NIHR Signal Lower is better: blood pressure targets for high-risk people with diabetes or kidney disease

Published on 26 January 2016

There were fewer heart attacks and strokes when people with cardiovascular conditions, diabetes or kidney disease followed lower blood pressure targets than usually recommended. This came at the expense of only a small increase in rates of severe low blood pressure.

This updated systematic review and meta-analysis provided reliable evidence that more intensive blood pressure lowering treatments can help people with high blood pressure who are at high risk, because of other cardiovascular conditions, kidney disease, or diabetes.

The authors suggest that intensive treatment to lower blood pressure could be considered even for high-risk people with systolic blood pressure lower than 140 mm Hg, i.e. within normally acceptable thresholds. This move would change recent higher target levels back to those that existed before 2011. This evidence supports the recommendations of current UK guidelines and could be considered in updates to some international guidelines, but given that it is hard to continue with lifelong medications, measures to increase compliance with medication will also be important.

Lower is better: blood pressure targets for high-risk people with diabetes or kidney disease

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Why was this study needed?

In 2013, over 3.2 million adults were diagnosed with diabetes, with prevalence rates of around 6 to 7% in England and Wales. For people with chronic kidney disease it has been estimated that about 7,000 excess strokes and 12,000 excess heart attacks occurred in the 2009–10, relative to a similar population without chronic kidney disease. The cost to the NHS of excess strokes and heart attacks in people suffering chronic kidney disease is estimated at £174 to £178 million. Each month, the NHS spends about £13 million on close to six million prescription items (drugs) for hypertension and heart failure in English primary care.

In the last decade clinical guidelines in several countries, but not the UK, have raised target blood pressure levels for treatment of people with high blood pressure who also have other cardiovascular conditions, kidney disease, or diabetes. Current US and European guidelines recommend target blood pressure levels of 140/90 or 150/90 mm Hg for older people. However, research has shown that about half of the disease burden linked to high blood pressure occurs in people with systolic blood pressure lower than 140 mm Hg. In this context, it is important to assess the efficacy and safety of additional blood pressure lowering in high-risk people. This study was undertaken to update a 2012 systematic review and to resolve the uncertainty whether more or less blood pressure lowering is required in high-risk patients.

What did this study do?

This was a systematic review of randomised controlled trials that had investigated the effectiveness of more intensive versus less intensive blood pressure-lowering treatments for reduction of major cardiovascular events such as stroke or heart attack, end-stage kidney disease or death.

This review and meta-analysis included 19 trials involving almost 45,000 people. All reported on all-cause death, while 14 of them reported major cardiovascular events (defined as heart attack, stroke, heart failure, or death from heart disease or stroke), and eight studies reported end-stage kidney disease. Five of the included studies recruited only people with diabetes, and six studies included people with chronic kidney disease. The blood pressure targets varied across the studies.

Standard systematic review methods were used with a search for published and unpublished studies. The results were combined in several meta-analyses.

What did it find?

  • Patients receiving more intensive blood pressure-lowering treatment had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group.
  • The results from 14 trials including over 43,000 people showed that more intensive blood pressure-lowering treatments reduced the risk of major cardiovascular events by 14% compared with less intensive treatments (relative risk [RR] 0.86, 95% confidence interval [CI] 0.78 to 0.96).
  • The reductions in strokes were proportionately more pronounced. Results of 14 studies showed 22% reduction in risk of stroke for more intensive therapy compared with less intensive treatments (RR 0.78, 95% CI 0.68 to 0.90).
  • The analysis showed no clear effect of more intensive blood pressure-lowering therapy on the risk of death compared with less intensive blood pressure control (RR 0.91, 95% CI 0.81 to 1.03). There was no clear effect for the risk of end-stage kidney disease or diabetes-related conditions (retinopathy or progression to microalbuminuria).
  • Adverse effects associated with more intensive treatment were not reported consistently in all trials. Serious adverse events occurred at a rate of 1.2% per year for intensive therapy compared with 0.9% for less intensive treatment which was not statistically significant (RR 1.35, 95% CI 0.93 to 1.97).
  • Severe hypotension was more frequent in the more intensive treatment regimen (RR 2.68, 95% CI 1.21 to 5.89), but the excess numbers with severe hypotension in the intensive treatment group was small, 1 per thousand compared to 3 per 1000 per person-year for the duration of follow-up.

