NHS Choices

People with gout have lower risk of Alzheimer’s disease

NHS Choices - Behind the Headlines - Thu, 05/03/2015 - 11:00

"Gout could help prevent Alzheimer's, research shows," The Independent reports. Researchers think that uric acid, which causes gout, may have a protective effect against Alzheimer's disease.

Uric acid is a waste product that is normally passed out of the body. In cases of gout, the acid builds up around one or more joints, forming tiny crystals. This can then trigger the symptoms of gout, which are typically a sudden severe pain and swelling around the affected joint(s).

Previous research has found that uric acid is also an antioxidant (which helps to protect against cell damage), so researchers wanted to see if uric acid protected against Alzheimer’s.

The researchers used information from a UK database of more than 3.7 million patients. They matched people aged over 40 who developed gout with controls who did not, and followed them, on average, for five years to see how many were diagnosed with Alzheimer’s disease. They took multiple factors into account when analysing the results, such as medication use and age.

They found that 309 out of the 59,224 people with gout (0.5%) developed Alzheimer’s disease, compared to 1,942 out of 238,805 people without gout (0.8%), which translates into a 24% reduction in risk.

The study does not prove that gout is protective against Alzheimer’s, as there could be unmeasured factors that affected the results.

 

Where did the story come from?

The study was carried out by researchers from Boston University School of Medicine, Harvard Medical School, Harvard School of Public Health, and the University of British Columbia. It was funded by these institutes and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

The study was published in the peer-reviewed medical journal Annals of the Rheumatic Diseases.

In general, the media reported the story accurately, though did not discuss the limitations of this type of study – that it can look for associations, but not prove cause and effect. The Independent helpfully provided expert opinion from Dr Laura Phipps from Alzheimer’s Research UK, who is reported to have said: "while this work does suggest a positive impact of gout on brain health, many of the risk factors related to gout, including obesity and diabetes, are also linked to increased dementia risk. Current evidence suggests that the best ways to maintain a healthy brain are to keep a healthy weight, exercise regularly, not smoke, eat a balanced diet, drink in moderation, and keep blood pressure and cholesterol in check."

 

What kind of research was this?

This was a case-controlled cohort study, which aimed to see if people with gout were less likely to develop Alzheimer’s disease.

Gout is a type of arthritis that most commonly affects the big toe, causing swelling and inflammation. It is due to a build-up of uric acid crystals in the blood. Uric acid is a breakdown product of purines, which are in all cells in the body and consumed in the diet, especially in beer, seafood, oily fish and liver.

However, uric acid is also an antioxidant and has previously been thought to protect against some neurodegenerative conditions, such as Parkinson’s disease and dementia. The researchers wanted to specifically see if higher levels of uric acid were associated with a reduced risk of Alzheimer’s disease.

This is an appropriate style of study to assess any link between higher levels of uric acid (people with gout) and risk of Alzheimer’s disease. Deliberately giving people an intervention to increase uric acid levels would be unethical, as this could lead to painful symptoms and joint damage.

 

What did the research involve?

The researchers compared the incidence of Alzheimer’s disease in people with and without a new diagnosis of gout during the study period.

The researchers used data from the Health Improvement Network database, which holds medical records from 580 GP practices in the UK. All the data is anonymised, so no personal data was provided to researchers.

The study period started in 1995 and the data for more than 3.7 million people aged 40 or more with no history of gout or dementia were eligible to be included in the study. When someone then had a diagnosis of gout, they entered the study. Five people of the same age and body mass index (BMI) who did not have gout entered the study at the same time, to act as controls. The researchers then followed these people up to 2013, comparing the incidence of Alzheimer’s disease between the two groups.

They took the following potential confounding factors into account when analysing the results:

  • age and sex
  • history of ischaemic heart disease, stroke, hypertension, hyperlipidaemia and diabetes
  • BMI
  • smoking status
  • alcohol consumption
  • social deprivation
  • use of cardiovascular medication
  • use of non-steroidal anti-inflammatory drugs (NSAIDs)

They repeated the process for people who developed osteoarthritis as a control, to see if the process was robust, as there has been no previous link between these diseases. 

 

What were the basic results?

There was a 24% reduced risk of developing Alzheimer’s for people with gout compared to those without, after adjusting for the potential confounders listed above (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.62 to 0.87).

Alzheimer’s disease occurred in:

  • 309 out of the 59,224 people with gout (0.5%)
  • 1,942 of the 238,805 people without gout (0.8%)

The average age was 65 in both groups and 71% were male. They were followed up for an average of five years.

