“Swings in blood pressure ‘could better predict stroke than average high readings’” reported The Daily Telegraph. The paper reported that “variations in people’s blood pressure rather than the average level predicts stroke most powerfully”.

The news story was based on a collection of studies published in The Lancet. The authors have  presented a compelling argument that fluctuations in blood pressure may help to predict the risk of vascular events such as stroke.

As mentioned in an accompanying editorial published in the same journal, it is important to point out that the authors are not questioning the validity of using average blood pressure to predict risk, but are suggesting that variable blood pressure could also be used as a supplementary indicator of increased risk.

At this stage, further evidence needs to be presented that fluctuating blood pressure can be used in this way before guidelines on identifying cardiac risk would be updated. Patients should not stop taking their blood pressure medication, but should consult their GP if they have any queries regarding it.

Where did the story come from?

The story is based on a collection of papers published in The Lancet and The Lancet Neurology, both peer-reviewed medical journals. The papers were written by Professor Peter Rothwell from the Stroke Prevention Research Unit at the John Radcliffe Hospital, Oxford, and colleagues from institutions in England, Ireland and Sweden. Funding was provided by several institutions and organisations, including the UK Medical Research Council, the National Institute for Health Research and Pfizer.

What kind of research was this?

The collection of papers includes a cohort study, a separate systematic review and meta analysis, and a narrative review in The Lancet, and an article in The Lancet Neurology. All papers looked at the relationship between blood pressure and the risk of vascular disease such as stroke.

Professor Rothwell says that high blood pressure is the most prevalent treatable risk factor for vascular events such as stroke, but how blood pressure causes the damage that leads to such vascular events is poorly understood. Most clinical guidelines base their advised courses of action on the risks of vascular events according to a person’s stable (usual) blood pressure. The stable blood pressure reading would be calculated as the average of measurements taken at the doctor’s surgery over a number of visits.

In this review, the professor puts forward the theory that fluctuations in blood pressure, rather than maintained high blood pressure readings, may be a more accurate prediction of the risk of vascular events.

What did the research involve?

The review covered the following areas:

• Whether there is likely to be variability in blood pressure measurements between an individual’s visits to the doctors. If there is high variability, an average measurement may not give a complete picture of the patient’s blood pressure status throughout time, and risk statistics for stroke calculated using average values may be affected.
• If drugs used to treat hypertension (high blood pressure) and the risk of vascular events also have an effect of reducing fluctuations in blood pressure.
• Particular attention was paid to the risk of stroke and its relationship to blood pressure. The author looked at studies where patients had their blood pressure monitored for 24 hours, and that had assessed the risk of stroke.

Professor Rothwell provides some background to these issues and discusses them in some detail. He mentions one study showing that 69% of people who had previously experienced a stroke had episodic (every now and again) hypertension, whereas 12% had stable hypertension as consistently demonstrated over a 24-hour period.

He reviews several epidemiological studies looking at how estimated stable blood pressure can predict the risk of vascular events. The author discusses how fluctuations in blood pressure may play a role in this. He notes that some epidemiological evidence appears to support this, including the fact that there appears to be an increase in strokes mid-morning, which matches the daily pattern of blood pressure variation, and that other reasons for increases in transient blood pressure are also risk factors for stroke.

The author says that risk calculations of stroke are based on the usual blood pressure measurement based on the average of measurements taken on multiple visits to the doctor. He argues that as there can be large variations in readings between visits, any risk predictions based on average readings alone may not reflect the whole picture.

In his review, Professor Rothwell also looks at trials examining the effect of calcium channel blockers (for reducing blood pressure variability) compared with other blood pressure lowering drugs such as angiotensin-converting enzyme inhibitors or beta-blockers, which have differing modes of action. He notes that all the drugs lowered patients’ blood pressure to the same extent, but the calcium channel blockers lowered the risk of stroke compared with the other drugs.

The cohort study by Professor Rothwell and his colleagues reappraised data from previous cohort studies to assess whether variations in blood pressure were a better predictor of stroke outcome than an averaged measurement of blood pressure. The first part of this review assessed the risk of stroke in relation to visit-to-visit variability in blood pressure in people who had experienced a previous stroke. For this, they used data from the UK-TIA aspirin trial and three similar cohort studies. The second part of the review used data from the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (which involved 24-hour blood pressure monitoring) to assess the effect of blood pressure variability in people treated for hypertension. The researchers found that visit-to-visit variation in blood pressure was a strong predictor of subsequent stroke, and this was independent of the average of all of the patients’ measurements. They also found that the maximum blood pressure measure recorded was also a strong predictor of stroke. They found that in studies where patients’ blood pressure was measured continually over 24 hours, the variation measured in this short period was also a weak predictor of stroke, and was most predictive in younger patients.