What does current guidance say on this issue?

The 2011 NICE guidance on high blood pressure in adults recommends treatment with drugs or life style modifications and a target below 140/90 mm Hg in people aged under 80 years. The recommended target for people aged 80 years and over is below 150/90 mmHg. However this guideline excludes certain high-risk groups of people, for example people with diabetes, who are covered in other guidelines.

The 2015 NICE guidance on type 2 diabetes recommends a target blood pressure below 130/80 mm Hg if there is kidney, eye or cerebrovascular damage. The 2014 NICE guidance for people with chronic kidney disease recommends to keep the systolic blood pressure below 130 mm Hg (target range 120–129 mm Hg) if diabetes is also present.

The 2007 SIGN guideline recommends a lower blood pressure target of <130/80 mm Hg for people with established cardiovascular disease and diabetes, chronic renal disease or target organ damage.

What are the implications?

This updated systematic review and meta-analysis provided clear evidence that more intensive blood pressure lowering treatments are beneficial for people at high risk because of diabetes, kidney disease or other vascular disease. This evidence is likely to be considered in any revision to current US and European guidelines. Current UK guidelines for people with diabetes and chronic kidney disease recommend lower blood pressure targets compared with the targets for people with no high-risk conditions. It would be helpful if there was international consistency in blood pressure standards and targets, and this study may start that discussion.

The cost of prescriptions and cost effectiveness were not examined in this study. More complex is how patients might be guided to balance the long term benefit against the small short term increase in risk of severe low blood pressure, and what measures might be possible to improve compliance with treatment.

Bibliography

Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2015. [Epub ahead of print].

Lv J, Neal B, Ehteshami P, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: a systematic review and meta-analysis. PLoS Med. 2012;9(8):e1001293.

NHS Choices. High blood pressure (hypertension). London: Department of Health; 2014.

NICE. Chronic kidney disease in adults: assessment and management. [CG 182] London: National Institute for Health and Care Excellence; 2014.

NICE. Hypertension in adults: diagnosis and management. [CG127] London: National Institute for Health and Care Excellence; 2011.

NICE. Type 2 diabetes in adults: management. [NG28] London: National Institute for Health and Care Excellence; 2015.

OpenPrescribing.net, Powell-Smith A, Goldacre B.  2.5: Hypertension and Heart Failure.  Oxford: OpenPrescribing.net; 2015.

SIGN. Risk estimation and the prevention of cardiovascular disease. Guideline No. 97. Edinburgh: Scottish Intercollegiate Guidelines Network (SIGN); 2007.

Why was this study needed?

In 2013, over 3.2 million adults were diagnosed with diabetes, with prevalence rates of around 6 to 7% in England and Wales. For people with chronic kidney disease it has been estimated that about 7,000 excess strokes and 12,000 excess heart attacks occurred in the 2009–10, relative to a similar population without chronic kidney disease. The cost to the NHS of excess strokes and heart attacks in people suffering chronic kidney disease is estimated at £174 to £178 million. Each month, the NHS spends about £13 million on close to six million prescription items (drugs) for hypertension and heart failure in English primary care.

In the last decade clinical guidelines in several countries, but not the UK, have raised target blood pressure levels for treatment of people with high blood pressure who also have other cardiovascular conditions, kidney disease, or diabetes. Current US and European guidelines recommend target blood pressure levels of 140/90 or 150/90 mm Hg for older people. However, research has shown that about half of the disease burden linked to high blood pressure occurs in people with systolic blood pressure lower than 140 mm Hg. In this context, it is important to assess the efficacy and safety of additional blood pressure lowering in high-risk people. This study was undertaken to update a 2012 systematic review and to resolve the uncertainty whether more or less blood pressure lowering is required in high-risk patients.

What did this study do?

