By focusing on blood pressure variability in addition to mean systolic BP a UK researcher may have found an important clue to solving some of the most important lingering mysteries in understanding and treating hypertension. With the extraordinary simultaneous publication of three papers in the Lancet and one in Lancet Neurology, Peter Rothwell has cut to the front of the line and appears to have placed hypertension variability as a top priority for further research.
In one of the publications, a review article in the Lancet, Rothwell acknowledges that “increased mean blood pressure is an important cause of arterial disease” but points out that “the usual blood-pressure hypothesis is inconsistent with much of the epidemiology of hypertension and stroke, and its clinical application is questionable in patients with variable blood pressure.”
In a second article in the Lancet, Rothwell and colleagues found that BP variability and maximum blood pressure were strong predictors of stroke, independent of mean systolic BP, in patients in the UK-TIA trial and three validation cohorts. Further, BP variability was a strong predictor of both stroke and coronary events in ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm).
In a third Lancet article, Rothwell and colleagues found that BP variability explained the previously “unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke.” In a meta-analysis that included 389 trials, the researchers found that calcium channel blockers and loop diuretics reduced BP variability while beta-blockers, ACE inhibitors, and ARBs increased BP variability.
In their article in Lancet Neurology, Rothwell et al use data from ASCOT-BPLA and the MRC (Medical Research Council) trial to explain previous observations that calcium channel blockers reduced the risk of stroke “more than expected on the basis of mean blood pressure alone” and that beta blockers “are less effective than expected.” The authors demonstrate that “the opposite effects of calcium-channel blockers and β blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure.”
Although Rothwell et al acknowledge that much work remains to be done, they write that there are some “immediate implications for the diagnosis and management of hypertension, choice of drug, design and reporting of trials, and drug development.” One implication is that physicians should no longer ignore isolated high blood pressure readings.
Rothwell doesn’t recommend abandoning traditional assessment of mean BP; instead he proposes measuring BP variability as a valuable addition to traditional measurements.
Rothwell also acknowledges that their results “do not prove a causal link between variability in blood pressure (or maximum SBP) and stroke,” but they suggest a number of plausible mechanisms. The review article also contains a long list of “testable predictions stemming from the hypotheses” of Rothwell.
Finally, the papers are accompanied by a comment by Bo Carlberg and Lars Hjalmar Lindholm. They generally praise the 4 papers but say it is too early for hypertension guidelines to be modified based on these findings. Additional light on this topic will be shed, they report, when the Blood Pressure Lowering Treatment Trialists’ Collaboration analyzes patient-level data on more than 200,000 subjects “to establish precisely the relation between visit-to-visit blood-pressure variability and major cardiovascular events.”
Here is the Lancet press release:
Rethinking guidelines for treating high blood pressure: variability is a risk factor too
Hypertension is the most prevalent treatable risk factor for stroke. One in two adults are affected by it, and the risk of being hypertensive during a lifetime is about 90%. Despite this, the underlying mechanisms by which raised blood pressure can cause cardiovascular disease are poorly understood. Clinical guidelines for the diagnosis and treatment of hypertension focus heavily on mean systolic blood pressure. However, in this collection of papers in The Lancet (two Articles and a Review) and The Lancet Neurology (an Article), Peter Rothwell, at the Stroke Prevention Research Unit, John Radcliffe Hospital, Oxford, UK, and colleagues suggest that variability in blood pressure could also have some prognostic value. “The hypothesis that has come to dominate is that we each have an underlying average “true” blood pressure, which is difficult to measure precisely, but which accounts for the vast majority of the complications of hypertension, and explains the benefits of blood-pressure-lowering drugs. Variability in blood pressure is dismissed as uninformative and “random”, only noteworthy as an obstacle in the measurement of the true underlying blood pressure,” says Rothwell.
In one Article, a cohort study, Rothwell’s team found that visit-to-visit variability of systolic blood pressure was a strong predictor of stroke, heart failure, angina, and myocardial infarction, independent of mean blood pressure. By contrast with assumptions in current guidelines that patients with only occasional high readings (“episodic hypertension”) do not require treatment, they show that such patients have a high risk of stroke and other complications. In this study, they investigated variability in blood pressure and maximum blood pressure in four cohorts with previous transient ischaemic attack (each cohort had more than 2000 patients). In one cohort, the researchers also looked at whether residual variability after treatment for hypertension would be a predictor of stroke.
They found that patients with the most variation in systolic blood pressure over seven clinic visits were six times more likely to have a stroke. Patients with the highest blood pressure over seven visits were 15 times more likely to have a stroke. Rothwell says that: “Persistent hypertension is a major cause of vascular disease and must be treated appropriately, but episodic hypertension is at least as common in routine practice and should no longer be ignored. We have shown that episodic hypertension is just as risky, and that patients and their doctors shouldn’t be reassured by the fact that blood pressure is sometimes normal.”
In a separate Article, a meta-analysis of 389 randomised controlled trials comparing the effects of blood-pressure-lowering drugs, Rothwell and other colleagues showed that drug-class effects on variability in blood pressure explain differences between these drugs in their efficacy in preventing stroke, and they introduce the idea of blood-pressure stabilising drugs. “Compared with other drug classes, calcium-channel blockers and non-loop diuretic drugs reduced interindividual variation in systolic blood pressure, whereas ACE inhibitors, angiotensin-2-receptor blockers, and β blockers increased it, with calcium-channel blockers reducing interindividual variation the most versus placebo,” say the authors.
In an Article in The Lancet Neurology, Rothwell and colleagues investigate why calcium-channel blockers reduce the risk of stroke more than expected on the basis of mean blood pressure alone, and why β blockers are less efficacious than expected. The researchers analysed the results of two large trials (one comparing amlodipine with atenolol in 19 257 patients with hypertension and other vascular risk factors, and one comparing atenolol and diuretics versus placebo in 4396 hypertensive patients aged 65–74 years). The authors say “The opposite effects of calcium-channel blockers and β blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure.”
In a Review, Rothwell “discusses shortcomings of the usual blood-pressure hypothesis, provides background to accompanying reports on the importance of blood-pressure 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.”
In a Comment in The Lancet on all the papers, Dr Bo Carlberg and Dr Lars Hjalmar Lindholm, Department of Public Health and Clinical Medicine, Umeå University Hospital, Sweden say: “Importantly, Rothwell and co-workers do not question the importance of mean blood pressure; rather, they make a strong argument for also measuring blood-pressure variability because it supplements blood pressure very well as a risk factor.”
They add: “further study of the relation of blood-pressure variability to the risk of different types of stroke (eg, cardioembolic, large-vessel disease, and small-vessel disease, etc) is important.”
Carlberg and Lindholm conclude: “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 every day practice in which patients often receive several different drugs, often changing over a short time. The notion presented by Rothwell and co-workers today is, however, challenging and will raise many questions. Researchers with data from population-based cohorts or randomised trials are likely to investigate whether Rothwell’s findings can be replicated, taking other risk factors into account.”