Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack trial ( ALLHAT )

• this trial originally enrolled 42,418 patients aged 55 years and older with Stage 1 or Stage 2 hypertension and at least one other cardivascular disease risk factor; at enrollement the average blood pressure was 146/84 mmHg (if treated) or 156/89 mmHg (if untreated) and began in 1994
  • nearly half of participants were women
  • more than one-third were African American
  • more than one-third had diagnosed diabetes
• patients were randomised to one of four first-line treatments
  • chlorthalidone (thiazide diuretic)
  • amlodipine
  • lisinopril
  • doxazosin
    • the doxazosin trial warm was stopped early (March 2000) because of a 25% higher rate of combined cerebrovascular disease and a two-fold higher rate of heart failure (see linked menu item)
  • 33,357 patients stayed on study drugs through to the end of the study (average of 4.9 years)
• trial results:
  • blood pressure - five year systolic pressures were significantly higher with both amlodipine (0.8 mmHg) and lisinopril (2 mmHg) compared with chlorthalidone
  • the primary end point of fatal coronary heart disease (CHD) and non-fatal myocardial infarction (MI) was almost identical for chlorthalidone, amlodipine and lisinopril treatment groups
  • secondary outcomes (all-cause mortality, stroke, combined CHD (fatal CHD, non-fatal MI, coronary revascularisation, or angina with hospitalisation), or combined cardiovascular risease (CVD) (combined CHD plus stroke, treated angina without hospitalisation, heart failure and peripheral arterial disease)
    • secondary outcomes were similar between amlodipine and chlorthalidone except there was a higher six year rate of heart failure (relative risk (RR) 1.38)
    • in comparing chlorthalidone and lisinopril, lisinopril showed significantly higher six year rates of combined CVD (RR 1.1), stroke (RR 1.15), and heart failure (RR 1.19)
      • differences in efficacy were especially marked in black patients - rates of stroke were higher in the lisinopril group for blacks (RR 1.40), with no difference in non-blacks; rates of combined CVD in the lisinopril group were also higher compared to non-blacks; these differences were attributed to the smaller reduction in blood pressure seen with lisinopril in black patients (the average systolic blood pressure was 4 mmHg higher in blacks treated with lisinopril than with chlorthalidone)
  • cholesterol reduction - the lipid-lowering study arm of ALLHAT was conducted in 10,355 patients with mildly elevelated low density lipoprotein (LDL) cholesterol; patients had LDL cholesterol between 3.10 and 4.89 mmol/L or between 2.59-3.34 mmol/L if CHD was already present. The patients were randomised to either treatment with pravastatin 40mg or usual care (however the trial was not 'blinded' and 'usual care' could include treatment with statins and 30% of the 'usual care' patients did receive a cholesterol lowering drug during the study)
    • cholesterol levels fell in both groups (17% in the statin group versus 8% in the usual care)
    • after six years follow-up, results only revealed a small non-significant reduction in CHD event rates with pravastatin (9.3% vs. 10.4% RR=0.91, p=0.16) and no reduction in deaths

The study investigators conclude that thiazide type diuretics should be the initial treatment of hypertension in most patients requiring drug therapy (including those with type 2 diabetes). Also most patients require more than one medication to adequately control blood pressure and diuretics should be part of most multi-drug regimens.

Notes:

• a post hoc analyses of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) investigating renoprotective effects of different agents has been undertaken (3):
  • hypertensive participants 55 years or older with at least 1 other coronary heart disease risk factor were randomized to receive chlorthalidone, amlodipine, or lisinopril for a mean of 4.9 years
  • the study authors concluded that, in hypertensive patients with reduced GFR, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Participants assigned to receive amlodipine had a higher GFR than those assigned to receive chlorthalidone, but rates of development of ESRD were not different between the groups
• lipid lowering treatment and renal effects
  • a a post hoc analysis of the lipid lowering effects of pravastatin in ALLHAT has been undertaken
    • data revealed that, in hypertensive patients with moderate dyslipidemia and decreased eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR (4)
• a substudy of the ALLHAT trial examined whether cardiovascular disease outcomes differed between black and non-black patients who were started on 1 of 3 different classes of antihypertensive agent (5)
  • amlodipine or lisinopril was not better than chlorthalidone for reducing cardiovascular disease
  • chlorthalidone was associated with a lower risk of heart failure than amlodipine or lisinopril in either racial subgroup

Reference:

1. JAMA 2002;288:2891-97
2. MeRec Extra (March 2003), 8.
3. Rahman M et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensve and Lipid-Loweriring Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165: 936-46.
4. Rahman M et al. Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Kidney Dis. 2008 Sep;52(3):412-24.
5. Wright JT et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopirl. JAMA 2005; 293:1595-608