This was a systematic review of randomised controlled trials that had investigated the effectiveness of more intensive versus less intensive blood pressure-lowering treatments for reduction of major cardiovascular events such as stroke or heart attack, end-stage kidney disease or death.

This review and meta-analysis included 19 trials involving almost 45,000 people. All reported on all-cause death, while 14 of them reported major cardiovascular events (defined as heart attack, stroke, heart failure, or death from heart disease or stroke), and eight studies reported end-stage kidney disease. Five of the included studies recruited only people with diabetes, and six studies included people with chronic kidney disease. The blood pressure targets varied across the studies.

Standard systematic review methods were used with a search for published and unpublished studies. The results were combined in several meta-analyses.

What did it find?

  • Patients receiving more intensive blood pressure-lowering treatment had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group.
  • The results from 14 trials including over 43,000 people showed that more intensive blood pressure-lowering treatments reduced the risk of major cardiovascular events by 14% compared with less intensive treatments (relative risk [RR] 0.86, 95% confidence interval [CI] 0.78 to 0.96).
  • The reductions in strokes were proportionately more pronounced. Results of 14 studies showed 22% reduction in risk of stroke for more intensive therapy compared with less intensive treatments (RR 0.78, 95% CI 0.68 to 0.90).
  • The analysis showed no clear effect of more intensive blood pressure-lowering therapy on the risk of death compared with less intensive blood pressure control (RR 0.91, 95% CI 0.81 to 1.03). There was no clear effect for the risk of end-stage kidney disease or diabetes-related conditions (retinopathy or progression to microalbuminuria).
  • Adverse effects associated with more intensive treatment were not reported consistently in all trials. Serious adverse events occurred at a rate of 1.2% per year for intensive therapy compared with 0.9% for less intensive treatment which was not statistically significant (RR 1.35, 95% CI 0.93 to 1.97).
  • Severe hypotension was more frequent in the more intensive treatment regimen (RR 2.68, 95% CI 1.21 to 5.89), but the excess numbers with severe hypotension in the intensive treatment group was small, 1 per thousand compared to 3 per 1000 per person-year for the duration of follow-up.

What does current guidance say on this issue?

The 2011 NICE guidance on high blood pressure in adults recommends treatment with drugs or life style modifications and a target below 140/90 mm Hg in people aged under 80 years. The recommended target for people aged 80 years and over is below 150/90 mmHg. However this guideline excludes certain high-risk groups of people, for example people with diabetes, who are covered in other guidelines.

The 2015 NICE guidance on type 2 diabetes recommends a target blood pressure below 130/80 mm Hg if there is kidney, eye or cerebrovascular damage. The 2014 NICE guidance for people with chronic kidney disease recommends to keep the systolic blood pressure below 130 mm Hg (target range 120–129 mm Hg) if diabetes is also present.

The 2007 SIGN guideline recommends a lower blood pressure target of <130/80 mm Hg for people with established cardiovascular disease and diabetes, chronic renal disease or target organ damage.

What are the implications?

This updated systematic review and meta-analysis provided clear evidence that more intensive blood pressure lowering treatments are beneficial for people at high risk because of diabetes, kidney disease or other vascular disease. This evidence is likely to be considered in any revision to current US and European guidelines. Current UK guidelines for people with diabetes and chronic kidney disease recommend lower blood pressure targets compared with the targets for people with no high-risk conditions. It would be helpful if there was international consistency in blood pressure standards and targets, and this study may start that discussion.

The cost of prescriptions and cost effectiveness were not examined in this study. More complex is how patients might be guided to balance the long term benefit against the small short term increase in risk of severe low blood pressure, and what measures might be possible to improve compliance with treatment.

Bibliography

Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2015. [Epub ahead of print].

Lv J, Neal B, Ehteshami P, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: a systematic review and meta-analysis. PLoS Med. 2012;9(8):e1001293.

NHS Choices. High blood pressure (hypertension). London: Department of Health; 2014.

NICE. Chronic kidney disease in adults: assessment and management. [CG 182] London: National Institute for Health and Care Excellence; 2014.