A separate systematic review and meta analysis of trials looked at the effects of different classes of blood pressure lowering drugs in preventing stroke. Those trials included took multiple measures of blood pressure at baseline and during follow-up, rather than just quoting a single average measure. The meta analysis found that, compared with other drugs - such as angiotensin-converting enzyme (ACE) inhibitors - there was 19% lower variation in participants’ blood pressure measurements when patients were taking calcium channel blockers and 13% less variation in patients receiving non-loop diuretic drugs.

How did the researchers interpret the results?

Professor Rothwell concludes that increased mean blood pressure is an important cause of arterial disease, but variability and instability in blood pressure also have important roles in the progression of organ damage and the likelihood of vascular events such as stroke. He suggests that variability in blood pressure measurements should be routinely reported in trials looking at the role of high blood pressure on stroke, and that more research is needed to quantify variability and instability of blood pressure in routine practice.

Conclusion

Professor Rothwell has presented a compelling argument in support of his theory that fluctuations in blood pressure may help to predict the risk of vascular events such as stroke.

As mentioned in an accompanying editorial, it is important to point out that Professor Rothwell is not questioning the validity of using average blood pressure to predict risk, but is advocating also using variable blood pressure as a supplementary indicator of increased risk.

As with all narrative reviews the research methods that the author used to identify evidence to support his theories are not definitively laid out. It is therefore not possible to carry out a full appraisal of this evidence. However, the systematic appraisal of data on blood pressure and stroke is a robust and standardised way of appraising all of the available data in a research area.

At this stage, further evidence needs to be presented that fluctuating blood pressure can be used in this way before guidelines on identifying cardiac risk would be updated. This research does not affect patients who are currently taking blood pressure lowering medications. Patients should not stop taking their blood pressure medication, but should consult their GP if they have any queries regarding it.

Currently NICE recommendations on the treatment of hypertension should be followed and drug therapy offered to those who:

• have persistent (measurement on >2 occasions) high blood pressure of 160/100 mmHg or more
• are at raised cardiovascular risk (10-year risk of cardiovascular disease (CVD) of 20% or more, or existing CVD or target organ damage) with persistent blood pressure of more than 140/90 mmHg

Links To The Headlines

Blood pressure fluctuations 'warning sign for stroke'. BBC News, March 12 2010

Swings in blood pressure 'could better predict stroke than high average readings'. The Daily Telegraph, March 12 2010

Blood pressure variations key indicator of stroke risk, research says. The Guardian, March 12 2010

Links To Science

Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. The Lancet 2010, 375: 895 - 905

Webb AJS, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. The Lancet 2010, 375: 906 - 915

Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. The Lancet 2010; 375: 938 - 948

Carlberg B, Hjalmar Lindholm L. Stroke and blood-pressure variation: new permutations on an old theme. The Lancet Neurology 2010; 375l: 867 – 869

Rothwell PM, Howard SC, et al. Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. The Lancet Neurology 2010

“Women who use the Pill can expect to live longer,” according to The Times. The news is based on research looking at the long-term effects of taking the contraceptive pill.

From 1968 to 2007 the study followed 46,000 women that had either used or never used oral contraceptives, comparing their mortality rates. The four decades of data showed that there was a small decrease in the mortality rates of women who had taken the Pill, as well as a small decrease in the overall risk of developing cancer.

This study has shown that the Pill is not associated with long-term health risks and also presents some associations between taking the Pill and decreased cancer risk. However, the study has some limitations in that it did not look at other lifestyle factors, such as diet and exercise, that can affect health. It also failed to adjust for some medical factors that may have a bearing on Pill use and mortality risk.

This study followed women who had taken the earliest forms of the Pill. Its results are not directly applicable to modern pills, which differ in hormone composition.

Where did the story come from?

Professor Philip Hannaford and colleagues from the University of Aberdeen carried out this research. The study was funded by the Royal College of General Practitioners, the Medical Research Council, the British Heart Foundation, the Cruden Foundatio, and several pharmaceutical companies including Schering Healthcare, Wyeth Ayerst International, Ortho Cilag and Searle. The study was published in the peer-reviewed British Medical Journal.

