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Therapeutics

Randomised controlled trial

Randomised controlled trial

Intensive lowering of systolic blood pressure to a target of less than 120 mm Hg has no effect on the rate of fatal and non-fatal major cardiovascular events in high-risk patients with type 2 diabetes

10.1136/ebm1099

1 Department of Cardiology, University of Louisville Medical Center, Louisville, Kentucky, USA 2 Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA

Correspondence to:

George Bakris Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC 1027, Chicago, IL 60637, USA; gbakris@gmail.com

Atul Chugh, 1 George Bakris 2

Commentary on: Cushman WC, Evans GW, Byington RP, et al.; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85.

Context

The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommends a blood pressure (BP) treat- ment goal of <130/80 mm Hg for patients with diabetes and hypertension. 1 This goal was derived from observational data. 23 The BP arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial prospectively addressed whether this lower BP further reduced cardiovascular events in high-risk patients with type 2 diabetes.

Methods

ACCORD was a prospective, open-label, randomised trial

that

enrolled 10 251 patients at high-cardiovascular risk

and

type 2 diabetes. Of these, 4733 patients were ran-

domised to either intensive (goal systolic BP (SBP) <120

mm Hg) or standard (goal SBP <140 mm Hg) control in

a two-by-two factorial design. High risk was defined as

a presence of clinical cardiovascular disease (CVD) or

a high likelihood of CVD based upon established car-

diovascular risk factors. Patients with baseline SBPs of 130–180 mm Hg taking three or less antihypertensive agents and a 24 h protein exertion rate of <1.0 g were included. Exclusion criteria included patients with body mass index >45 and/or a serum creatinine level >1.5 mg/dl. Antihypertensive regimens included a drug class demonstrating cardiovascular benefit in diabetics. In the

intensive group, a combination of a diuretic and either an angiotensin-converting enzyme inhibitor or a β -blocker

was recommended as initial therapy. The primary end

point was the composite of non-fatal myocardial infarc- tion, non-fatal stoke or cardiovascular death. Mean fol-

low-up time was 4.7 years.

Findings

The average SBP was 119.3 mm Hg (95% CI 118.9 to 119.7)

in

the intensive-therapy group and 133.5 mm Hg (95%

CI

133.1 to 133.8) in the standard-therapy group while

mean diastolic BP (DBP) in the intensive-therapy group

was 64.4 mm Hg (95% CI 64.1 to 64.7) and 70.5 mm Hg in

the standard-therapy group (95% CI 70.2 to 70.8). The pri-

mary composite outcome rate was 1.87% per year in the intensive-therapy group as compared with 2.09% per year in the standard-therapy group (HR with intensive therapy 0.88; 95% CI 0.73 to 1.06; p=0.20). Similarly, no differ- ence in all-cause or cardiovascular mortality was noted between groups. (All-cause mortality: 1.28% per year in the intensive-therapy group and 1.19% in the standard-

therapy group (HR with intensive therapy 1.07; 95% CI 0.85 to 1.35; p=0.55); CV death rate: 0.52% per year in the intensive-therapy group vs 0.49% per year (HR 1.06; 95%

CI 0.74 to 1.52; p=0.74)). In the intensive-therapy group,

a statistically lower rate of total stroke (0.32% per year vs

0.53% per year; HR 0.59; 95% CI 0.39 to 0.89; p=0.01) and non-fatal stroke (0.30% per year vs 0.47% per year; HR 0.63; 95% CI 0.41 to 0.96; p=0.03) were shown. Higher rates of serious adverse events and hypokalaemia were attributed to the intensive-therapy arm.

Commentary

This study fails to support the contention that a lower SBP is associated with a lower cardiovascular event rate. Moreover, the intensive-therapy group had almost three times more adverse events. A benefit was seen on stroke rate and this bears further examination. Similar results were garnered from retrospective analyses of large out- come trials. 4 5 Taken together, these studies suggest that a

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Therapeutics

lower BP is not always better. A factor contributing to this lack of benefit may be related to a DBP that is too low rela- tive to the SBP, as this has been independently associated with higher cardiovascular events. A DBP <70 mm Hg was the nadir established where risk starts to increase; a BP cut-off significantly higher than the mean DBP achieved in the intensive-therapy arm of this trial. 6 Thus, this may also be a contributing factor and is being evaluated. ACCORD will play an important role in changing BP goals in future guidelines for patients with diabetes.

Competing interests GB is a consultant for NIH/NIDDK, GSK, Merck, Novartis, Boehringer-Ingelheim, Takeda, Abbott, Walgreen’s, BMS/Sanofi, Gilead, Forest, CVRx, Fibrogen, Spherix, Johnson & Johnson, Daiichi-Sankyo. GB has also received investigator initiated grants from GSK Forest Labs.

References

1. Chobanian AV , Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72.

2. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412–19.

3. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care

1993;16:434–44.

4. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease – an observational subanalysis from the INternational VErapamil SR-Trandolapril STudy (INVEST). JAMA 2010; (In Press).

5. Sleight P, Redon J, Verdecchia P, et al. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens 2009;27:1360–9.

6. Messerli FH, Panjrath GS. The J-curve between blood pressure and coronary artery disease or essential hypertension: exactly how essential? J Am Coll Cardiol 2009;54:1827–34.

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