Several news sources today reported that elderly people taking a range of common medications have an increased risk of death. Many reports highlighted a danger from taking combinations of the drugs, with The Daily Telegraph calling the use of multiple drugs a “fatal cocktail”.
The study behind the news analysed data collected between 1991 and 1993 as part of a large study into the decline of mental functioning in people aged over 65. The new research re-analysed the participants’ records to look at how their mental decline was linked to their use of drugs with “anticholinergic” side effects (such as dry mouth, reduced mucous secretion and constipation). Anticholinergic drugs block the chemical acetylcholine, which is involved in the transmission of electrical impulses between nerve cells. The drugs in question have a range of applications, from blocking hayfever to improving breathing in some chronic lung conditions. Researchers found that the 4% of people who used drugs with definite anticholinergic effects had a small but significantly greater decline in mental ability compared to people not using these drugs. People using drugs with definite or possible anticholinergic effects had an increased risk of death within the two-year period.
The study had some important limitations, including not being able to verify whether participants had used the drugs as prescribed and difficulties gauging whether the slight mental decline seen in testing translated into a decline in functioning in everyday life. Also, given that the data were gathered around 20 years ago, the study may not reflect the way drugs are currently prescribed and monitored.
These are important findings, but people should not stop taking any of their prescribed medications and should contact their doctor if they have any concerns about adverse effects.
Where did the story come from?
The study was carried out by researchers from the University of East Anglia, University of Cambridge and other institutions in the US and UK. Funding was provided by the Medical Research Council. The study is awaiting publication in the Journal of American Geriatrics Society , a peer-reviewed medical journal.
In general, the news stories reported this complex issue well, although The Daily Telegraph ’s headline that “combinations” or “cocktails” of common medicines are the key risk factor does not reflect the main finding of this report. It should also be highlighted that, although the use of drugs with anticholinergic effects was associated with higher mortality in the two year follow-up, the increased mortality rates may have been influenced by the underlying conditions being treated. In other words, the most ill patients may have both a greater risk of death and a greater need for medication. While the researchers say they have accounted for this phenomenon, it is difficult to adjust for factors such as underlying disease, and the subjects’ conditions may still have influenced the mortality rates to some extent.
Although certain news sources focussed on the potential risks of various medications, they did not mention the proven benefits. Many of the drugs in question are of great importance in treating and managing serious health problems. The research does not in itself show that these benefits are outweighed by the risks, and people should not stop taking their medication because of this study. If patients have any concerns, they should speak to their doctor or pharmacist, who can review their medicine usage and advise them accordingly.
What kind of research was this?
This was a retrospective analysis of data from participants enrolled in a large ongoing, observational study, called the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). The aim of the current analysis was to determine whether the use of medications with anticholinergic activity increases the risk of cognitive decline and death in older people. Anticholinergic drugs are those that block the chemical acetylcholine, which is involved in the transmission of electrical impulses between nerve cells.
Blocking acetylcholine has an effect on involuntary processes in the body, and typical effects are dry mouth, decreased mucous secretion, increased heart rate, pupil dilation, slowing of bowel movements (causing constipation), and urinary retention. The medicines can also have an effect on brain function, which affects concentration, memory and attention, and causes confusion. Among commonly used anticholinergic drugs is a special group of bronchodilator medicines used in chronic obstructive pulmonary disease (chronic bronchitis) to decrease inflammation and mucous secretion in the lungs. This group of drugs includes ipratropium bromide (brand name Atrovent).
The researchers were inspired to conduct this analysis because a recently published systematic review highlighted a link between cognitive impairment and the anticholingeric strength of medications (how much the medication lowers the activity of nerve cells). They looked back at data extracted as part of the large ongoing MRC CFAS study in order to assess whether the use of anticholinergic medications in this population supported the earlier review’s findings. The original study commenced in 1991, and the researchers looked back at data collected two years later in 1993.
What did the research involve?
In 1991, the MRC CFAS study enrolled a random, community-based sample of people aged 65 or over. Across five recruitment centres in England and Wales, 13,004 individuals completed a structured interview collecting sociodemographic and health-related information, including a list of medications (provided by 96% of participants). The participants also had a Mini-Mental State Examination (MMSE), a recognised method for testing cognitive function.
The researchers asked the participants about any medications they were taking and assessed the participants’ exposure to drugs with anticholinergic effects using the Anticholinergic Cognitive Burden Scale (ACB). This is a validated scale developed following a systematic review to identify all drugs with documented anticholinergic effects. Medications were classed as having absent, possible (score 1) or definite (score 2-3) cholinergic effects.
