Blog entry by Meguid El Nahas
In the June issue of cJASN Rahman and colleagues from the ALLHAT Collaborative Group report the long-term (9 year) renal and cardiovascular outcomes of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
This is a randomised, double blind, multicentre clinical trial that compares the impact of 5 year treatment with an ACE inhibitor (lisinopril), a calcium antagonist (Amlodipine), an alpha blocker (Doxazosin) and a thiazide diuretic (Chlorthalidone) on the incidence of major coronary heart disease (CHD) in high risk hypertensive patients. The initial analysis over a 5 years observation and follow-up period showed that neither lisinopril not amlodipine were superior to the diuretic chlorthalidone. The Doxazosin arm had to be discontinued earlier due to side effects and increased mortality (ALLHAT Collaborative Research Group: JAMA 283:1967-1975, 2000).
The current posthoc analysis reports on 31,350 participants followed up for up to 9years, based on hospitalisation records, in term of cardiovascular outcomes; total mortality, CHD, CVD, Stroke, Heart Failure and ESRD.
In the whole study group, there was no difference between lisinopril, amlodipine and chlorthalidone isn relation to CVD or renal outcomes/ESRD. Subgroup analysis of pateints with CKD and an eGFR<60 (with minimal proteinuria), also showed no difference in renal or cardiovascular outcomes between the groups. Of interest, the morbidity and mortality from CVD causes was similar to those observed in the RENAAL and AASK trials.
The authors conclude that independently of BP lowering effect, no antihypertensive drug class has significant advantage over others in preventing CVD; morbidity and mortality. Of note amlodipine was less effective than chlorthalidone in preventing heart failure; although this may simply reflect that the former favours fluid retention whilst the latter minimises it...!!!
This observation agrees with a review of controlled trials by Segall et al (J Nephrol 2008;21:374-383) that showed no specific benefit of anti-hypertensive drug class beyond BP control. Other studies suggested a therapeutic advantage of RAAS inhibition on CVD but it was unclear whether this was independent from improved BP control. Of note the much quoted HOPE study, also failed to dissociate the CVD protective effect of Ramipril from its antihypertensive impact. More recently, HOPE study posthoc analysis based on 24h ambulatory BP Monitoring failed to convincingly dissociate cardioprotection from improved BP control (Svensson et al. Hypertension. 2001;38:e28-e32).
From the above one is entitled to ask whether the much publicised cardioprotective effect of RAAS inhibitors is real or a bais generated by:
1. Poorly designed clinical trials (RCT); with unequal BP control between groups
2. Inadequate BP measurements in RCT; with occasional office BP measurements now known to be poorly reflective of 24h BP recordings measuring nocturnal BP and nocturnal dip in BP, both known to be closely associated with CV events.
3. An industry led brainwashing of ill informed Nephrologists; who follow the trend without asking questions....?!
I suspect the answer lies in all three...!!!