Mortality Associated with Proton Pump Inhibitors

Proton pump inhibitors (PPI) are very widely used in society. Moreover, their use is often prolonged, lasting years if not decades. These agents have an important effect upon a fundamental biological mechanism: the transport of positively-charged ions across cell membranes. It is therefore a matter of great importance to investigate the potential risks of widespread and prolonged use of an agent with such a profound effect on the body’s metabolism.

It is already known, or at least frequent investigations have found, that, in addition to an increased risk of diarrhoea, there is an association between PPI use and all-cause mortality. A recent paper in the BMJ has investigated this matter further.[1] The study was based on a cohort of US Veterans. The investigators compared all-cause and specific-cause mortality in patients taking PPIs with those who were not, and also examined the strength of any association by duration of use. They also examined for possible reverse causality by looking at outcomes only after a considerable duration from the start of therapy. They examined for selection bias by comparing outcomes among people taking PPIs with those taking other medicines for upper abdominal symptoms.

The study replicated the findings of previous studies, confirming an association between PPI use and all-cause mortality. In fact there was an extra 45 deaths per thousand people taking PPIs (95% confidence interval 28.20–61.40). Kidney disease and cancer of the upper gastrointestinal tract were significantly increased. Risks increased in proportion to duration of use.

Of course, such an observational study cannot prove causality beyond all reasonable doubt. However, the finding that the results were not consistent with reverse causality and that they were unlikely to be due to selection bias, makes a causal explanation highly plausible. The increasing association of deaths with duration of use is of particular practical importance. Since the burden of evidence favours a causal explanation between increasing duration of use and risk of premature death, people taking these medicines should be weaned off them as soon as possible.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019; 365: l1580.

Rotavirus Vaccine

Gastroenteritis as a result of rotavirus infection is a major cause of morbidity and mortality among children under 5 years old, with around 215,000 deaths in 2013.[1] Thankfully there is now a vaccine available, and hospital admissions and deaths have been shown to have declined significantly since its introduction. However, not all countries have incorporated the rotavirus vaccine into their national immunisation programmes. A recent paper in Lancet Global Health used data from the WHO-coordinated Global Rotavirus Surveillance Network to look at the impact the vaccine has had worldwide, as it had not previously been analysed using primary data.[2]

More than 400,000 children from 82 countries were admitted to hospital with acute gastroenteritis over the study period, with around one-third being tested positive for rotavirus. The impact analysis of the study looked at a subset of ~300,000 children and found that there was a decline of 39.6% (95% CI 35.4-43.8) in admissions in countries that had introduced the vaccine into their immunisation programme, compared to the years before, resulting in rotavirus being detected in around 23% of admissions. Meanwhile, in countries that did not include the vaccine there was no significant change in rotavirus detected over time, remaining stable at around 38% of admissions. Further, in countries that had introduced the vaccine, the age distribution of children that tested positive for rotavirus gastroenteritis was skewed towards older children, perhaps as a result of the improved protection.

References:

1. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD; World Health Organization-Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis. 2016; 62: S96-S105.
2. Aliabadi N, Antoni S, Mwenda JM, et al. Global impact of rotavirus vaccine introduction on rotavirus hospitalisations among children under 5 years of age, 2008–16: findings from the Global Rotavirus Surveillance Network. Lancet Glob Health. 2019; 7(7): e893-903.

Stop Taking Those Supplements: Just Stop

There is a strong natural human instinct to take precautions to delay the death the lies ahead for us all. So strong is this instinct that we are predisposed to believe in all sorts of measures with a superficial, but fundamentally facile, theoretical basis. Food supplements are such a measure.

So yet another study shows that they do no good, and in some cases they likely increase the very risks that they are designed to prevent.[1] A recent article by Chen and colleagues follows up a cohort of over 30,000 adults who completed a nutrition questionnaire yearly for six years. A healthy diet was associated with lowered cancer mortality risk, but supplements were not, and could even raise risks. With respect to minerals, NEVER take supplements, because it is the balance between metal couples (sodium/potassium; magnesium/calcium; copper/zinc) that is important. So it is not surprising that calcium supplements were harmful in the above study.

Studies of this type are subject to personal and recall bias but, in my opinion, these work against the findings. People who take care of their health usually have better outcomes than people at large, and recall bias is augmented if the bad endpoint materialises, whereas the overall results in this study were null.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Chen F, Du M, Blumberg JB, et al. Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults. Ann Intern Med. 2019; 170: 604-13.