Two years later, they gave the participants another MMSE. They looked at the MMSE score at the start of the study (the baseline) and examined how it related to the total ACB score of the medicines. The main outcome assessed was the change in cognitive ability from baseline to follow-up and how this related to ACB score. The participants were flagged through the National Health Service Central Register of the UK Office of National Statistics, which enabled the researchers to record people who died over the course of the study. Analyses were adjusted for age, sex, educational level, social class, number of non-anticholinergic medications, other conditions (comorbidity), and cognitive performance at baseline.
The study only reported data collected between 1991 and 1993, and does not appear to have examined longer-term cognitive decline or mortality.
What were the basic results?
The mean (average) age at the start of the study was 75 years, and the mean MMSE score was 25.9 out of a maximum score of 30 (10% scored 0-21, 25% scored 22-25 and 65% scored 26-30). A score of over 25 is considered to be cognitively normal. Of the 12,250 participants with complete medication data and MMSE score at baseline, two years later 1,223 (10%) had died, 2,493 (20%) had dropped out, and 8,334 completed the two-year follow-up survey, including a second MMSE.
In 1991, 47% of participants (5,709 people) reported using a medication that had possible anticholinergic effects, and 4% (508 people) used a drug with definite anticholinergic properties. In the fully adjusted analyses, people using a medication with definite anticholinergic effects had a 0.33 point greater decline in MMSE score at follow-up (95% confidence interval [CI] 0.03 to 0.64 decline) compared to people not taking anticholinergics. The use of drugs with possible anticholinergic effects was not associated with any greater decline in MMSE compared to people who did not use anticholinergics.
Compared to those not taking anticholinergics, people taking drugs with definite anticholinergic effects had a 68% increased odds of dying by two years (odds ratio [OR] 1.68, 95% CI 1.30 to 2.16), and people taking drugs with possible anticholinergic effects had a 56% increased risk of dying (OR 1.56, 95% CI 1.36 to 1.79).
How did the researchers interpret the results?
The researchers concluded from their analyses that use of medications with anticholinergic effects increases the risk of cognitive impairment and mortality.
This retrospective study looked back at data collected 20 years ago as part of the Medical Research Council Cognitive Function and Ageing Study, a large community-based study of people aged over 65 in 1991. The original study collected information on the participants’ health, medication use and cognitive function, and carried out regular follow-up surveys. The current researchers were inspired to look back at this data as a recent systematic review highlighted associations between use of drugs with anticholinergic effects and cognitive decline. They found that data collected from 13,004 people (average age 75) between 1991 and 1993 supported this theory.
An example of commonly used anticholinergic drugs is a special group of bronchodilators used in chronic obstructive pulmonary disease, which decrease inflammation and mucous secretion in the lungs. This group of drugs includes ipratropium bromide (brand name Atrovent). However, drugs with anticholinergic effects are used in many areas of medicine, including the treatment of people with gastrointestinal and genitourinary problems and certain psychiatric conditions.
The study’s strengths include its large, community-representative population size, high level of follow-up and use of a validated score to analyse the strength of anticholinergic properties of the drugs used. However, it does have important limitations:
- From the data collected, it is not possible to verify whether participants used the reported drugs as prescribed, the duration of their use, any interrupted use, or the effects of different doses. The researchers say these factors require consideration in future studies in this area.
- MMSE was the only reported measure of cognitive function. While the score indicates the degree of cognitive impairment, it is not clear how the decline in score observed among the small number of people using definite anticholinergic drugs related to their functioning in everyday life (as there was only a 0.3 point difference, it’s unclear what clinical significance this would have). Likewise, no assumptions can be made about associations with specific conditions such as Alzheimer’s disease, which cannot be diagnosed from an MMSE test score.
- Though analyses adjusted for the effects of other conditions, the health status of the individuals was not reported. As the researcher say, it is not known how the cognitive test performance of the individuals related to their current health status. In other words, poorer health could be related to both higher drug use and to poorer cognitive function. Therefore, health itself could have affected the relationship between drug use and cognitive function.
- Finally, data were collected between 1991 and 1993, but there may have been changes in prescribing practice and follow-up in the last 20 years.
While this study has indicated a possible effect of drugs with anticholinergic properties, it has not identified how they might affect the risk of death or found a causative link between the two factors. In other words, the findings do not necessarily prove that the drugs themselves increased the risk of death. However, the study has identified an area worthy of further research, which should ideally consider more complete records of medication use and feature a more in-depth analysis into cognitive performance and functioning.
The Medicines and Healthcare Regulatory Agency, the UK’s drug watchdog, has commented on the study’s findings, saying:
“All medicines have side effects - no effective medicine is without risk. Our priority is to ensure that the benefits of medication outweigh the risks. The known side effects of anticholinergic medicines are described in the product information for prescribers and in patient information leaflets. Where it is known that taking a combination of medicines may increase the risk of experiencing side effects, it will be reflected in the product information.
“It is important for people taking anticholinergic medicines not to stop taking them. If they have any questions or concerns then they should contact their doctor in the first instance.”