There was no association between osteoarthritis and Alzheimer’s disease.

 

How did the researchers interpret the results?

The researchers concluded that their "findings provide the first population-based evidence for the potential protective effect of gout on the risk of AD [Alzheimer’s disease] and support the purported neuroprotective role of uric acid." They say that "if confirmed by future studies, a therapeutic investigation that has been employed to prevent progression of PD [Parkinson’s disease] may be warranted".

 

Conclusion

This population-based study has found that people with gout had a 24% reduced risk of developing Alzheimer’s disease. It was a well-designed study, in that there were large numbers of people in each group and multiple potential confounding factors were taken into account. The validation of the study was also valuable in showing the expected lack of a link between osteoarthritis and Alzheimer’s disease.

However, there are some limitations with this type of study, with a major one being that it cannot prove cause and effect. While some potential confounding factors were accounted for in the statistical analysis, there could be others which influenced the results.

The study participants were followed for an average of five years, so there will be a number of cases of early Alzheimer’s disease that would not have been picked up or fully diagnosed.

Gout was used as a proxy for increased levels of uric acid. However, gout is an inflammatory type of arthritis and some people only have one attack, or attacks that are spread out over a number of years. Therefore, it is not clear that a high level of uric acid caused the results seen.

It is not advisable that you try to increase your levels of uric acid through your diet, as this could increase your risk of developing gout, which is a very painful condition. The best way to reduce the risk of Alzheimer’s and other types of dementia are all the usual suspects: stop smoking, drink alcohol within recommended limits, be physically active, eat a balanced diet, reduce weight if you are overweight or obese, and keep blood pressure and cholesterol down.

Read more about reducing your dementia risk

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Gout could help prevent Alzheimer's, research shows. The Independent, March 4 2015

Gout sufferers 'have less chance of developing Alzheimer's': Sufferers risk of developing condition is reduced by quarter. Mail Online, March 5 2015

Gout sufferers are a quarter less likely to develop Alzheimer's. Daily Mirror, March 4 2015

Links To Science

Lu N, Dubreuil M, Zhang Y, et al. Gout and the risk of Alzheimer's disease: a population-based, BMI-matched cohort study. Annals of the Rheumatic Diseases. Published online March 4 2015

Categories: NHS Choices

Gene testing could find those who would benefit most from statins

NHS Choices - Behind the Headlines - Wed, 04/03/2015 - 13:00

"Patients with the highest genetic risk of suffering a heart attack benefit the most from cholesterol-lowering statin drugs," The Guardian reports.

Statins are drugs that lower cholesterol and can help reduce the risk of coronary heart disease (CHD) developing – the leading cause of death both in the UK and worldwide.

Researchers studied genetic risk factors previously discovered for CHD in 48,421 adults, and used them to group people into low, intermediate and high risk categories. They next looked at the effect of statins on reducing new and recurring CHD "events" such as heart attacks. Compared with not taking them, statins reduced CHD events by 13% in the low-risk group, 29% in the intermediate group and 48% in the high-risk group.

Current UK recommendations are that people should be offered statins if there is at least a one in 10 chance of them developing CHD at some point in the next 10 years.

Critics of these recommendations argue that this means they are given to people who don’t really need them, which could waste money and subject people unnecessarily to the possible side effects of statins.

The work carried out in this study could improve the ability to assess who is at high risk.

The findings need to be confirmed by other research, but suggest that genetic risk factor categories could be used, alongside other risk factors, to identify groups who may benefit most from statins.

 

Where did the story come from?

The study was carried out by academic and medical research institutions in the US and Sweden, and was funded by the National Institutes of Health and a large number of public and private sources. The study used data from existing trials that were supported by drugs companies, as well as public research councils. 

Many of the authors have received funding, such as research grants, from drugs companies. Due to the nature of the research, this is not surprising. A study of this size and scale, involving so many researchers, would be near-impossible to carry out without any industry involvement. 

A detailed list of these declarations of interest was given in the publication. The publication stated: "For this analysis, the funders of the individual clinical trials had no role in the analysis or interpretation of the data, or writing of the report."

The study was published in the peer-reviewed medical journal The Lancet.

Generally, The Guardian reported the story accurately, but linked the risk reduction figures solely to heart attacks. The figures actually referred to a mixed group of CHD events. Most of them were fatal or non-fatal heart attacks, but it also included some cases of unstable angina, heart bypasses, or other heart interventions. This isn’t a big issue, but something to be aware of.

What kind of research was this?