The Mortality Gradient

A young man was admitted to a hospital in North KwaZulu-Natal (a province of South Africa) with a stab wound in the upper left quadrant of the abdomen and a falling blood pressure. Only a skeleton staff was on duty, thanks to a public sector strike taking place at the time. Further, only one member of the team was medically qualified, and she was assisted by two medical students on their elective periods. The doctor anaesthetised and intubated the patient, scrubbed, and then started to open the abdomen. A number of things then happened in rapid succession: the blood was found to have turned a blue colour, the oximetry alarm sounded, and the heart stopped. The doctor opened the chest to give internal cardiac compression but to no avail. On opening the chest the problem was identified. Firstly, the knife had penetrated the diaphragm to enter the left lung; a frequent finding with stab wounds to the upper left abdomen. Secondly, the left main bronchus (windpipe) had been intubated. The result was that only the left lung had been ventilated and air had been forced under pressure into the cavity around the lung. This air, forced into the plural space under pressure, had compressed the chest contents, causing the patient’s oxygen levels to plummet.

Mortality rates from surgery for a given condition are roughly twice as high in low- and middle-income countries (LMICs) as in high-income countries. Why is this?

A very large number of recent studies [1-4] have replicated Aneel Bhangu’s classic study in the British Journal of Surgery,[5] confirming the mortality gradient. That the gradient exists is not in real doubt but its causes are. Possible, non exclusive, causes are:

1. The patient arrives in worse condition in LMICs than in high-income countries because they are in worse shape generally, and/or there were large delays in reaching the health care system.
2. Care is worse before surgery, including longer delays within the health care system, and/or post operative care was suboptimal.
3. Intraoperative care was worse, either in terms of anaesthesia (as in the above example – intubation of the left bronchus is a classic error requiring special vigilance in cases where there is a risk that the integrity of the lung has been compromised), and/or surgery itself.

A fashion has broken out to compare death rates for given conditions across high- and low-income countries, and then ascribe observed differences in outcome to differences in healthcare provision, expressed in terms of lives (or even DALYs) lost. Such an approach can work well at the specific level when two conditions are met:

1. A specific condition is examined and this condition has a poor natural history, but an extremely good prognosis given appropriate medical care. Perinatal haemorrhage and eclampsia are good examples.
2. The way in which healthcare can remedy the situation is well defined. Treatment of ruptured spleen or meningitis are good examples.

Absent conditions fulfilling the above criteria, comparisons between high- and low-income countries should motivate serious investigation for causes. Until the cause of the difference is determined, advocacy based only on differences between high- and low-income countries is without intellectual or moral value. Decisions should be based on the best use of restricted resources and simply pointing out north-south differences in outcomes adds no value to determining priorities within LMICs. It is wasteful to advocate resource allocation under scarcity until the payback among different competing causes has been examined. The correct use of measuring differences in outcome over countries should not be to advocate for resources for action. These differences in outcome should motivate a sober search for these causes, and then for cost-effective short- and long-term solutions.

To that end I am leading a cross NIHR initiative into one particular candidate area – access to hospital when care is sought. I also lead the access theme for the NIHR Global Health Research Unit on Global Surgery. One of our tasks is to model the cost-effectiveness of various solutions to overcome the second barrier to access identified above. Our work is hampered by poor data (poor because it is hard to collect) on effects of delay on outcome. Strangely enough, snakebites is the one area where rather good data exist, so we are starting our work in this, otherwise rather narrow, topic. We also plan to study survival rates in UK by measuring distances from local hospitals in conditions such as leaking aortic aneurysms and heart attack.

In the meantime Dr Bruce Biccard of Cape Town, who leads the hospital care work stream in Global Surgery, is turning his attention from differences in outcome to the causes and remedies.

— Richard Lilford, CLAHRC WM Director

References:

1. Abbott TEF, Fowler AJ, Dobbs TD, Harrison EM, Gillies MA, Pearse RM. Frequency of surgical treatment and related hospital procedures in the UK: a national ecological study using hospital episode statistics. Br J Anaesthesia. 2017; 119(2): 249-57.
2. Anderson GA, Ilcisin L, Abesiga L, et al. Surgical volume and postoperative mortality rate at a referral hospital in Western Uganda: Measuring the Lancet Commission on Global Surgery indicators in low-resource settings. Surgery. 2017; 161(6): 1710-9.
3. GlobalSurg Collaborative. Management and Outcomes Following Surgery for Gastrointestinal Typhoid: An International, Prospective, Multicentre Cohort Study. World J Surg. 2018; 42(10): 3179-88.
4. Biccard BM, Madiba TE, Kluyts H-L. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-day prospective observational cohort study. Lancet. 2018; 391: 1589-98.
5. GlobalSurg Collaborative. Mortality of emergency abdominal surgery in high-, middle- and low-income countries. Br J Surg. 2016; 103(8): 971-88.

