ALLHAT: What Outcomes Would Have Been Expected? Comparisons Among Placebo- or No Treatment Controlled Trials

Effect of Antihypertensive Therapy on CV Events Fatal/nonfatal strokes CVD deaths Fatal/nonfatal CHD events CHF LVH Percent decrease in events vs placebo Meta-analyses of placebo-controlled trials using diuretics or beta-blockers as initial therapy show reductions of over 50% in HF, about 40% in strokes, and 16% in CHD. The mean BP differences in these trials was about 5-6mm Hg diastolic and 10-12 mm Hg systolic. 17 randomized, placebo-controlled trials using diuretic or b-blocker (n=48,000) All reductions are statistically significant Moser M et al. J Am Coll Cardiol. 1996;27:1214-1218. Hebert PR et al. Arch Intern Med. 1993;153:578-581.

Event Reduction with “Low Dose” Diuretic or b-Blocker ns ns Beta-blockers, while usually effective in reducing CV events compared with placebo, appear to be inferior to diuretics, especially in elderly hypertensive patients. In addition, there have been no placebo-controlled beta-blocker hypertension morbidity trials in the U.S. nor with many blacks. The doses of diuretics used in “low dose” trials were at least the equivalent of 25-50 mg HCTZ, e.g. 12.5 -25 mg chlorthalidone in SHEP. 25-50 mg HCTZ Psaty, et al. JAMA 1997;277:739-745

Event Reduction:SHEP & Syst-Eur Randomized Controlled Trials in Isolated Systolic Hypertension (ISH) ns separately, but p<.05 combined ns ns BP differences between randomized treatment groups were 12/4 in SHEP, 10/4 in Syst-Eur. All differences in this slide were significant unless otherwise stated. Although Syst-Eur was stopped after about 2 years of follow-up compared with almost 5 years for SHEP and the number of events were therefore much less, the sample sizes and entry criteria were similar and the relative risk reductions were similar for stroke, CHD, CVD, and death when regimens beginning with a thiazide-type diuretic or a DHP-CCB were compared with placebo. However, consistent with the greater CHF benefit with chlorthalidone vs amlodipine in ALLHAT, HF was reduced 20% more with chlorthalidone in SHEP than with a DHP-CCB in Syst-Eur. SHEP: Systolic Hypertension in the Elderly, n=4,736; 1st drug: chlorthalidone Syst-Eur: Systolic Hypertension in Europe, n=4,695; 1st drug: nitrendipine Syst-Eur (1997) was the only randomized placebo-controlled morbidity trial in hypertension with a calcium channel blocker

Effect of ACE Inhibition vs Placebo on CV Outcomes HOPE Trial Effect of ACE Inhibition vs Placebo on CV Outcomes CV Death Nonfatal MI Nonfatal Stroke P < .001 New/Worsening CHF Revascularization Worsening Angina P = .001 Compared to the pooled analyses of diuretic/beta-blocker trials, an ACE inhibitor in HOPE reduced most fatal and non-fatal events similarly (a little more for MI and CVD mortality, a little less for stroke) except for heart failure, which was reduced only 22%. This is similar to the 20% reduction in new or worsening HF with enalapril in the SOLVD Prevention Trial. These effects are less than half as great as the reduction in HF in the diuretic/BB hypertension treatment trials. This is consistent with the 19% higher risk of HF (10% for hospitalized HF) with lisinopril compared with chlorthalidone in ALLHAT. HOPE was conducted with both hypertensive and non-hypertensive patients (with similar benefits in both sub-groups), and the BP reduction was reported as only 3/2 mm Hg. However, in a sub-study, mean 24-hr BP was reduced 10/3 mm Hg. Risk Reduction (%) Yusuf S, et al. N Engl J Med. 2000;342:145-53

Event Reduction in SHEP, Syst-Eur, and HOPE There are no placebo-controlled hypertension CV morbidity trials of an ACE inhibitor as initial therapy, but HOPE compared an ACEI (ramipril) vs placebo in a population with similar age entry criteria to the ALLHAT – many of the HOPE participants had hypertension, had prior CHD and/or had diabetes. Although different than Syst-Eur and SHEP, HOPE did assess CV outcomes in a placebo-controlled trial of an ACE inhibitor and tended to have smaller relative risk reductions than the diuretic or DHP-CCB except for death, which was similar. HF relative risk reduction was less than half of what was seen with the diuretic in SHEP. SHEP: Systolic Hypertension in the Elderly, n=4,736; chlorthalidone Syst-Eur: Systolic Hypertension in Europe, n=4,695; nitrendipine HOPE: Heart Outcomes Prevention Evaluation Study, n=9,297; ramipril