This was a mixed method study looking at whether genetic risk factors can predict CHD, and if these might be used to identify people who would get the most benefit from using statins.

CHD is the leading cause of death both in the UK and worldwide.

It's responsible for around 73,000 deaths in the UK each year. About one in six men and one in 10 women die from CHD.

In the UK, there are an estimated 2.3 million people living with the condition and around 2 million people affected by angina – the most common symptom of CHD. Read more about the symptoms of CHD.

Genetic variations in DNA have been linked to higher risk of CHD in previous research. In this new study, they tested whether or not a combination of these variants could predict the risk of new or recurrent CHD events, and whether this could identify people who get the most benefit from statin therapy.

 

What did the research involve?

The researchers analysed data from four randomised controlled trials (RCTs) and one cohort study, to look at the link between genetic risk factors and CHD events. They then looked at the relative risk and absolute risk reductions in CHD through using statins, stratified across the different genetic risk groups.

The studies included were a Swedish community-based cohort study (the Malmo Diet and Cancer Study) and four RCTs. Two of the RCTs looked at the ability of statins or anti-hypertension medication to prevent cardiovascular disease (CVD) compared with placebo (JUPITER and ASCOT). The other two recruited people with a history of CVD and assessed statin therapy to prevent recurrences (CARE and PROVE IT-TIMI 22).

The researchers studied the association of a genetic risk score based on 27 genetic variants with new or recurrent CHD, which had been identified in previous studies. Risk scores were used to group people into low, intermediate and high-risk categories.

This provided results for 48,421 individuals, with 3,477 CHD events for the final analyses.

Results were pooled in a meta-analysis, which adjusted for traditional CHD risk factors:

  • age
  • sex
  • diabetes status
  • smoking
  • race (if applicable)
  • family history of coronary heart disease
  • HDL cholesterol
  • LDL cholesterol
  • hypertension

Definitions of CHD differed across the studies, so they used CHD events as the main outcome.

This covered:

 

What were the basic results?

Higher genetic risk scores were associated with a higher risk of CHD, independent of the known risk factors.

The main findings combined all four studies and outcomes for new and recurring CHD events. Compared with the lowest-risk group, those in the intermediate-risk category were 34% more likely to have a CHD event (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.22 to 1.47). Those in the high-risk group were 73% more likely (HR 1.72, 95% CI 1.55 to 1.92) to have a CHD event.

This was confirmation that the genetic grouping was potentially useful in signalling the risk of a CHD event.

The next results were on how effective statins were across the genetic risk groups. Compared with not taking them, statins reduced CHD events by 13% in the low-risk group, 29% in the intermediate group and 48% in the high-risk group.

Focussing on the JUPITER primary prevention trial, the number of people needed to take statins to prevent one CHD event in 10 years was 66 in the low-risk group, 42 for intermediate risk and 25 for the highest-risk.

The corresponding figures in the ASCOT cohort were 57 low, 47 intermediate and 20 high.

Across all four studies, there were statistically significant reductions in relative and absolute risk reduction using statins, with higher-risk groups benefiting more.

 

How did the researchers interpret the results?

The authors said: "When combined into a 27-variant risk score, our multivariable-adjusted analyses showed that these variants could identify people at increased risk of CHD events, including incident CHD in primary prevention populations and recurrent CHD events in secondary prevention populations.

"Furthermore, when compared with people at low genetic risk, those with the highest genetic risk scores derived greater relative risk reduction and absolute risk reduction with statin therapy. Notably, in the primary prevention trials, we found a roughly threefold difference between the low and high genetic risk score groups in the number needed to treat to prevent one CHD event.

Dr Nathan Stitziel, from Washington University, in the US, who co-led the research, was quoted in the Guardian as saying: "We need more research to confirm these results. Regardless, we can say that patients with a high genetic risk score appear to benefit more from statin therapy, because they’re starting at a higher baseline risk, even controlling for all the clinical measures we routinely examine."

 

Conclusion

This study showed how a genetic risk factor score can categorise people into groups at low, intermediate and high risk of having a CHD event, like a heart attack. They found that statins helped all the groups reduce their risk of a CHD event, but helped those with the higher risks more.

The genetic risk categories were tested in over 48,000 people, but the authors themselves acknowledge that more research is needed to confirm the findings.

That withstanding, this type of research has potentially interesting implications. It may, for example, help us to understand how different groups may or may not benefit from statins, and attempt to quantify this benefit. This has the potential to help optimise statin prescriptions, taking into account genetic factors, as well as other risk factors used now, like age, diabetes status, smoking, cholesterol levels and high blood pressure.

