Placebocontrolled trials of diureticbased and betablockerbased therapy

By 1990, the benefits of blood pressure lowering on the risk of initial stroke among hypertensives had been clearly established from an overview of 14 randomised controlled trials that principally used regimens based on diuretics and beta-blockers [15]. The findings of these trials, which were mainly conducted among middle-aged subjects with mild-moderate essential hypertension, were subsequently extended by results of trials in older subjects with both essential hypertension and systolic hypertension. In combination, these trials demonstrated that net reductions of 10-12mmHg in usual systolic blood pressure and of 5-6 mm Hg in usual diastolic blood pressure were associated with a 38% reduction in the risk of stroke within just a few years of starting treatment [16], matching the benefit predicted from epidemiological studies [6,7].

Table 1. Characteristics of placebo-controlled trials of antihypertensive therapy that included participants with diabetes

Trial

Entry criteria

N

Mean age (years)

Entry BP (mmHg)

Difference in BP (active - placebo) during follow-up (mmHg)

Duration of follow-up

(years)

Overall

Diabetic (%)

Overall

Diabetic

Overall

Diabetic

Overall Diabetic

Diuretics vs. placebo

SHEP [19, 22]

>60 years, ISH

4,736

583

72

70

170/77

170/76

-12/4

-10/-2

4.5

(12.3)

PATS [23]

Stroke/TIA

5,665

NA

60

NA

154/93

NA

-5/-2

NA

2

ACE inhibitors vs. placebo

HOPE [24,25]

CHD, CVD or

9,297

3,577

66

65

139/79

142/80

-3/-1

-2/-1

4.5

DM+CVD RF

(38.5)

PROGRESS [26]

Stroke/TIA

6,105

762

64

NA

147/86

NA

-91- 4

NA

4

(12.5)

Calcium antagonists

vs. placebo

Syst-Eur [27, 28]

>60 years, ISH

4,695

492

70

NA

174/85

175/84

-10/-5

-91- 4

2

(10.5)

Syst-China [29]

>60 years, ISH

2,394

98

67

NA

170/86

NA

-91- 3

-61-5

3

(4.1)

Angiotensin receptor blockers vs. placebo

IDNT [30]

DM + HBP +

1,715

1,715

59

-

159/87

-

-4/-3

-

2.6

nephropathy

(100%)

IRMA2 [31]

DM + HBP +

590

590

58

-

153/90

-

-2/0

-

2

microalbuminuria

(100%)

RENAAL [32]

DM +

1,513

1,513

60

-

152/82

-

-2/0

-

nephropathy (100%)

Trial acronyms listed at end of chapter.

BP, blood pressure; CHD, coronary heart disease; CVD, cardiovascular disease; DM, diabetes mellitus; HBP, high blood pressure; ISH, isolated systolic hypertension; NA, data not available; RF, risk factor; TIA, transient ischaemic attack.

Table 2. Characteristics of trials comparing blood pressure lowering regimens based on different drug classes

Trial

Primary treatments

Entry criteria

n

Mean age (years)

Entry BP (mmHg)

Duration

compared

of follow-up

Overall

Diabetic (%)

Overall

Diabetic

Overall

Diabetic

(years)

ABCD

CA vs. ACE-I

HBP + DM

470

470

57

-

155/98

-

5

hypertensive [46]

(100%)

ABCD

CA vs, ACE-I

DM +

480

480

59

-

136/84

-

5.3

normotensive [47]

BP<140/90mmHg

(100%)

ALLHAT [33]

CA vs. ACE-I vs. D

HBP + CVD RF

33,357

12,063 (36.2%)

67

NA

146/84

NA

4.9

ALLHAT [45]

AB vs. D

HBP + CVD RF

24,335

NA (35.6%)

67

NA

145/83

NA

3.3

ANBP2 [34]

ACE-I vs. D

>65 years + HBP

6,083

NA (7%)

72

NA

168/91

NA

4.1

CAPP [35, 36]

ACE-I vs. D or BB

HBP

10,985

572 (4.9%)