PROGRESS: Study Design Eligibility (7121 patients) Randomization (6105 patients) Study end Active therapy Patients with a History of Cerebrovascular Disease 4mg perindopril  indapamide (2.5mg*) perindopril run-in 2 mg qd 4 mg qd Some hints about the relative efficacy of a diuretic and an ACE inhibitor are provided by a trial called PROGRESS; the results were reported in 2001. In PROGRESS, patients with a history of cerebrovascular disease (previous stroke or transient ischaemic attack) were treated with a 4 week run-in period with perindopril. The aim was to exclude before randomization those patients who could not tolerate perindopril or showed very little compliance to treatment or schedule of visits. This should have decreased the number of subsequent drop outs. They were then randomized to treatment with either perindopril 4 mg (along with indapamide in about 60%) or to placebo (or double placebo). It is important to remember that the decision to add indapamide on top of perindopril therapy was made at the doctor ’s discretion; there was no randomization between these two subgroups. Thus, the common factor was that 100% of patients received perindopril 4 mg. Patients were followed up over a period of 4 years. The reasons for not receiving indapamide could have been: patient already receives a diuretic contraindication for a diuretic concerns about symptomatic hypotension The reason for starting as often as possible with combined perindopril and indapamide is the target of a sufficient BP difference between the 2 groups during follow-up, in order to obtain a clear cut answer to PROGRESS’ question. Placebo 2 weeks 2 weeks 4 years (open) (double-blind) (*2 mg in Japan) Neal B, MacMahon S. J Hypertens 1995;13:1869-1873

Stroke Risk Reduction in PROGRESS All participants 0.20 0.15 0.10 0.05 0.00 95% CI 17 - 38% P<0.0001 Placebo Active: perindopril +/- indapamide Proportion with event Here is a graph showing the main result of the PROGRESS study. It can be clearly seen that treatment with a perindopril-based regimen led to a reduction in relative risk of recurrent stroke of 28%. This is highly significant. The curves can be seen to separate very early (early in the first year of treatment) meaning in theory that if a patient were started on perindopril-based therapy, the beneficial effects for that patient would start almost immediately. Furthermore, it can be seen from the fact that the graphs are continuing to diverge throughout the course of the study, that the beneficial effect on recurrent stroke of treatment with perindopril-based therapy increases during the course of treatment. BP difference 9/4 mm Hg 1 2 3 4 (Years) PROGRESS Collaborative Group. Lancet 2001;358:1033-41

Stroke and Major CVD Reduction in PROGRESS This slide adds a breakdown of the results for those active patients who were on perindopril alone (in red) compared with those on perindopril plus indapamide (in yellow), versus the respective placebos. It can be seen that the overall effect (in blue) seems to be coming largely from the 60% of patients on combined therapy. This is probably attributable in large part to the lesser BP reduction with ACEI alone (5/3 mm Hg) compared to dual therapy (12/5 mm Hg). It is consistent with ALLHAT results that imply no special effect of ACE inhibition beyond that of BP reduction on major CVD events. PROGRESS Collaborative Group. Lancet 2001; 358: 1033-41

ALLHAT: What Outcomes Would Have Been Expected? Comparisons Among Active Comparator Trials Involving Diuretic +/- Beta-Blocker (D/BB)