NICE. Hypertension in adults: diagnosis and management. [CG127] London: National Institute for Health and Care Excellence; 2011.

NICE. Type 2 diabetes in adults: management. [NG28] London: National Institute for Health and Care Excellence; 2015.

OpenPrescribing.net, Powell-Smith A, Goldacre B.  2.5: Hypertension and Heart Failure.  Oxford: OpenPrescribing.net; 2015.

SIGN. Risk estimation and the prevention of cardiovascular disease. Guideline No. 97. Edinburgh: Scottish Intercollegiate Guidelines Network (SIGN); 2007.

Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis

Published on 13 November 2015

Xie, X.,Atkins, E.,Lv, J.,Bennett, A.,Neal, B.,Ninomiya, T.,Woodward, M.,MacMahon, S.,Turnbull, F.,Hillis, G. S.,Chalmers, J.,Mant, J.,Salam, A.,Rahimi, K.,Perkovic, V.,Rodgers, A.

Lancet , 2015

BACKGROUND: Recent hypertension guidelines have reversed previous recommendations for lower blood pressure targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies. METHODS: For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled trials with at least 6 months' follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes. FINDINGS: We identified 19 trials including 44 989 participants, in whom 2496 major cardiovascular events were recorded during a mean 3.8 years of follow-up (range 1.0-8.4 years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4-22]), myocardial infarction (13% [0-24]), stroke (22% [10-32]), albuminuria (10% [3-16]), and retinopathy progression (19% [0-34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI -11 to 34]), cardiovascular death (9% [-11 to 26]), total mortality (9% [-3 to 19]), or end-stage kidney disease (10% [-6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1.2% per year in intensive blood pressure-lowering group participants, compared with 0.9% in the less intensive treatment group (RR 1.35 [95% CI 0.93-1.97]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2.68 [1.21-5.89], p=0.015), but the absolute excess was small (0.3% vs 0.1% per person-year for the duration of follow-up). INTERPRETATION: Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large. FUNDING: National Health and Medical Research Council of Australia.

Blood pressure is measured in millimetres of mercury (mm Hg) and is recorded as two figures:  systolic pressure (the pressure of the blood when the heart beats to pump blood out) and diastolic pressure (the pressure of the blood when the heart rests in between beats, which reflects how strongly the arteries are resisting blood flow).

Expert commentary

Many international guidelines are currently re-evaluating the definition of the ideal blood pressure target for the management of hypertension. This meta-analysis of large treatment trials in high-risk patients (with previous cardiovascular disease, renal disease or diabetes) shows that a more intensive blood pressure lowering (target 133/76 mm Hg) provides greater vascular protection (both in relative and absolute risk reductions) than less intensive management (target 140/81 mm Hg). The relative risk of severe adverse events is slightly greater during more intensive treatment but the absolute excess was small. This review is in keeping with recent evidence that systolic blood pressure lowering below 130 mmHg significantly reduces vascular risk across various baseline blood pressure levels and comorbidities (Ettehad et al. 2015).

The key questions are: is more intensive blood pressure control cost-effective?  How could we achieve lower targets?  How to maintain good blood pressure control?

Currently, the British Hypertension Society (BHS) PATHWAY trials of 2015 have identified additional effective combinations for managing higher risk patients. At the same time a significant barrier to achieving lower targets is the lack of adherence to prescribed therapy, the frequency of adverse drug reactions and the lack of implementations of non-pharmacological manoeuvres like weight loss and reductions in salt consumption. The BHS is right now reviewing and updating its Guideline for the Management of Patients with High Blood Pressure. Whilst we should re-examine such guidelines, it is also crucial to invest in further studies to help improve achievement and adherence of good blood pressure control for our UK patients.

Francesco Cappuccio, Professor of Cardiovascular Medicine and Epidemiology, University of Warwick and Vice-President, British Hypertension Society

Dr Adrian Brady, Associate Professor and Consultant Cardiologist, University of Glasgow and President, British Hypertension Society

Categories

  •   Cardiovascular system disorders, Renal and urogenital disorders, Stroke