosis in fatal and non-fatal stroke. Do the data of VALUE invalidate the conclusions of the LIFE study? We do not think so, because there are important differences between the two studies. In VALUE, patients were selected to ensure that the great majority of patients already had established cardiovascular disease. In the LIFE study, selection only required the presence of one type of target organ damage, namely left ventricular hypertrophy (LVH), and patients had a lower degree of global cardiovascular risk because they were in an earlier stage of development of cardiovascular disease. In agreement with this is the lower incidence of cardiac events in the LIFE study despite the average achieved systolic blood pressure being 7 mmHg higher in LIFE than in VALUE [8,12]. On the other hand, the higher systolic blood pressure may explain the higher stroke incidence in LIFE, which may also have been facilitated by the presence of LVH [13]. The lower incidence of cardiac events and death in LIFE than in VALUE, despite the higher achieved blood pressure control, strengthens the interpretation that it is not only the level of blood pressure that accounts for development of events and death, but also the stage of development of vascular damage, mostly atherosclerosis. On the other hand, selecting patients on the basis of target organ damage may demonstrate that regression of some types of target organ damage, such as LVH and microalbuminuria, contributes toward preventing the subsequent development of cardiovascular events and death. A better regression of LVH throughout the length of the study was observed for losartan as compared to atenolol in the LIFE study [12]. The same was true for regression of microalbuminuria [14]. Regression of LVH has been shown to be accompanied by a decreased incidence of cardiovascular events and death [15], and LIFE has also shown that regression of urinary albumin excretion is associated with a decreased prevalence of cardiovascular events and death [16]. In summary, VALUE is a landmark trial that has greatly contributed to our better understanding of the results of previous outcome studies. It also suggests that, in future trials, patients will need to be selected at earlier stages of cardiovascular disease with measurable target organ alterations (intermediate endpoints), whose relationship to future events and death could then be investigated.