Well This Really Did Make Me Think

I have always been a fan of patient satisfaction scores. Unlike nonsense SMRs (Standardised Mortality Rates), which are virtually all noise and scant signal,[1] patient satisfaction really does tell us what the patient thought. Of course, some patients, and some patient groups, are more easily satisfied than others, and it is important to bear this in mind when making comparisons. But it never occurred to me that the ethnic group of the provider was material. It turns out that there is a big, disturbingly big, effect. A recent article in the New England Journal of Medicine shows that, try as they might, black doctors get lower scores from their white patients than from their black patients.[2] The authors argue that this finding is unlikely to have arisen from black doctors not being attuned to white patient’s cultural needs since they have trained and practised in hospitals delivering care to mainly white patients. I think we should be really careful when comparing performance by patient feedback scores. Nor do I think that we should channel people according to their ethnic or gender groups. That way lies self-enforcing attitudes and behaviour. No, institutional apartheid is not the way to go. The whole point of being a doctor is that you are blind to a patient’s ethnic group, their gender, whether they are obese, or any personal characteristic whatsoever. Remember the CLAHRC WM director’s hero, Baron Dominique Jean Larrey, surgeon general to the emperor Napoleon, whose system of triage was blind to rank or enemy status.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford R & Pronovost P. Using hospital mortality rates to judge hospital performance: a bad idea that just won’t go away. BMJ. 2010; 340: c2016.
2. Poole Jr KG. Patient-Experience Data and Bias — What Ratings Don’t Tell Us. New Engl J Med. 2019; 380: 801-3.

Do Physicians From Higher Ranking Medical Schools Get Better Patient Outcomes?

Here is another fascinating paper deriving its data from Medicare services.[1] The authors took a random sample of nearly 1,000,000 patients age 65 or over who had been admitted to hospital as an emergency. They looked to see whether physicians from higher ranking medical schools achieved better mortalities, lower spending or lower rates of readmission. There were no differences whatsoever in mortality, despite the very high precision afforded by a study of nearly 1,000,000 patients. Spending per patient was slightly lower among the physicians from high ranking medical schools than among their colleagues from lower ranking schools. Two different rankings were used – for one of these the alumni of higher ranking schools had lower readmission rates, whereas there was no difference when the other ranking system was used.

It is known that there is quite a large variation in practice between doctors, but the variation between doctors would seem to be much greater than the variation between the graduates of different medical schools. Of course, the outcome as measured here might not be highly sensitive to a physician quality. It is likely that process measures would be a more sensitive reflection of performance than summary measures such as mortality and readmission rates. In fact, this is born out when propensity to write opioid prescriptions are compared, showing that graduates from lower ranking schools are more likely to overprescribe.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Tsugawa Y, Blumenthal DM, Jha AK, Li KT, Orav EJ, Jena AB, Newhouse RL. Association between physician US News & World Report medical school ranking and patient outcomes and costs of care: observational study. BMJ. 2018; 362: k3640.

Risk of Death or Readmission over Christmas Period

I thank Prof Kamlesh Khunti for drawing my attention to this article.[1] It uses a Canadian database of hospital use to compare the outcomes for patients admitted over the Christmas period with those admitted over two control periods of one month on either side of the holiday. The study finds that there were less subsequent outpatient attendances, but more deaths or readmissions, for patients discharged over the Christmas period when compared to those admitted over the control periods.

What to make of such a study? Is it really the case that the reduction in outpatient supervision is the cause of the deaths or readmissions? Certainly, if one looked only  at deaths, the difference is minute, although statistically significant after adjustment for confounders. The trouble is that small magnitudes of effects can be the result of small biases, which are impossible to detect statistically.

All the same, this is an interesting study and it might be worthwhile to try and replicate it on an English data set.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Lapointe-Shaw L, Austin PC, Ivers NM, Luo J, Redelmeier DA, Bell CM. Death and readmissions after hospital discharge during the December holiday period: cohort study. BMJ. 2018; 363: k4481.