Many media outlets correctly highlighted that the women in this study had taken the Pill approximately 20 to 40 years ago and that the composition of contraceptive pills available then may differ from those used today. They also highlighted that the decreased relative mortality rates were quite small and that the important message from this research was that there was not a long-term increase in death rates following the use of contraceptive pills.

The Times quoted from the study that younger women were at slightly higher risk of suffering heart attack, stroke or breast cancers while taking the Pill. This research study did not provide evidence for risk of these particular diseases, although its sub-analyses did reveal there to be a greater risk of overall mortality in Pill users recruited to the study at a young age (below 30). The reasons for these differences are unclear and need to be investigated further.

What kind of research was this?

This was a cohort study that looked at whether taking the contraceptive pill had any effect on mortality risk.

The Royal College of General Practitioners Oral Contraception Study is a continuing investigation into the health effects of contraceptive pills. The study has been following women who have used the Pill since 1968. In its early days, the Pill was reported to be associated with increased risks of mortality; however, the researchers note that further studies suggest that oral-contraceptive use is associated with a reduced overall risk of cancer. This study aimed to assess the risks over a period of several decades, and to see how these risks altered if women stopped taking the Pill.

What did the research involve?

In 1968 approximately 23,000 women who were using the oral contraceptive pill were recruited through 1,400 GP surgeries. These women were termed the “ever users”. The researchers recruited a similar number of women who had never taken the Pill, classed as the “never-users”. All of the women were married or living as married. Most were white and their average age at recruitment was 29.

At this time, information about whether they had children, whether they smoked, their medical history and their social class (based on their husband’s occupation) were recorded. Every six months the women’s GPs supplied information about any prescriptions for the Pill, any pregnancies and any illnesses or deaths that had occurred.

The women were monitored until one of the following occurred:

• they left the area of the recruiting doctor
• their doctor left the study
• they obtained the Pill from a source other than their GP
• follow-up by GP practices ended, which eventually happened in 1996

Medical records were also flagged so that data on cancer or death would be gathered on women who dropped out of the study and after GP follow-up had ended. These flagged records were examined up until 2007.

The researchers analysed two different datasets. The first contained all of the information up until 1996 (when the GP follow-up ended), while the second also included data from the flagged records followed until 2007.

In total, 46,112 women were followed up. As women were followed for different lengths of time, the researchers analysed the data in terms of a measure called “women years”: the number of women in a group multiplied by the number of years that they each participated in the study. The full study up to 2007 contained more than 819,000 women years for women who had ever used the Pill, and 378,000 women years for women who had never taken the Pill. The GP follow-up only study had 343,000 women years for “ever” users, and 237,000 for “never” users.

What were the basic results?

In the full study up to 2007, the risk of death due to any cause was lower in the women who had ever taken the Pill compared with women who had never used it. The relative risks were adjusted to account for the influence of age, smoking, social class and whether the women had had children.

The researchers found a 15% lowered risk of any cancer in ever users than in never users (Relative Risk 0.85, 95% Confidence Interval 0.78 to 0.93). Ever users also had a decreased risk of cancers of the large bowel and rectum, uterus and ovaries. Ever users were also found to have a higher rate of accidental violent death (Relative Risk 1.49 95% Confidence Interval 1.09 to 2.05).

Age seemed to play a large role in the risk of death due to any cause. In women who were under 30 at the time of recruitment, the relative risk of death was three times greater in ever users compared with never users; however, if the women were over 50 at the time of recruitment, the rate of death was lower in ever compared to never users.

Analysis of the smaller dataset of GP follow-up data showed no difference between never or ever users of the Pill in terms of overall mortality or cancer.

The average length of time that women took the Pill in this study was 44 months. The length of time taking the Pill did not affect the risk of death.

How did the researchers interpret the results?

The researchers concluded that “oral contraception was not associated with an increased long-term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral-contraception usage and background risk of disease”.

Conclusion

This study followed a large number of women who had taken the contraceptive pill over 39 years. It showed that there was a small decrease in mortality rates for women who had ever used the Pill compared to those who had never used it.