Knowing about genetic risk factors may not be necessary in all decisions regarding statins, but might help in some.

A final factor not discussed in the study is the issue of cost. Genetic sequencing is a lot cheaper than it was a decade ago, and costs are expected to continue to fall, but it may not be cost-effective to run gene tests on large sections of the population.

You can always reduce your need to take statins and reduce your risk of a CHD event by stopping smoking, eating healthily, being physically active, and keeping your blood pressure and cholesterol within normal limits.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Statins work for those at highest risk of heart attack – study. The Guardian, February March 4 2015

Links To Science

Mega JL, Stitzel NO, Smith JG, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. The Lancet. Published online March 4 2015

Categories: NHS Choices

Adults may only get 'real flu' every five years

NHS Choices - Behind the Headlines - Wed, 04/03/2015 - 11:30

"Average adult catches virus just once every five years," the Daily Mail reports.

A study has estimated that influenza infections become less frequent with age and occur every five years from the age of 30.

The study analysed blood samples from volunteers in southern China, looking at antibody levels against nine different strains of influenza that circulated from 1968 to 2009. Using complex mathematical models, researchers estimated the frequency of influenza infections and how immunity changes over a lifetime as people encounter different strains of the virus.

The "twice in a decade" figure may sound surprisingly low, but it is only an estimated average for influenza A. It does not include infections with strains of influenza B or C. Also, the estimate is based on a small sample of just 150 people with an age range from seven to 64. Results may well differ in other countries.

It is important not to be complacent as flu can be dangerous. Precise figures are hard to come by, as flu is often a factor in increasing the risk of fatal complications, rather than a cause of death. A 2013 study estimated that flu was implicated in around 13,000 elderly deaths in England and Wales during the flu season from 2008 to 2009.

Despite the doubts raised about the most recent flu jab, it is important to get vaccinated if you are vulnerable to the flu. Read more about who should get the flu jab.

 

Where did the story come from?

The study was carried out by researchers from the London School of Hygiene and Tropical Medicine, Imperial College London and University of Liverpool in the UK; Johns Hopkins Bloomberg School of Public Health in the US; the University of Hong Kong; and Shantou University and Guangzhou No 12 Hospital, in China.

It was funded by the Medical Research Council, the National Institute for Health Research and the Wellcome Trust in the UK; and Fogarty International Centre, the Department of Homeland Security and the National Institute for General Medical Sciences in the US. 

The study was published in the peer-reviewed journal PLOS Biology. This is an open-access journal so the study is free to read online.

This was a highly complex scientific paper (a sample quote – "Hence the titre μ was scaled by a factor s1(X, j) = (1 + τ1)|X"), so unsurprisingly, the media focused on the simple message that according to this study, flu is far less common than many people think. The Daily Mail also reported that "man flu" may be a myth, with no evidence that men are more likely than women to be "struck down" by the bug. The study itself does not look at rates of infection for each sex.

 

What kind of research was this?

In this study, scientists aimed to look at how our immunity to flu – specifically to influenza A strain (H3N2) – changes over a lifetime as we encounter different strains of the virus. It is important to understand this they say, because how the immune response develops influences the emergence of new strains of the virus, the size and severity of flu epidemics and the effectiveness of vaccination programmes. They say that factors that shape the human immune response are poorly understood, since individual infections and the development of immunity over a lifetime are rarely observed directly.

The immune system responds to flu viruses by producing antibodies that specifically target proteins on the virus surface. These proteins can change as the virus evolves, but we keep antibodies in the blood that have a memory for strains we have encountered before.

 

What did the research involve?

There were two parts to this study.

Scientists used data from a survey in southern China that examined people’s antibody levels against nine different strains of influenza A (H3N2) from 1968 to 2009. Participants were selected from five different locations, with 20 households randomly selected from each location. Samples of blood were taken and tested for the presence of antibodies against different strains of flu.

To determine the effect of a lifetime of influenza infections on immunity, scientists developed a mathematical model capturing the specific strains with which an individual has been infected and the corresponding antibody response. They examined whether this was affected by factors such as:

  • "cross-reactivity", increased immune response to a new strain due to previous antibody response to a different strain
  • "antigenic seniority" – whether strains encountered earlier in life provoked a stronger immune response

 

What were the basic results?

Their model found that "antigenic seniority" and the reduction in cross-reactivity over time were important components of the immune response. 

They estimate that while children on average get flu every other year, infections become less frequent as people get older. From the age of 30 onwards, they estimate that flu infections tend to occur at the rate of about two every 10 years.