Vertical Health Care Programmes or Health System Strengthening: A False Dichotomy

Health care development is sometimes classified as vertical or horizontal. Vertical programmes target specific diseases or disease clusters. For example tuberculosis, HIV and malaria, are targeted by the Global Fund. Horizontal programmes, by contrast, seek to strengthen the system within which health care is embedded. Such programmes are concerned with human resources, financing, education, and supply chains, among many other functions.

There has been a strong push to move from vertical to horizontal programmes from many corners, including from this News Blog. Supporters of such a change in emphasis cannot but acknowledge the massive successes that vertical programmes have notched up, especially in the fields of infant health, maternal health, and infectious diseases.

However, the limitations of a purely diseased-based approach have become increasingly evident. Logically, it is not even possible to instigate a vertical approach in a complete system vacuum. For example, it would be difficult, if not impossible, to instigate a programme to improve HIV care, if the supply chain could not make drugs available and if the health system could not support basic diagnostic services. That said, vertical surfaces should not be able to siphon off more than their fair share of the health services infrastructure.

A recent Lancet paper on health services in Ethiopia made a further important point,[1] that vertical systems can make a very good platform to extend and deepen generic health systems. In fact, that is precisely what has happened in that country, with full support from the Global Fund and GAVI, the Vaccine Alliance. They refer to this combination of vertical and generic development as a “diagonal” investment approach. We would prefer to describe the relationship as one of symbiosis in which vertical and horizontal programmes are designed to reinforce each other.

The Ethiopian initiative involved strengthening the system at multiple levels, from health service financing, human resources policies, education, investment in primary care, and community outreach activities, along with support for community action and self-help (including the “IKEA model” previously described in this news blog).[2] Certainly, Ethiopia, along with other countries such as Bangladesh, Thailand and Rwanda, stand out for having achieved remarkable improvements over many dimensions of health. In Ethiopia the reduction in mortality for children under the age of five years was 67% from the 1990 baseline, while there was a 71% decline in the maternal mortality ratio and deaths from malaria, tuberculosis and HIV were halved. This took place against a financial backdrop of declining international aid but increasing domestic expenditure. The combination of vertical programmes and health system strengthening seems to have ensured that the money was not wasted.

— Richard Lilford, CLAHRC WM Director

References:

1. Assefa Y, Tesfaye D, Van Damme W, Hill PS. Effectiveness and sustainability of a diagonal investment approach to strengthen the primary health-care system in Ethiopia. Lancet. 2018; 392: 1473-81.
2. Lilford RJ. Pre-payment Systems for Access to Healthcare. NIHR CLAHRC West Midlands News Blog. 18 May 2018.

Childhood IQ and Mortality

Many studies have shown an association between childhood intelligence and mortality. However, most studies have been conducted with male participants, and potential mechanisms for the putative association are poorly understood. A recent paper looked at a large sample of Swedish people in an attempt to clarify these issues.[1]

The authors looked at IQ data from 19,919 Swedes who were 13 years old at the time (9,817 women), along with socioeconomic data from their childhood and middle age over the following 53 years. The analysis found an association between lower IQ and increased all-cause mortality. A one standard deviation decrease in IQ was associated with increased risk of all-cause mortality in both men (hazard ratio 1.31, 95% CI 1.23-1.39) and women (HR 1.16, 95% CI 1.08-1.25). Most causes of death were associated with lower IQ in men, while in women a lower IQ was associated with an increased risk of death from cancer and cardiovascular disease. When the authors adjusted for childhood socioeconomic factors the associations were slightly attenuated; but were further attenuated when adjusting for adulthood factors – considerably in men (overall mortality HR=1.17, 95% CI 1.08-1.26), and almost completely in women (HR 1.02, 95% CI 0.93-1.12). These results suggest that it is the social and socioeconomic circumstances in adulthood that contribute to the association between IQ and mortality, particularly in women, though the authors state that more research is needed to clarify the pathways linking childhood IQ and mortality across genders.

— Peter Chilton, Research Fellow

Reference:

1. Wallin AS, Allebeck P, Gustafsson J-E, Hemmingsson T. Childhood IQ and mortality during 53 years’ follow-up of Swedish men and women. J Epidemiol Community Health. 2018; 72(10): 926-32.

A Casualty of Evidence-Based Medicine – Or Just One of Those Things. Balancing a Personal and Population Approach

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. diffinfection 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 – andit’s a good paper).[1] It helps to raise the problem of whatmay 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 controlsin 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^thbirthday, 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

References:

1. Sheppard JP, Stevens S, Stevens R, et al. Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension. JAMA Intern Med. 2018.
2. Goldacre B. Personal communication. 2018.