-- Richard Lilford, CLAHRC WM Director

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My mother-in-law, Celia, died last Christmas. She died in a nursing care home after a short illness – a UTI that precipitated prescription of two courses of antibiotics followed by an overwhelming C. diff infection from which she did not recover. She had suffered from mild COPD after years of cigarette smoking, although she had given up more than 35 years previously, and she also had hypertension (high blood pressure) treated with a variety of different medications (more of which later). She was an organised and sensible Jewish woman who would not let you leave her flat without a food parcel of one kind or another, and who had arranged private health insurance to have her knees and cataracts replaced in good time. Officially, medically she had multimorbidity; unofficially her life was a full and active one, which she enjoyed. She moved house sensibly and in good time, to a much smaller warden-supervised flat with a stair lift, ready to enjoy her declining years in comfort and with support. She had a wide circle of friends, loved going out to matinées at the theatre, and was a passionate bridge player and doting grandma. So far so typical, but I wonder if indirectly she died of iatrogenesis – doctor induced disease – and I have been worrying about exactly how to understand and interpret the pattern of events that afflicted her for some time.

A couple of weeks ago a case-control study was published in JAMA (I can already hear you say ‘case control in JAMA!’ yes – and it’s a good paper).[1] It helps to raise the problem of what may have happened to my son’s grandma and has implications for evidence use in health care. The important issue is that my mother-in-law also suffered from recurrent syncope, or fainting and falls. It became inconvenient – actually more than inconvenient. She would faint after getting up from a meal, after going upstairs, after rising in the morning – in fact at any time when she stood up. She fell a lot, maybe ten times that I knew about and perhaps there were more. She badly bruised her face once, falling onto her stair lift and on three occasions she broke her bones as a result of falling. She broke her ankle requiring surgical intervention and her arm, and her little finger. Her GP ordered a 24-hour ECG and referred her to a cardiologist where she had a heap of expensive investigations.
Ever the over-enthusiastic medically-qualified, meddling epidemiologist, I went with her to see her cardiologist. We had a long discussion about my presumptive diagnosis: postural hypotension – low blood pressure on standing up – and her blood pressure readings confirmed my suspicion. Postural hypotension can be caused by rare abnormalities, but one of the commonest causes is antihypertensive medication – medication for high blood pressure. The cardiologist and the GP were interested in my view, but were unhappy to change her medication. As far as they were concerned, she definitely came into the category of high blood pressure, which should be treated.

The JAMA paper describes the mortality and morbidity experience of 19,143 treated patients matched to untreated controls in the UK using CPRD data. Patients entered the study on an ‘index date’, defined as 12 months after the date of the third consecutive blood pressure reading in specific a range (140-159/90-99mmHg). It says: “During a median follow-up period of 5.8 years (interquartile range, 2.6-9.0 years), no evidence of an association was found between antihypertensive treatment and mortality (hazard ratio [HR], 1.02; 95% CI, 0.88-1.17) or between antihypertensive treatment and CVD (HR, 1.09; 95% CI, 0.95-1.25). Treatment was associated with an increased risk of adverse events, including hypotension (HR, 1.69; 95% CI, 1.30-2.20; number needed to harm at 10 years [NNH10], 41), and syncope (HR, 1.28; 95% CI, 1.10-1.50; NNH10, 35).”

Translated into plain English, this implies that the high blood pressure medication did not make a difference to the outcomes that it was meant to prevent (cardiovascular disease or death). However, it did make a difference to the likelihood of getting adverse events including hypotension (low blood pressure) and syncope (fainting). The paper concludes: “This prespecified analysis found no evidence to support guideline recommendations that encourage initiation of treatment in patients with low-risk mild hypertension. There was evidence of an increased risk of adverse events, which suggests that physicians should exercise caution when following guidelines that generalize findings from trials conducted in high-risk individuals to those at lower risk.”

Of course, there are plenty of possible criticisms that can never be completely ironed out of a retrospective case control study relying on routine data, even by the eagle-eyed scrutineers at CLAHRC WM and the JAMA editorial office. Were there underlying pre-existing characteristics that differentiated case and controls at inception into the study, which might affect their subsequent mortality or morbidity experience? Perhaps those who were the untreated controls were already ‘survivors’ in some way that could not be adjusted for. Was the follow-up period long enough for the participants to experience the relevant outcomes of interest? A median of 5.8 years is not long when considering the development of major cardiovascular illness. Was attention to methods of dealing with missing data adequate? For example, the study says: “Where there was no record of blood pressure lowering, statin or antiplatelet treatment, it was assumed that patients were not prescribed treatment.” Nevertheless, some patients might have been receiving prescriptions that, for whatever reason, were not properly recorded. The article is interesting, and food for thought. We must always bear in mind, however, that observational designs are subject to the play of those well-known, apparently causative variables, ‘confoundings.’[2]

What does all this mean for my mother-in-law? I did not have access to her full medical record and do not know the exact pattern of her blood pressure readings over the years. I am sure that current guideless would clearly have stated that she should be prescribed antihypertensive medication. The risk of her getting a cardiovascular event must have been high, but the falls devastated her life completely. Her individual GP and consultant took a reasonable, defensible and completely sensible decision to continue with her medication and her falls continued. Finally, a family decision was taken that she couldn’t stay in her own home – she had to be watched 24 hours a day. Her unpredictable and devastating falls were very much a factor in the decision.
 
Celia hated losing her autonomy and she never really agreed with the decision. From the day that the decision was taken she went downhill. She stopped eating when she went in to the nursing home and wouldn’t even take the family’s chicken soup, (the Jewish antibiotic) however lovingly prepared. It was not surprising that after a few weeks, and within days of her 89^th birthday, she finally succumbed to infection and died.

How can we rationalise all this? Any prescription for any medication should be a balance of risks and benefits, and we need to assess these at both the population level, for guidelines, and at the individual level, for individuals. It’s very hard to calculate precisely how the risk of possible future cardiovascular disease (heart attack or stroke) stacked up for my mother-in-law, against the real and present danger of her falls. But I can easily see what apparently went wrong in her medical care, with the benefit of hindsight. I think that the conclusion has to be that in health care we should never lose sight of the individual. Was my mother-in-law an appropriately treated elderly woman experiencing the best of evidence-based medicine? Or was she the victim of iatrogenesis, a casualty of evidence-based medicine whose personal experiences and circumstances were not fully taken into account in the application of guidelines? Certainly, in retrospect it seems to me that I may have failed her – I wish I’d supported her more to have her health care planned around her life, rather than to have her shortened life planned around her health care.

-- Aileen Clarke, Professor at Warwick Medical School.

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