However, there are several things to consider when interpreting these results, many of which the researchers highlight:

• Medical diseases and risk factors may have differed between the two groups of women but were not adjusted for in the analyses.
• A lack of adjustment for medical history may have influenced the results as the oral contraceptive pill is not suitable for all women as a number of medical factors make taking the Pill undesirable or unsafe, including a history of vascular disease (e.g. deep vein thrombosis, DVT), past strokes or mini-strokes, heart disease and liver disease. Other women with risk factors for these diseases may only be cautiously considered for the Pill. On this basis, medical reasons may potentially have confounded any increase in mortality in the “never used” group.
• Equally, “ever use” of the Pill in this cohort was associated with an overall decreased risk of death from any circulatory diseases. However, it is unclear whether differences in cardiovascular diseases or disease risk were already present at the time decisions were being made to prescribe the Pill.

There are a number of other points to consider when interpreting this research:

• Although the analysis adjusted for whether the women smoked, the smoking data was not routinely updated throughout the study. Using only the information about smoking collected at the start of the study may have underestimated the effects of smoking.
• Other lifestyle factors such as diet and exercise were not measured. This may have affected the outcome of the study.
• There are many different formulations available, but the study did not assess whether the risk of death differed according to hormonal content of the contraceptive pill used. In the early 1970s there were few oral contraceptive pills available compared to the numerous brands there are today. The hormone content of the early contraceptive pills is likely to differ from those taken today, principally in that the oestrogen concentration in today’s tablets is often lower, and today’s combined pills contains the hormones oestrogen and progestegen rather than oestrogen alone.
• The women in the cohort were all married and mostly white, so these results may not be applicable to other ethnicities and society as a whole.
• The researchers’ subanalyses did reveal there to be a greater risk of overall mortality in pill-users recruited to the study at a young age (below 30). The reasons for these apparent differences in risk according to age need to be further investigated.
• Although the overall risk of cancer was less in ever users, the specific cancers that did demonstrate an association with Pill use had relatively small case numbers (e.g. 19 cases of uterine cancer in the Pill group compared to 13 in the never used group). There is a high possibility that calculated differences between such small numbers have occurred by chance. Further research is needed to see whether there is a direct causal link between hormone treatments such as the Pill and cancer risk and the mechanism behind it.
• As the authors say, there has been a substantial loss of subjects during follow-up, and their full dataset represents only two-thirds of their potential cohort.

Overall, this study demonstrates that use of the contraceptive pill is not associated with increased long-term mortality rates, as early research may have suggested. 

Links To The Headlines

Women on pill 'may live longer'. BBC News, March 11 2010

Girls who take pill live longer. The Mirror,  March 11 2010

Is the Pill saving lives? Women who use it 'cut their chances of dying of cancer and heart disease'. Daily Mail, March 11 2010

The pill is given health all-clear. The Independent, March 11 2010

Women who use the Pill can expect to live longer, Royal College of GPs finds. The Times, March 11 2010

Taking the pill can prolong women's lives. Metro, March 11 2010

The pill cuts risk of serious illness. Daily Express, March 11 2010

Taking the Pill 'could help women live longer'. The Daily Telegraph, March 11 2010

Links To Science

Hannaford PC, Iversen L, Macfarlane TV, et al. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study. BMJ 2010; 340: c927

“Having a massage is no better at beating stress than home relaxation techniques like breathing deeply and listening to soothing music,” reports The Daily Telegraph. It said that while all methods can ease anxiety, simple relaxation at home costs nothing and can be just as effect an expensive massage or thermotherapy (using a heat-based treatment) session.

This news is based on a trial on the effectiveness of therapeutic massage in treating generalised anxiety disorder (GAD), compared to thermotherapy or relaxation room therapy. After 12 weeks, anxiety scores improved in all three groups.

But this was a very small trial with limitations. So it is likely that the findings are due to chance only. There is no suggestion that these treatments are alternatives to medical drugs or psychotherapies. Nor can it be inferred that similar results would be seen in people without GAD or that the treatments would get similar scores on other scales of mental wellbeing.

Overall, the findings of this small trial indicate that any of these three therapies may help people with GAD, but not in place of prescribed drug treatments or psychotherapies.

Where did the story come from?

The research was carried out by Dr Karen J. Sherman and colleagues from the University of Washington. The study was funded by the National Center for Complementary and Alternative Medicine. The paper was published in the (peer-reviewed) medical journal Depression and Anxiety.