 

How did the researchers interpret the results?

The researchers say that the strains encountered early in life and the order in which individuals were infected with the flu virus influence their immune response, which in turn could shape the evolution of the flu virus. These findings, they argue, could also help us better understand future susceptibility to new strains and develop future vaccination programmes.

 

Conclusion

This complex scientific study looked at which factors might influence the immune response to flu over someone’s lifetime and also produced an estimate of how frequently people in different age groups are affected by flu. The details are of interest mainly to other scientists involved in studying the flu virus, how it may evolve and the best way to protect ourselves against it.

When considering the results, it is important to note that these are estimates. They are based on blood samples from 150 people. This means there would have been a limited number of people in each age group, which spanned age seven to 64. In addition, the participants were selected from 20 households in each of five study locations in southern China. People living together are more likely to infect each other with the virus, and so the results may be different among other population groups.

The estimates are also based on nine strains that were originally recorded in 1968, 1975, 1979, 1989, 1995, 2002, 2003, 2005 and 2008. It does not cover other strains, influenza B or C, or whether the immune response was due to previous vaccination or infection.

Additionally, the researchers had to make a number of assumptions, which need to be taken into account when considering the results:

  • They estimated the number of times people had been infected by each strain by assuming each subsequent infection with the same strain of virus would boost the immune response.
  • They considered that the immune response to a new strain would not be as high as to previous strains, with the first-ever infection creating the biggest immune response.

It’s important to protect yourself from flu as much as possible and to get vaccinated if you are elderly or particularly vulnerable to complications.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Why your flu is probably just a cold: Average adult catches virus just once every five YEARS. Daily Mail, March 4 2015

Flu is much less common in adults than you might think. The Independent, March 3 2015

Adults get flu 'about once every five years'. BBC News, March 4 2015

Adults only get flu twice a decade, say scientists. The Daily Telegraph, March 3 2015

Links To Science

Kucharski AJ, Lessler J, Read JM, et al. Estimating the Life Course of Influenza A(H3N2) Antibody Responses from Cross-Sectional Data. PLOS Biology. Published online March 3 2015

Categories: NHS Choices

Coffee can 'cut risks of heart attack' claims

NHS Choices - Behind the Headlines - Tue, 03/03/2015 - 12:00

"Three coffees a day cuts the risk of heart disease and strokes," the Daily Mirror reports.

A large study of 25,000 adults from South Korea has found that people who drink between three and five cups of coffee per day were less likely to have the first signs of coronary heart disease.

This is a condition where atherosclerosis (hardening of the arteries) restricts the supply of blood to the heart. In some cases atherosclerosis can cause a blood clot to develop, which can trigger a heart attack.

The participants had a CT scan in which the level of calcium deposits in the coronary arteries was measured. Calcium deposits are one of the first signs of atherosclerosis.

They also completed a food frequency questionnaire to estimate their average food and drink consumption over the previous year.

People who drank between three and five cups of coffee were 19% less likely to have calcium deposits than people who did not drink coffee.

Despite media reports, as the study only looked at data from one point in time, it does not prove that drinking this amount of coffee each day is good for the heart.

 

Where did the story come from?

The study was carried out by researchers from Kangbuk Samsung Hospital in South Korea and there was no external funding.

The study was published in the peer-reviewed medical journal Heart.

In general, the UK media reported on the study accurately, but they did not explain that the only statistically significant result was for people drinking between three and five cups of coffee per day compared to those who do not drink coffee.

Also, the claim that the reduction in calcium deposits would help prevent heart attacks in later life, while arguably plausible, is unproven.

 

What kind of research was this?

This was a cross-sectional study that aimed to see if there was an association between coffee consumption and the early signs of heart disease. As it was a cross-sectional study it looked at data from one point in time. This means that it can only show an association, it cannot prove that coffee causes reduced levels of calcium to be deposited in the coronary arteries.

randomised controlled trial would ideally be required, though studies randomising people to food or drink items over a long period of time to look at cardiovascular outcomes would have serious feasibility issues; especially regarding compliance. For example, asking a seasoned "coffee addict" not to drink any coffee for the next 10 years probably won’t meet with much success.

 

What did the research involve?

The researchers used information from a large cohort of 30,485 adults who were taking part in the Kangbuk Samsung Health study, which is an ongoing cohort study organised out of a Korean hospital.

All participants had a full health screen and a CT scan of the heart between March 2011 and April 2013 to measure the level of calcium in the coronary arteries. This was taken as an early indicator of atherosclerosis, hardening of the arteries, which leads to heart disease.

