Variability in blood pressure is a predictor of stroke

Variability in blood pressure is a predictor of stroke continued

Visit-to-visit variability and maximum systolic BP

Clinical trials examining reductions in BP have tended to rely on mean values, but a recent series of papers published in the Lancet has investigated whether there may be other reasons for the various treatment effects observed and if they can be related to the types of drugs used in the trials.⁶ Rothwell et al (2010) studied two cohorts of patients, from the UK Transient Ischaemic Attack (UK-TIA) trial and the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial.⁶

UK-TIA
The UK-TIA was a double-blind randomised trial, which was conducted between 1979 and 1985. It compared two doses of aspirin (1200 mg and 300 mg) with placebo in 2435 patients who had experienced a recent TIA or ischaemic stroke.⁷ Analysis of the UK-TIA cohort determined that:⁶

• visit-to-visit variability in SBP was a strong predictor of subsequent stroke (top-decile hazard ratio [HR] for SBP over seven visits 6.22; 95% confidence interval [CI] 4.16–9.29, p<0.0001) independent of mean SBP
• the maximum SBP reached was also a strong predictor of stroke (top decile HR over seven visits 15.01; 95% CI 6.56–34.38, p<0.0001) after adjustment for mean SBP.

ASCOT-BPLA
The ASCOT-BPLA study published in 2005, which recruited 19,257 patients, showed that a combination of amlodipine plus the ACE inhibitor, perindopril, was significantly more effective at reducing strokes (327 versus 422) than the use of the beta blocker, atenolol, in combination with bendroflumethiazide (unadjusted HR 0.77; 95% CI 0.66–0.89, p=0.0003).^1,8 Analysis of data from the ASCOT-BPLA study demonstrated that:⁶

• residual visit-to-visit variability in SBP on treatment was a strong predictor of stroke and coronary events (top-decile HR for stroke 3.25; 95% CI 2.32–4.54, p<0.0001) independent of mean SBP in clinic or ambulatory blood pressure monitoring (ABPM).

Influence of variability in SBP
The conclusions from this cohort study were that:⁶

• visit-to-visit variability in SBP is a powerful predictor of stroke and coronary events and is independent of mean SBP
• maximum SBP is more predictive of stroke than mean SBP
• patients receiving treatment for hypertension who have residual variability in SBP have a poor prognosis
• stable hypertension has a better prognosis than episodic hypertension
• visit-to-visit variability in SBP was unrelated to the white-coat effect.

Rothwell et al also indicated that the lower event rate in the ASCOT-BPLA study in the amlodipine group compared with the atenolol group could not be explained by changes in mean BP or other risk factors, but can be attributed to the reduced visit-to-visit variability in SBP.⁶

The findings from the Rothwell study do not prove a causal link between variability in BP or maximum SBP and stroke. Further work is needed to identify measures that would combine the prognostic information associated with visit-to-visit variability in BP in routine clinical practice.⁶

Effect of drug classes on BP variability and risk of stroke

The results of a meta-analysis investigating the effectiveness of different classes of antihypertensive drugs that included data for BP follow up in 682 treatment groups from almost 400 eligible trials are shown in Table 1.⁹ Calcium-channel blockers reduced variability in SBP to the largest degree when compared with placebo (HR 0.76; 95% CI 0.67–0.85, p<0.0001).⁹ The study concluded that the class effect of these drug therapies on variation in BP can account for the differing effect on the risk of stroke independently of the effect on mean SBP.⁹

Table 1: Effect of blood-pressure lowering drugs on variability in SBP9
Drug treatment	Effect on variability of SBP	Variation ratio (95% confidence interval)	p value
Calcium-channel blockers	↓	0.81 (0.76–0.86)	0.0001
Non-loop diuretic drugs	↓	0.87 (0.79–0.96)	0.0007
ACE-inhibitors	↑	1.08 (1.02–1.15)	0.0080
Angiotensin II receptor blockers	↑	1.16 (1.07–1.25)	0.0002
Beta blockers	↑	1.17 (1.07–1.28)	0.0007
SBP=systolic blood pressure; ACE=angiotensin-converting enzyme

Variability in blood pressure is a predictor of stroke continued

Importance of variability in BP

A further review by Rothwell discusses what he sees on the basis of these results as the shortcomings of the usual approach to managing raised BP and what it may mean for clinical practice.¹⁰ The review highlights that:¹⁰

• patients with only episodic hypertension—which is often left untreated—are at high risk of vascular events
• residual visit-to-visit variability in BP on treatment has poor prognosis despite good control of mean BP
• the benefits of some anti-hypertensive drugs are partly due to reduced variability in BP.