53

55

161/99

163/97

6.1

FACET [48]

CA vs. ACE-I

DM + HBP

380

380 (100%)

63

-

170/95

-

2.5

INSIGHT [40]

CA vs. D

HBP + CVD RF

6,321

1,302 (20.6%)

65

NA

173/99

NA

4

LIFE [43, 44]

ARB vs. BB

HBP + LVH

9,193

1,195 (13.0%)

67

67

174/98

177/96

4.8

NORDIL [41]

CA vs. BB or D

HBP

10,881

727 (6.7%)

60

NA

173/106

NA

4.5

STOP-2 [37, 38]

CA vs. ACE-I vs. D or BB

>70 years + HBP

6,614

719 (10.9%)

76

76

194/98

195/96

5

UKPDS [39]

ACE-I vs. BB

HBP + DM

758

758 (100%)

56

-

160/94

-

8.4

Trial acronyms listed at end of chapter.

AB, alpha-blocker; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; CA, calcium antagonist; CVD, cardiovascular disease; D, diuretic; DM, diabetes mellitus; HBP, high blood pressure; LVH, left ventricular hypertrophy; NA, data not available; RF, risk factor.

Table 3. Characteristics of trials comparing blood pressure lowering strategies of different intensity

Trial

Target BP compared

Entry criteria

n

Mean age (years)

Entry BP (mmHg)

Achieved

Duration

(mmHg)

BP of follow-up

Overall

Diabetic (%)

Overall

Diabetic

Overall

Diabetic

(mmHg)

(years)

AB CD

DBP <75 mmHg vs.

HBP + DM

470

470

57

-

155/98

-

132/78 vs.

5

hypertensive [46]

80-89 mmHg

(100%)

138/86

AB CD

DBP 10 mmHG

DM +

480

480

59

-

136/84

-

137/81

5.3

normotensive [47]

cbaseline vs. 80-89

BP<140/90 mmHg

(480%)

mmHg

HOT [49]

DBP <80 mmHg vs.

HBP

18,790

1501

61

NA

170/105

NA

140/81 vs.

3.8

<85 mmHg vs.

(8.0%)

141/83 vs.

<90 mmHg

144/85

UKPDS [53]

BP <150/85 mmHg

HBP + DM

1,148

1148

56

-

160/94

-

144/82 vs.

8.4

vs. <180/105 mmHg

(100%)

154/87

Trial acronyms listed at end of chapter.

BP, blood pressure; DBP, diastolic blood pressure; DM, diabetes mellitus; HBP, high blood pressure; NA, data not available.

Despite the fact that raised blood pressure is frequent among individuals with diabetes [4,5], many of the earliest randomised trials either excluded diabetic patients or failed to report their inclusion. This may have been due to concerns about possible adverse metabolic effects of diuretics and beta-blockers [17] or concern that diuretics might increase mortality among hypertensive subjects with diabetes [9,10]. The INDANA Collaborative Group conducted a metaanalysis of individual participant data from three trials (HDFP, STOP-Hypertension and SHEP [18-20]) that did include diabetic participants, that used mainly diuretics as first-line therapy (with some use of beta-blockers), and that collected data on fatal and non-fatal stroke [21]. In combination, among 2,162 diabetic participants with hypertension, active treatment lowered blood pressure by 11/4mmHg more than placebo. The relative risk of stroke was reduced by 36% (95%CI 10-55) (Figure 2), a result virtually identical to that observed among non-diabetics (37% reduction [95%CI 24-47]). The results of SHEP, the only trial to have published results separately in diabetic and non-diabetic subgroups, were consistent with these overall findings (Figure 2) [22].

However, despite the similar relative benefits of treatment, the absolute benefit was almost twice as great among those with diabetes (29 vs. 15 strokes avoided for every 1,000 patients treated for 5 years), due to their greater absolute risk of stroke [21].

A single large-scale study, PATS, has compared a diuretic with placebo among individuals with prior stroke. The study was not adequately randomised and the preliminary published results provide no information about diabetic participants [23]. Overall, however, active treatment lowered blood pressure by 5/2mmHg and the relative risk of stroke by 29% (95%CI 12-42) compared with placebo.