A self-administered 103-item food frequency questionnaire was also completed. The participants were asked to estimate how often, on average, they consumed each type of food or drink in the previous year. This included coffee, but did not discriminate between caffeinated and decaffeinated. The researchers say that decaffeinated coffee is not widespread in South Korea.

The researchers then compared the level of coffee consumption with the amount of calcium in the coronary arteries. They adjusted their results to take into account the following confounders:

  • age
  • sex
  • educational level
  • physical activity level (inactive, minimally active or "health enhancing physically active")
  • smoking status
  • body mass index (BMI)
  • parental history of heart disease
  • alcohol consumption
  • total energy consumption
  • consumption of fruit and vegetables
  • consumption of red and processed meats
  • systolic blood pressure
  • fasting blood sugar
  • cholesterol and triglycerides (levels of fat in the blood)

People were excluded from the study if they already had a history of cardiovascular disease or incomplete information.

 

What were the basic results?

The final sample consisted of 25,138 adults. The average age was 41 years and 83.7% were male.

After adjusting the results for all the potential confounding factors listed above, compared to people who did not drink coffee:

  • people who drank between three and five cups of coffee were 19% less likely to have calcium in the coronary arteries (odds ratio (OR) 0.81, 95% confidence interval (CI) 0.66 to 0.98)
  • there were no statistically significant changes in risk for people who drank less than one cup, between one and three cups or five or more cups of coffee

 

How did the researchers interpret the results?

The researchers concluded that "moderate daily coffee consumption was associated with decreased prevalence of CAC [coronary artery calcium] in a large sample of [symptom-free] adults free of CVD".  They say that "further research is warranted to confirm our findings and establish the biological basis of coffee’s potential preventive effects on coronary artery disease".

 

Conclusion

This large cross-sectional study found that people who reported drinking between three to five cups of coffee per day in the previous year were less likely to have calcium deposits in the coronary arteries than people who did not drink coffee. There was no statistically significant difference for people consuming any other level of coffee compared to those who don’t drink coffee.

This type of study cannot prove that drinking this level of coffee stopped calcium being deposited in the arteries, an early sign of atherosclerosis (hardening of the arteries). It shows there is an association, but does not explain why.

Strengths of the study include the large sample size and extent to which potential confounding factors were taken into account. However, there are some limitations:

  • As with many attempts to collect data on dietary consumption, there is the potential for inaccurate estimates and recall bias.
  • Most of the participants were male, so the results may not be as robust for women.
  • It is not clear how applicable the results would be to the UK population as there may be many unmeasured features of the South Korean diet that could have affected the results. Indeed, South Korea has a lower cardiovascular disease death rate than the UK, though reasons for this are likely to be multifactorial.
  • None of the participants had any symptoms of cardiovascular disease. The study provides a snapshot of the level of calcium in their coronary arteries. It does not show how drinking coffee might affect these levels over time.

Though the results of this study are interesting and warrant further investigation, they do not prove that drinking three to five cups of coffee a day is good for the heart.

You can reduce your risk of heart disease by stopping smoking, eating healthily, being physically active, and keeping your blood pressure and cholesterol within normal limits, through lifestyle choices and use of medication, where required.

Read more about reducing your heart disease risk.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Three to five cups of coffee a day may prevent heart attacks, says study. The Guardian, March 3 2015

Regular coffee drinkers have 'cleaner' arteries. BBC News, March 3 2015

Drinking three to five cups of a coffee a day could reduce risk of heart attacks, study finds. The Independent, March 3 2015

Coffee Prevents Heart Attacks, Study Says. Sky News, March 3 2015

Three to five cups of coffee a day could reduce the risk of heart attack. The Daily Telegraph, March 3 2015

Links To Science

Choi Y, Chang Y, Ryu S, et al. Coffee consumption and coronary artery calcium in young and middle-aged asymptomatic adults. Heart. Published online March 2 2015

Categories: NHS Choices

Is long-term paracetamol use not as safe as we thought?

NHS Choices - Behind the Headlines - Tue, 03/03/2015 - 12:00

"Daily paracetamol could raise the risk of heart attacks, stroke and early death," the Mail Online reports.

A new review of previous observational studies found that long-term use of paracetamol was linked with a small increased risk of adverse events such as heart attacks, gastrointestinal bleeds (bleeding inside the digestive system) and impaired kidney function.

