What is the background to this? – The ALLHAT trial of patients with hypertension showed very similar rates of fatal coronary heard disease (CHD)/nonfatal myocardial infarction (MI), the primary end point, with the calcium channel blocker (amlodipine), ACE inhibitor (lisinopril) and thiazide diuretic (chlortalidone), but better results in terms of secondary outcomes with the diuretic. As reflected in the NICE guideline for Hypertension, there are concerns regarding metabolic side effects of diuretics and the development of diabetes in some people, as discussed on the hypertension section of NPC.
What does this study claim? – This subgroup analysis of patients with metabolic syndrome in the ALLHAT study (these comprised about half of the patients in the study, 23,000 people) identified similar findings to those of the whole ALLHAT study population. However, it found the incidence of heart failure were significantly higher in patients initially treated with amlodipine and lisinopril (and doxazosin) than in those initially treated with a diuretic. These findings were particularly apparent in black patients. Further advantages for diuretics were found in comparison with the other treatments for some other secondary outcomes (see Study details below).
How does this relate to other studies? – Despite their lower acquisition cost, and similar efficacy, the NICE guideline did not recommend diuretics as the first-line treatment for hypertension ahead of calcium channel blockers for those aged 55 years or black (of any age). This was largely based on the supposition that diuretics were associated with a higher incidence of the development of diabetes (and this was associated with higher costs). However, the guideline did not specifically consider patients with metabolic syndrome or diabetes. There is, however, no convincing clinical trial evidence to support the view that the use of diuretics in people with these conditions are at any greater cardiovascular risk than those who are treated with ACE inhibitors or calcium channel blockers. See the MeReC Bulletin — the management of hypertension in primary care: updated guidance from NICE — for more information on this. A previous subgroup analysis of patients with diabetes (n>13,000) in ALLHAT provides support for the first-line use of diuretics in this population as discussed in workshop 4 of the NPC <60minute eLearning workshop on hypertension.
So what? – This analysis adds weight to the positioning of thiazide diuretics as first-line antihypertensive in the vast majority of patients with hypertension. This study fails to support the use of calcium channel blockers, ACE inhibitors (or alpha-blockers) ahead of diuretics in patients with metabolic syndrome.
In a US National Heart, Lung, and Blood Institute press release, director Elizabeth Nabel said these new findings were important because “many doctors currently prescribe alpha blockers, calcium-channel blockers, and ACE inhibitors due to their more favourable short-term effects on blood sugar and blood cholesterol levels. However, this new analysis shows that diuretics are better at preventing cardiovascular disease and thus does not support the selection of the newer drugs over diuretics for preventing poor health outcomes related to hypertension or for lowering high blood pressure.”
Action – Clinicians should consider their current practice in comparison with the recommendations made by NICE.
Patients – the ALLHAT trial enrolled 42,418 adults who were 55 years or older with hypertension and at least one additional risk factor for CHD who were randomised to either a chlortalidone, amlodipine, lisinopril, or doxazosin-based regimen. This subgroup analysis compared outcomes in 23,077 patients with metabolic syndrome, of which 7327 were black. Metabolic syndrome was defined as hypertension plus at least two of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men or less than 50 mg/dL in women.
Results – there were no significant differences between chlortalidone and amlodipine, lisinopril, or doxazosin in black or non-black patients with regard to:
- CHD events
- all cause mortality
- CV mortality.
However, compared with chlortalidone, there were significantly higher rates of heart failure for all treatment comparisons in black participants for:
- amlodipine (relative risk (RR) (95% confidence intervals [CIs]) 1.50 (1.18 to1.90),
- lisinopril RR=1.49 (1.17 to1.90), and
- doxazosin RR=1.88 (1.42 to 2.47)
and in nonblack participants for:
- amlodipine RR=1.25 (1.06 to 1.47),
- lisinopril RR=1.20 (1.01 to 1.41), and
- doxazosin RR=1.82 (1.51 to 2.19).
There were also higher rates of combined cardiovascular disease in black people compared with chlortalidone for:
- lisinopril (RR=1.24 [1.09 to 1.40], and
- doxazosin (RR= 1.37 [1.19 to 1.58]
and also in nonblack participants for:
- lisinopril RR=1.10 [1.02 to 1.19],
- doxazosin RR=1.18 [1.08 to 1.30],
Higher rates of stroke were seen in black participants only when compared with chlortalidone for:
- lisinopril RR=1.37 [1.07 to 1.76]
- doxazosin RR=1.49 [1.09 to 2.03].
Higher rates of end-stage renal disease were seen in black participants only when compared with chlortalidone for:
- lisinopril RR=1.70 [1.13 to 2.55]
For further information on the treatment of hypertension please visit the Cardiovascular (including diabetes) Floor on NPC.