Five papers published in the Lancet and Lancet Neurology focus on the variability in blood pressure (BP) and the effects on cardiovascular and stroke risk. Readers with a more in depth interest in the management of hypertension are advised to view the complete papers (subscription required) for more detailed information.

In the first paper, the authors carried out a cohort study to establish the prognostic significance of visit-to-visit variability in blood pressure, maximum blood pressure reached, untreated episodic hypertension, and residual variability in treated patients. They studied a large cohort of patients with previous transient ischaemic attack (TIA) from the UK-TIA aspirin trial with validation in three similar cohorts and a broad population of patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA). In ASCOT-BPLA, the authors also measured the prognostic value of short-term variability during individual visits and on 24-h ambulatory blood-pressure monitoring (ABPM). The results indicated that visit-to-visit variability in systolic BP (SBP) is a strong predictor of stroke and coronary events independent of mean SBP, that maximum SBP is more predictive than is mean SBP (on clinic readings or on ABPM), that residual variability in SBP on treatment has a poor prognosis, and that stable hypertension has a better prognosis than does episodic hypertension.

The authors add that their findings “Have immediate implications for the diagnosis and management of hypertension, choice of drug, design and reporting of trials, and drug development. Briefly, patients with episodic hypertension should no longer be excluded from trials of antihypertensive drugs; increased residual variability in SBP in treated patients has a poor prognosis, despite greater use of add-on drugs; and stabilisation of blood pressure should be regarded as a potentially important target in the development of new agents and new combinations of drugs. Furthermore, in secondary prevention after TIA or stroke, for which rates of treatment with antihypertensive drugs are low in routine clinical practice despite good evidence of benefit, the high risk of stroke in patients with episodic hypertension draws attention to the false reassurance of a few normal blood-pressure readings.”

The second paper is presented as a systematic review and meta-analysis of seven randomised trials which investigates whether unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intra-individual variability in BP. The authors identified RCTs from published systematic reviews and extracted baseline and follow-up data for mean (SD) of SBP from the trial reports. The effect of treatment on inter-individual variance in blood pressure, expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis. Overall, mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. The results found:

• Compared with other drugs, inter-individual variation in SBP was reduced by calcium-channel blockers (CCBs; VR 0.81, 95% CI 0.76–0.86, p<0.0001) and non-loop diuretic drugs (0.87, 0.79–0.96, p=0.007), and increased by angiotensin-converting enzyme inhibitors (ACEi;1.08, 1.02–1.15, p=0.008), angiotensin-receptor blockers (ARBs; 1.16, 1.07–1.25, p=0.0002), and beta-blockers (BB; 1.17, 1.07–1.28, p=0.0007).
• Compared with placebo only, inter-individual variation in SBP was reduced the most by CCBs (0.76, 0.67–0.85, p<0.0001).

The authors conclude, “Our results provide strong evidence to support the hypothesis that differences in risk of stroke due to different classes of antihypertensive drugs are due to effects on intra-individual variability in blood pressure.”

The 3rd study (published in Lancet Neurology), investigated whether the effects of BBs and CCBs on variability in blood pressure in the ASCOT-BPLA and the Medical Research Council (MRC) trial could explain the unexpected effects of treatment on stroke risk. The ASCOT-BPLA trial compared amlodipine-based regimens with atenolol-based regimens and the MRC trial compared atenolol-based and diuretic-based regimens versus placebo. The authors found that atenolol-based treatment and amlodipine-based treatment had opposite effects on within-individual variability in blood pressure (within-visit, visit-to-visit, and ABPM), independently of their effects on mean BP. The results reported include (from source):

• In ASCOT-BPLA, group SBP SD was lower in the amlodipine group than in the atenolol group at all follow-up visits (p<0•0001), mainly because of lower within-individual visit-to-visit variability.
• Analysis of changes from baseline showed that variability decreased over time in the amlodipine group and increased in the atenolol group.
• The authors note that the lower risk of stroke in the amlodipine group (hazard ratio 0.78, 95% CI 0.67–0.90) was partly attenuated by adjusting for mean SBP during follow-up (0.84, 0.72–0.98), but was abolished by also adjusting for within-individual SD of clinic SBP (0.99, 0.85–1.16).
• In the MRC trial, group SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo group and the diuretic group during initial follow-up (all p<0.0001). Temporal trends in variability in the atenolol group (probably caused by add-on use of thiazides and nifedipine) were associated with stroke risk.

The authors conclude that the opposite effects of CCBs and BBs on variability of BP account for the disparity in observed effects on risk of stroke and expected effects based on mean BP. They add that to prevent stroke most effectively, BP-lowering drugs should reduce mean BP without increasing variability; ideally they should reduce both. The authors write, “ We have shown that effects of specific agents on within-individual variability of blood pressure can explain differences in clinical efficacy, consistent with the findings in the accompanying systematic review of all published data on group distributions of blood pressure during follow-up in trials of blood-pressure-lowering drugs. Data on blood pressure during follow-up should be reported in more detail in future trials, and stabilisation of blood pressure is a potentially important target for drug development and combination therapy. New drugs or combinations of drugs that reduce variability even more effectively than calcium-channel blockers could have a great effect on risk of stroke.”

The 4th paper is a review article in which the author (involved in all the studies above) proposes that current hypertension guidelines are too simplistic as they assume that cardiovascular risk is related to average (usual) blood pressure values. He suggests that consideration of blood pressure variability should be taken into account. The author discusses shortcomings of the usual BP hypothesis, provides background to accompanying reports on the importance of BP variability in prediction of risk of vascular events and in accounting for benefits of antihypertensive drugs, and draws attention to clinical implications and directions for future research.

The final paper is a Comment article in which the authors discuss the findings of the studies and their strengths and weaknesses. They write, “So, should indications for starting or escalating treatment of hypertension be updated, taking into account episodic high blood pressure? Not quite yet, because results from clinical trials with standardised recordings and treatment care are difficult to translate into everyday practice in which patients often receive several different drugs that can change over a short time. The notion presented is, however, challenging and will raise many questions. Researchers with data from population-based cohorts or randomised trials are likely to investigate whether the findings can be replicated, taking other risk factors into account.”

The National Institute for Health and Clinical Excellence has announced that in light of this new research, the guidelines on the management of hypertension will be reviewed, and expects to issue its updated hypertension guidance in August 2011

NHS Choices has also featured a discussion of these studies – please see link below.