It is important to be aware that, as these are observational studies, there is the potential for various sources of bias. The studies were highly variable in their study populations. For example, four studies included female nurses, one male doctor, one person with kidney disease, and other adults prescribed paracetamol (i.e. they weren’t taking it over the counter). They also examined highly variable paracetamol exposures (e.g. days of use per month, grams intake in a lifetime, or number of prescriptions). Overall, this gives quite a mixed group of study designs and results, which may be influenced by many things, including inaccurate estimations of intake and significant health differences between users and non-users of paracetamol.

Nevertheless, the findings that paracetamol could potentially have adverse longer-term effects, particularly when used at higher doses, is important, especially as the drug is used by millions. Therefore, further investigation is needed.

 

Where did the story come from?

The study was carried out by researchers from the Maudsley Hospital, London; University of Leeds; Newcastle University; Keele University; and other UK institutions. The review was undertaken by the National Clinical Guidelines Centre, UK, and the authors report no conflict of interest.

The study was published in the peer-reviewed Annals of the Rheumatic Diseases, a British Medical Journal, on an open-access basis, so it is free to read online or download as a PDF.

Some of the UK’s media reporting is likely to cause needless alarm, particularly with figures such as the Mail’s "63% more likely to die suddenly" and claims that "risk of heart attack or stroke 68% higher". Such reporting takes a rather simplistic view of research that has included a highly variable mix of studies.

Ideally, the studies that have contributed different risk figures would benefit from being considered on an individual basis (i.e. taking into account their specific study designs and methods, and potential biases) rather than it simply being applied to the general population.

For example, the 63% figure for mortality accounted for adults prescribed paracetamol or ibuprofen in one particular study participant who had been receiving the highest number of repeat prescriptions for paracetamol, with the shortest gaps between prescriptions. The 68% risk figure for heart attacks was for US female nurses taking more than 15 paracetamol tablets a week.

 

What kind of research was this?

This was a systematic review of observational studies that aimed to look at the adverse effects of paracetamol.

As the researchers say, paracetamol is the most widely used over-the-counter and prescription painkiller worldwide, and is often the first painkiller taken for a wide variety of conditions. It is generally considered to be safer than other painkillers that may be considered in later steps on the "pain ladder", such as non-steroidal anti-inflammatory drugs (NSAIDs) or opiates. However, both health professionals and patients need to have up-to-date evidence on the possible harms of a drug, and recent estimates of the possible risks of paracetamol are not currently available. Therefore, this review aimed to address this gap.

A systematic review is the best way of gathering all the available studies that have addressed the effects of a particular treatment. However, the findings of the review are always going to be inherently limited by the underlying studies. The best way of looking at the benefits and harms of a treatment is a randomised controlled trial. However, it is not ethical to randomise a person to take, for example, a daily dose of paracetamol for a long period of time purely to look at its adverse effects.

When looking at adverse effects of a treatment in observational studies, there is always the possibility that results are being influenced by other factors, such as health differences between people who choose to take the treatment or not. This is known as channelling bias – people who are in poor health are more likely to be "channelled" on to a specific drug regime than people who are healthy.

 

What did the research involve?

The researchers searched two literature databases up to May 2013 to identify observational studies in adults (aged >18 years) that had examined the adverse effects of taking standard dose oral paracetamol (0.5 to 1g, 4 to 6 hourly to a maximum of 4g per day) compared with non-use.

The main outcomes examined were all-cause mortality, cardiovascular effects (specifically heart attacks, strokes and high blood pressure), gastrointestinal (gut) effects (specifically bleeding), and kidney effects (poorer kidney function as indicated by kidney filtration rate, blood chemistry or need for replacement therapy, such as dialysis).

 

What were the basic results?

Eight studies met the inclusion criteria, all were cohort studies. Five were conducted in the US, one in the UK, one in Sweden and one in Denmark. Included sample size ranged from 801 to 382,404 participants, and duration of follow-up ranged between two and 20 years. The studies included specific populations:

  • four of the US studies included female registered nurses aged 30-55 years
  • the other US study included male doctors
  • the UK study involved people over 18 years prescribed paracetamol or ibuprofen
  • the Swedish study included people diagnosed with chronic kidney disease
  • the Danish study comprised of people over 16 years (though the systematic review inclusion criteria did specify 18 years) that were prescribed paracetamol

The studies each looked at some of the outcomes being studied, and examined various levels of exposure compared with non-use. For example, some looked at number of days use per month (e.g. one to four days, ranging to more than 22 days); others looked at number of grams (g) of lifetime intake (e.g. ranging from 100g lifetime intake to >3000g); the gaps between prescriptions; another looked at the number of pills taken over a set 14-year time period.