Generally, the newspaper accurately reflected the findings of the study, but it did not discuss its limitations, including the fact that the results are only directly applicable to people with diagnosed generalised anxiety disorder.

What kind of research was this?

This randomised controlled trial investigated the effectiveness of therapeutic massage for treating generalised anxiety disorder (GAD) and compared it to other forms of relaxation.

This kind of trial is the best way of assessing the efficacy of a treatment. There needs to be adequate numbers of people in each of the treatment arms to detect differences between the groups, and the trial should preferably follow people for an adequate amount of time to determine the short and longer-term effects of treatment.

What did the research involve?

This was a three arm, randomised trial conducted at Group Health, an integrated healthcare system with about 600,000 members from the Washington and Idaho states in the US. From these members, the researchers identified people who met recognised diagnostic criteria for GAD. Participants were identified through telephone canvassing, electronic records, mailed questionnaires and face-to-face interviews.

The researchers excluded anyone with other mental health disorders or medical disorders that may have affected their participation in the trial. This left 68 people who met recognised diagnostic criteria for GAD. Some participants were taking antidepressant or anti-anxiety medications, and some were seeing mental health professionals.

Participants were randomised to therapeutic massage (23 people), thermotherapy (22), or relaxing room therapy (23) for 10 one-hour sessions over 12 weeks. All treatments were performed by licensed therapists in a softly lit room with nature sounds or relaxing music being played at a low volume. Therapeutic massage involved ‘releases’ of specific body regions or muscle groups, Swedish massage techniques and deep breathing instruction. Thermotherapy involved the use of customised warm and cool contrast treatments, while the control group simply relaxed comfortably in the same relaxation room and had no therapist interaction.

The main outcome was a reduction in anxiety on a recognised clinical scale (Hamilton Anxiety Rating Scale, HARS), measured immediately after treatment and six weeks later.

What were the basic results?

Follow-up rates were 94% at six weeks and 85% at 12 weeks, with similar numbers of people across groups. All groups had improved anxiety scores at the end of treatment (an average 10-13 point improvement on HARS), and these improvements were maintained at six weeks. All three groups had the same success rate in reducing anxiety. There were also improvements on the secondary outcome of symptom reduction.

How did the researchers interpret the results?

The researchers conclude that massage was not superior to thermotherapy or relaxation room therapy, and all gave clinically important improvements for people with generalized anxiety disorder.  They say that as simple relaxation room therapy is substantially less expensive than the other treatments, a similar treatment package may be the most cost-effective option for people with GAD who wish to try relaxation-orientated therapy.

Conclusion

This trial carefully recruited people with diagnosed GAD with the aim of comparing three different relaxation techniques over a period of 12 weeks. However, it has a number of important limitations:

• There were relatively few participants in each of the three groups. With such small numbers, there is a stronger chance that the findings are due to chance only.
• Participants could not be blinded to the fact that they were receiving relaxation treatment. Simply by receiving some form of relaxation therapy over 12 weeks may have helped people to feel less anxious. As the researchers admit, a ‘no treatment’ group who received no form of therapy of at all would have addressed some of this uncertainty.
• This was a specific group of people with diagnosed GAD, a considerable number of whom were taking medications for their anxiety. The effect of the treatments were measured using a clinical score for rating anxiety. As such, it cannot be inferred that similar results would be seen in people without GAD or that the treatments would get similar scores on other scales of mental wellbeing.
• Massage and thermotherapy were both carried out by qualified professionals. The effects of the techniques used here may not be directly transferable to other forms of these therapies. Additionally, the control of simple relaxation was performed in a controlled environment in the therapy centre, which may give slightly different results compared to the person trying to relax at home. The participant is entering an environment geared towards their comfort and relaxation, free of the many distractions of home.
• This finding does not suggest that these therapies are an alternative to formal treatments such as medication or psychotherapies.

As the researchers conclude, the findings of this small trial indicate that these three therapies may help people with GAD, but would not replace prescribed drug treatment or psychotherapies. Further research needs to establish whether the relaxation therapies are as effective as each other.

Links To The Headlines

Massage no better at beating stress than deep breathing and soft music. The Daily Telegraph, March 11 2010

Links To Science

Sherman KJ, Ludman EJ, Cook AJ, et al. Effectiveness of therapeutic massage for generalized anxiety disorder: a randomized controlled trial. Depression and anxiety 2010