Epidemiological evidence demonstrates that mean BP is a very strong risk factor for vascular events, but other parameters may also be important. White-coat hypertension with high BP in the clinic, but normal at home or on ABPM was thought to be benign, but long-term follow up suggests an association with target organ damage independent of mean BP.¹⁰ Visit-to-visit variability in office BP is not due to white-coat effect and no relationship was correlated in ASCOT-BPLA.¹⁰ However, white-coat hypertension may be a precursor of sustained hypertension and may be associated with an increased cardiovascular disease risk.⁴

Rothwell suggests that the cohort study of UK-TIA and ASCOT-BPLA, and the meta-analysis of the effects of different drug classes may provide the first trial evidence that benefits of antihypertensive drugs are determined by effects on variability of BP, as well as on mean BP. There is an implication that the patient with normal mean BP, but increased variability and episodic hypertension may benefit from antihypertensive drugs. Patients with episodic hypertension will benefit most from drugs such as CCBs that reduce the variability in BP. Patients receiving treatment for hypertension who have variable SBP despite good compliance and good control of mean SBP will also benefit from the addition of a drug that will reduce variability.

The Rothwell review concludes that variability and instability in BP have important roles in progression of organ damage and triggering vascular events, but that further research is needed. In the meantime the authors believe we should be aware of the prognostic implications of visit-to-visit variability in BP and the related drug class effects.

Beta blockers and CCBs: effect on BP variability and risk of stroke

A paper published in Lancet Neurology, which analysed data from two cohort studies, ASCOT-BPLA and the Medical Research Council (MRC) trial, has added to the evidence by showing that the link between variability in BP and the risk of stroke may be causal.¹¹ In the MRC trial, 4396 patients with hypertension aged 65–74 years were assigned atenolol 50 mg daily or 25 mg hydrochlorothiazide plus 2.5 mg amiloride (the diuretic-based regimen), or placebo.¹²

Systolic blood pressure, DBP, and pulse pressure within individual visit-to-visit variability were expressed as the standard deviation and coefficient of variation of readings taken over multiple follow-up visits.¹³ Central to the study was the hypothesis that usual traditional measuring of BP may not be an adequate marker of stroke, whereas visit-to-visit variability in SBP might be a more powerful predictor of stroke independent of mean SBP.¹³ In ASCOT-BPLA, SBP was lower in the amlodipine group than in the atenolol group (p<0.001) because of lower visit-to-visit variability; this variability decreased with time in the amlodipine group and increased in the atenolol group. In the MRC trial, atenolol increased visit-to-visit variability in SBP compared with the placebo and the diuretic combination.¹¹

The interpretation of the results are that CCBs reduce stroke risk to a greater extent and beta blockers to a lesser extent than expected based on the effects on BP lowering because of their individual effects on variability.¹¹

Conclusion

What does this mean for our patients who have a raised BP reading or who are receiving treatment for hypertension? In response to these papers the British Hypertension Society has advised that every person’s BP is variable and more work is required to define an acceptable level of variability.¹⁴ It is possible that in time we may have to change our approach: this may include the increased use of home BP monitoring or ambulatory monitoring for those patients noted to have a high isolated reading and greater use of drugs that reduce variability.

The NICE A/CD algorithm acknowledges that not all drugs have the same effect and at present we should continue to use this guidance to prioritise treatment and to aim for best possible control of BP.³ For GPs who continue to prescribe beta blockers for uncomplicated raised blood pressure despite the NICE guidance, this is an opportunity to consider that approach unless there is compelling indication for their use such as angina or left ventricular systolic function.

References

1. Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease. SIGN 97. Edinburgh: SIGN, 2007. Available at: www.sign.ac.uk
2. British Cardiac Society, British Hypertension Society, Diabetes UK et al. JBS2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005: 91 (Supplement V): v1–v52.
3. National Institute for Health and Clinical Excellence. Hypertension: Management of hypertension in adults in primary care (partial update). Clinical Guideline 34. London: NICE, 2006. Available at: guidance.nice.org.uk/CG34
4. Williams B, Poulter N, Brown M et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004—BHS IV. J Hum Hypertens 2004; 18 (3): 139–185. Available at: www.bhsoc.org/Latest_BHS_management_Guidelines.stm
5. Julius S, Kjeldsen S, Weber M et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363 (9426): 2022–2031.
6. Rothwell P, Howard S, Dolan E et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375 (9718): 895–905.
7. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54 (12): 1044–1054.
8. Dahlöf B, Sever P, Poulter N et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366 (9489): 895–906.
9. Webb A, Fischer U, Mehta Z. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375 (9718): 906–915.
10. Rothwell P. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010; 375 (9718): 938–948.
11. Rothwell P, Howard S, Dolan E et al. Trial investigators effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010 March ¹¹. [Epub ahead of print].
12. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304 (6824): 405–412.
13. Gorelick P. Reducing blood pressure variability to prevent stroke? Lancet Neurol 2010; March 12. [Epub ahead of print].
14. British Hypertension Society statement on blood pressure variability. Variability of blood pressure. March 2010. Available at: www.bhsoc.org/G

Dr Alan Begg
Chair of the SIGN Stable Angina Guideline Development Group, Member of the SIGN CHD Steering Group