Looking at outcomes:

  • One of two studies looking at mortality reported an increased mortality ratio for paracetamol users compared with non-users (overall 28% increased risk). This was in a study of adults prescribed paracetamol or ibuprofen. Sub-analyses found the highest risk with the greatest number of prescriptions (63% increased risk).
  • Four studies found paracetamol use was associated with cardiovascular effects, with increased risk linked to increased exposure. One study found a 68% risk of cardiovascular events for people (one of the nurses’ studies) who took more than 15 tablets per week. Another study also found higher doses was associated with heart attack and stroke, and two others found associations with high blood pressure.
  • One study reported gastrointestinal effects and found overall (36%) increased risk of gastrointestinal bleeds. This was in the study of adults prescribed paracetamol or ibuprofen, with the highest associated with first prescription (74%) and greatest number of prescriptions (49%).
  • Four studies reported kidney effects, and three found a poorer kidney function with increasing dose.

 

How did the researchers interpret the results?

The researchers conclude that, "the dose-response seen for most endpoints suggests a considerable degree of paracetamol toxicity, especially at the upper end of standard analgesic doses". However, they give due caution that, "given the observational nature of the data, bias may have had an important impact".

 

Conclusion

This is a valuable review that has searched the literature and identified eight observational studies in adults that have looked at the adverse effects that may be associated with paracetamol use. As the researchers say, it will add to information on the potential harms of paracetamol – an area where up-to-date information has been lacking.

The studies included very large population sizes, and collectively provide some evidence suggesting potential effects upon the cardiovascular system, kidney and gastrointestinal system. There was also a suggestion of increased risk of all-cause mortality.

However, it is very important that these findings are interpreted in the right context. The eight studies were a very variable mix, with very different populations, study duration, measurement of paracetamol exposure and outcomes examined. Most of the individual risk figures identified and reported in the media (e.g. 63% increased risk of mortality or 68% increased risk of heart attack) actually came from individual studies, and would ideally benefit from being interpreted in the specific context of that study. For example, the 68% risk figure for heart attacks was for US female nurses taking more than 15 paracetamol tablets a week.

A possibility for all of these studies is that their results could be influenced by confounding factors (confounders); that is, other differences between the non-users and users of paracetamol that are accounting for the differences. When looking at people using the greatest amounts of paracetamol in these studies – those with, generally, the highest risk figures – their health differences compared to non-users may be even more considerable. For example, increased paracetamol use was associated with increased risk of gastrointestinal bleeds, but this was in a study where people were prescribed paracetamol or ibuprofen.

Ibuprofen, like other NSAIDs, is known to be associated with gastrointestinal bleeds, and it could be that people needing to take more paracetamol were also needing to take more ibuprofen, which could have been influencing the risk. Similarly, other studies included people who may have been suffering from various chronic diseases, which could have increased their risk of cardiovascular events, poorer kidney function and mortality, and also cause them to need more painkilling medication.

It is not known whether, or how well, these studies took into account all the potential health and lifestyle differences that may be associated with increased paracetamol use, as well as increased risk of adverse health outcomes.

Another potential source of inaccuracy is in estimations of paracetamol intake. For example, it is difficult to know how someone could reliably estimate the number of grams of paracetamol they had taken in a lifetime, or how many pills they had taken over a 14-year period.

Overall, the findings that paracetamol could potentially have adverse longer-term effects, particularly higher doses, are undoubtedly important and will need further investigation. 

Paracetamol is an effective treatment for mild to moderate pain and fever in adults and children, when used as directed in product information. The maximum dose within a 24-hour period must not be exceeded. However, if you find you need to use paracetamol on a regular basis, it is worth consulting your GP to look at the cause, and possible treatments. You may find your symptoms respond better to an alternative painkiller or possibly a non-drug type of treatment, such as physiotherapy.

There are also a number of self-help techniques that can help people cope better with chronic pain.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Paracetamol linked to heart attack risk: Fears over high doses taken for a long time. Mail Online, March 3 2015

Paracetamol should come with warnings about possible long-term health risks, say scientists. The Independent, March 3 2015

Long-term use of paracetamol can lead to high blood pressure and stroke. The Daily Telegraph, March 3 2015

Paracetamol in new health ALERT: Doctors warned over prescribing daily painkiller. Daily Express, March 3 2015

Links To Science

Roberts E, Nunes VD, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Annals of the Rheumatic Diseases. Published online March 2 2015

Categories: NHS Choices

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