Cardiovascular protection by β-blockade in hypertensive haemodialysis patients: the Hypertension in Haemodialysis Patients Treated With Atenolol or Lisinopril (HDPAL) trial

In the pioneer years of chronic haemodialysis (HD), hypertension was recognized as the main undisputable cause of death in end-stage kidney disease (ESKD) patients [1]. Nearly a halfcentury later, sparse data in various countries indicate that control of hypertension in the HD population still remains a major unmet clinical need worldwide. In the USA, the prevalence of hypertension exceeds 80% [2], in Great Britain it is about 50% [3] and in Italy about 70% [4]. Progress in this area has been in part hindered by the ‘reverse epidemiology’ scenario that characterizes the HD population. Uncertainty about blood pressure (BP) targets and methods of measurement is such that the Renal Association guidelines cautiously state that ‘It would be sensible to avoid sustained BP extremes and, in order to try to provide some guidance, we suggest that systolic blood pressure during the interdialytic period on HD and for peritoneal dialysis (PD) patients should not regularly exceed >160 mmHg’ [3]. Low pre-dialysis BP rather than high BP is associated with death risk. Furthermore, in sharp contrast to a large meta-analysis in individuals in the general population without a background of cardiovascular events [5], the pre-dialysis relationship between BP and death risk in end-stage kidney disease (ESKD) is definitely non-linear [6]. However, peri-dialytic BP measurements are inherently inadequate metrics of the BP burden because measurements before dialysis overestimate the underlying average BP while post-dialysis BP underestimates the same parameter. In studies applying ambulatory blood pressure monitoring (ABPM) in the HD population without severe heart failure, the link between BP and clinical outcomes is comparable with that registered in the general population with the same technique [7]. Indeed, high average ambulatory systolic pressure [8] and nocturnal systolic hypertension [9] during the dialysis intervals are strong death predictors in HD patients. Notwithstanding the public health relevance of the problem and the peculiar risk profile of the ESKD population, the number of randomized, controlled trials (RCTs) testing antihypertensive drugs in dialysis patients is very limited indeed. A meta-analysis performed in 2009 [10] identified only eight randomized trials. Of these, one was performed in patients on peritoneal dialysis, two dealt with normotensive or hypotensive patients affected by left ventricular systolic dysfunction or heart failure and another trial (FOSIDIAL) selected patients with left ventricular hypertrophy (LVH), independent of BP [11]. After this meta-analysis, the OCTOPUS trial was published [12]. Thus, we have just four relatively small RCTs specifically focusing on drug treatment of hypertension in HD patients without severe heart failure (NYHA class III or IV) (Fig. 1). Of these trials, one tested a calcium antagonist (amlodipine) [13] and three various angiotensin II receptor blockers (ARBs): candesartan in the first [14]; candesartan, losartan or valsartan in the second [15] and olmesartan in the third [12]). In trials testing ARBs, the antihypertensive effect of these drugs was comparable with that achieved by other drugs. Nonetheless, of these three trials, two documented a reduction in the risk of cardiovascular events (−47% [3] and −71% [4]). If we consider also the FOSIDIAL trial where about half of the patients were hypertensive, the combined analysis (random-effects) of trials based on ARBs and angiotensin-converting enzyme inhibitors (ACEi) shows a 31% risk reduction [RR: 0.69, 95% confidence interval (95% CI) 0.45–1.05, P = 0.086], which just fails to achieve statistical significance. Because BP in patients randomized to ACEi or ARBs in these trials was almost identical to that in patients randomized to other drugs, the apparent benefit of ACEi or ARBS appears attributable to the interference with angiotensin II effects on the cardiovascular system beyond vasoconstriction. These results are similar to those of a recent meta-analysis reporting a substantial, BP-independent, benefit of ACEi and ARBs in over 100 000 high-risk patients without heart failure [16] most of whom were hypertensive. IN F O C U S