Placebo-controlled trials of ACE-inhibitor-based therapy

More recently, two large placebo-controlled trials (HOPE and PROGRESS) have reported on the use of ACE-inhibitor-based drug regimens in different patient groups (Table 1).

The HOPE trial was conducted among high-risk hypertensive and normotensive patients, many of who had coronary artery disease at baseline [24]. Among diabetics, ACE inhibitor treatment lowered clinic blood pressure by 2/1mmHg more than placebo and the relative risk of stroke by 33% (95%CI 10-50) (Figure 2), results similar to those observed among the study population as a whole [24,25]. PROGRESS was conducted among normotensive and hypertensive participants with a history of cerebrovascular disease (stroke or transient ischaemic attack) [26]. Compared with placebo, ACE inhibitor-based treatment (with the addition of a diuretic if neither indicated nor contraindicated) lowered blood pressure by 9/4mmHg and the risk of stroke by 28% (95%CI 17-38). The benefits observed were similar among participants with and without diabetes (unpublished data), and among those with and without hypertension at baseline.

Number of strokes/ total patients with diabetes

Favours active

Favours placebo

Relative Risk (95% CI)

Active

Placebo

Trials of conventional therapy

SHEP 25/283 INDANA NA PATS* -

36/300 NA

t

Trials of ACE inhibitor-based therapy

HOPE 76/1,808 PROGRESS* -

108/1,769

0.67 (0.50-0.90)

Trials of CA-based therapy

Syst-China* -Syst-Eur 5/252

15/240

0.31 (0.11-0.86)

Trials of ARB-based therapy

renaalL -

-

--

Relative Risk & 95% CI

Relative Risk & 95% CI

Figure 2: Results of placebo-controlled trials of blood pressure lowering therapy that included participants with diabetes

Relative risks of fatal and non-fatal stroke among diabetic participants in placebo-controlled trials of blood pressure lowering therapy. The size of each box is proportional to the number of strokes that occurred and horizontal lines represent 95% confidence intervals. The diamond represents the pooled estimate of treatment effect in three trials (HDFP, STOP-Hypertension and SHEP) included in the INDANA meta-analysis [21]. *Complete data in diabetic subgroup not published separately. ^Data for the outcome of stroke not published.

(ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CA, calcium antagonist; CI, confidence interval; NA, data not available)

Placebo-controlled trials of calcium antagonist-based therapy

Although observational evidence led to concerns about the safety of calcium antagonist use among hypertensive diabetics [11-13], this has not been supported by evidence from clinical trials (Table 1).

Syst-Eur compared a dihydropyridine calcium antagonist with placebo among elderly subjects with systolic hypertension [27,28]. Among diabetic participants, active treatment lowered blood pressure by 9/4mmHg more than placebo and was associated with a 69% (95%CI 14-89) lower relative risk of stroke (Figure 2) [28]. These reductions were not significantly different from those observed among non-diabetics [27]. However, as in trials of diuretic therapy, the absolute treatment benefits were substantially greater among diabetics due to their greater absolute risk of stroke [28]. Similar, though nonsignificant, trends were observed in the smaller non-randomised Syst-China trial [29].

Placebo-controlled trials of angiotensin receptor blocker-based therapy

Three published trials (IDNT, IRMA2 and RENAAL) have assessed the effects of angiotensin receptor blockers among populations with diabetes (Table 1) [30-32]. In each case, active treatment was associated with a reduction in the primary endpoint, progression of renal disease. However, none had sufficient power to detect reductions in the risks of individual cardiovascular endpoints, and no results have so far been reported separately for the outcome of stroke.

In summary, placebo-controlled trials of blood pressure lowering therapy demonstrate that diuretics, beta-blockers, ACE inhibitors and calcium antagonists all substantially reduce the risk of stroke among individuals with diabetes. There is insufficient evidence from placebo-controlled trials of angiotensin receptor blockers to determine whether they confer similar benefits.

Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook


Post a comment