Large Hypertension Trials Comparing Two or More Regimens: CVD or CV Mortality Trial n BPΔ Outcomes CAPPP 10,985 +3/+1 captopril not superior to D/BB NORDIL 10,881 +3/ 0 diltiazem not superior to D/BB CONVINCE 16,602 0/+1 verapamil not superior to D/BB (?equivalent?) STOP-2 6,628 0/-1 isradipine/felodipine & 0/ 0 ACEIs not superior to D/BB INSIGHT 6,592 0/ 0 nifed GITS not superior to diuretic ANBP-2 6,083 +1/0 ACEIs not superior to diuretics ALLHAT 42,418 -3/-1 chlorthalidone superior to doxazosin, -1/+1,-2/ 0 amlodipine (HF only), lisinopril The most convincing evidence should come from head-to-head comparison trials, and these are the large trials that compared regimens in which the standard treatment was a diuretic, or investigator option between a diuretic and BB, to other 1st step classes—ALLHAT being the largest by any of several metrics, including person-years per arm. It should be noted that in none of them was the other class found superior to the standard for the most inclusive CVD endpoint, and seldom for any endpoint. In only 3 of the trials (INSIGHT, ANBP2, and ALLHAT) was a thiazide the first-step standard drug, and they will be compared separately. Only 3 of the trials were double-blind (CONVINCE, INSIGHT, ALLHAT). By and large, BP reductions were similar across randomized groups—in CAPPP, NORDIL, and ALLHAT, the diuretic-containing regimens reduced SBP by 3 mm Hg more than the captopril, diltiazem, and doxazosin arms, respectively, and chlorthalidone lowered SBP by 2 mm Hg more than lisinopril in ALLHAT.

ALLHAT vs. ANBP2 Blood Pressure & Endpoints N (ACE / diuretic) 9,054 / 15,255 3,044 / 3,039 1-year BP delta (ACE - diuretic) 3 / 1 2 / 0 1st CVD / Total Mortality 1.07 (1.03-1.12) p=.002 0.89 (0.79-1.01) p=.06 1st CHD 1.05 (0.98-1.11) p=.18 0.86 (0.70-1.06) p=.16 Heart Failure 1.19 (1.07-1.31) p<.001 0.85 (0.62-1.18) p=.85 Stroke 1.15 (1.02-1.30) p=.02 1.02 (0.78-1.33) p=.91 Here are the results for the two trials that compared thiazide-based with ACE inhibitor-based regimens in hypertensive patients. The main differences were that ALLHAT was double-blind while ANBP-2 was an open trial (a so-called PROBE design); and that ALLHT was much larger measured by sample size, and even more so measured by numbers of CV events. Regarding the results, blood pressure changes slightly favored the diuretic in each trial, and group differences were similar between trials. Results for 1st CVD/total mortality, heart failure, and stroke favored the diuretic in ALLHAT overall. These findings were similar in the white, non-Hispanic subgroup, except for stroke. There were no significant overall differences for any of these outcomes in ANBP2. For CHD, heart failure, and stroke, the 95% confidence limits in ANBP-2 include or are close to the point estimate for treatment effects in ALLHAT, which has much narrower confidence limits. Thus, ANBP2 does not really contradict ALLHAT.

ALLHAT vs. INSIGHT Blood Pressure & Endpoints N (CCB / diuretic) 9,048 / 15,255 3,157 / 3,164 1-year BP delta (CCB - diuretic) 2 / -1 0 / 0 Major CVD (MI, HF, stroke, CV death) 1.06 (0.99-1.12) p=.08 1.11 (0.92-1.34) p=NS CHD 0.98 (0.90-1.07) p=.65 1.10 (0.83-1.46) Heart Failure 1.38 (1.25-1.52) p<.001 1.75 (0.95-3.24) Stroke 0.93 (0.82-1.06) p=.28 1.03 (0.75-1.42) INSIGHT was the one other large trial besides ALLHAT which compared diuretic-based versus CCB-based regimens; both used a long-acting dihydropyridine CCB. Systolic blood pressure change slightly favored the diuretic in ALLHAT, while diastolic pressure was 1 mm lower in the CCB group. There were no differences in INSIGHT. Results for major CVD (nonfatal MI, heart failure, stroke or CVD death) tended to favor the diuretic in both. This difference was clearest and consistent between trials for heart failure. (The ALLHAT data shown are for total HF, but results were essentially identical for hospitalized HF.) For INSIGHT, none of the endpoint results presented are significant, but the confidence intervals are wide. The results are entirely consistent with those from ALLHAT. There is no advantage for CCB for stroke.

ALLHAT Compared to Other Large CVD Endpoint Trials: Conclusion Findings from other major trials are totally consistent with ALLHAT’s conclusion that diuretic-based antihypertensive treatment is unsurpassed in preventing major cardiovascular morbidity and mortality, and offer some support for its superiority in reducing risk of heart failure.