107 studies published in a cancer journal have just been retracted 


In a massive cleanup, 107 articles have just been retracted from the open-access cancer research journal Tumor Biology.

“After a thorough investigation we have strong reason to believe that the peer review process was compromised,” writes editor-in-chief Torgny Stigbrand in the retraction notice.

Peer review is one of the golden standards that help sort the wheat from pseudoscientific babbling, making the process an integral part of academic publishing.

But there is massive publishing pressure in the scientific community, and with about 2.5 million papers published each year, some of those inevitably end up cutting corners. In this case, the transgression was what’s known as ‘fake peer review’.

Scientists are often asked to provide recommendations for potential reviewers of their work. While that sounds like an obvious invitation to cheat, it actually makes sense when the work is really specific and few others do similar research.

But it’s easy to game the system by providing a fake reviewer email address, impersonating an actual researcher and sending the journal a super-positive review in their name.

“The articles were submitted with reviewer suggestions, which had real researcher names but fabricated email addresses,” Springer representative Peter Butler told Yan Jie at Sixth Tone.

It’s a pretty massive lot of retractions all at once, but a few of the big academic publishers have been sweeping their portfolios for potential breaches, including fake peer review, plagiarism, data fabrication and more.

This time, the 107 papers were published between 2012 and 2016, and most were authored by Chinese researchers, although that doesn’t automatically reflect poorly on their scientific work.

Chinese scientists are known to rely on third-party agencies that provide language editing services, which give the papers a polish, increasing the chance of getting accepted. But it’s possible those companies have also done the authors a massive disservice.

“There is some evidence that so-called third-party language-editing services play a role in manipulating the reviewing process,” an unnamed Springer spokesperson told Cathleen O’Grady at Ars Technica.

While we don’t have details on whether any of the authors had a hand in contributing fake reviews, experts are willing to chalk at least some of the breaches up to those third-party companies, some of which are known to operate unethically.

“If the authors didn’t realise that this is what the editing company was doing, then I feel the authors should have a fair chance,” Elizabeth Wager, editor of the journal Research Integrity & Peer Review, told Ars Technica.

“There’s probably nothing wrong with the research; it just hasn’t been peer reviewed.”

China is one of the biggest scientific contributors in the world, producing more than 300,000 papers every year. With strides in nuclear fusion and revolutionary CRISPR experiments, Chinese researchers are major players in the international research scene.

But any large industry gets its share of scandals. For example, just last year news broke that 80 percent of data in Chinese clinical trials had been fabricated.

As for Tumor Biology, the journal actually moved from Springer to SAGE late last year, and the new publisher was made aware of the investigation into potential peer review fraud. The journal is run by the International Society of Oncology and BioMarkers.

“The society were open about the past instances of peer review fraud, and as part of the relaunch they wanted to address the underlying reasons,” a SAGE spokesperson told Alison McCook at Retraction Watch.

“As part of their transition to a new publisher, the Tumor Biology editorial team have already introduced new robust peer review practices expected from all SAGE journals.”

Generic drugs: Review and experiences from South India


Abstract

The cost of pharmaceuticals, as a percentage of total healthcare spending, has been rising worldwide. This has resulted in strained national budgets and a high proportion of people without access to essential medications. Though India has become a global hub of generic drug manufacturing, the expected benefits of cheaper drugs are not translating into savings for ordinary people. This is in part due to the rise of branded generics, which are marketed at a price point close to the innovator brands. Unbranded generic medicines are not finding their way into prescriptions due to issues of confidence and perception, though they are proven to be much cheaper and comparable in efficacy to branded medicines. The drug inventory of unbranded generic manufacturers fares reasonably when reviewed using the World Health Organization-Health Action International (WHO-HAI) tool for analysing drug availability. Also, unbranded generic medicines are much cheaper when compared to the most selling brands and they can bring down the treatment costs in primary care and family practice. We share our experience in running a community pharmacy for an urban health center in the Pathanamthitta district of Kerala State, which is run solely on generic medicines. The drug availability at the community pharmacy was 73.3% when analyzed using WHO-HAI tool and the savings for the final consumers were up to 93.1%, when compared with most-selling brand of the same formulation.

Keywords: Drug availability, drug industry/legislation and jurisprudence, drugs, economic competition, essential medicines, generic*, generic medicines, global health, India, patents as topic/legislation and jurisprudence*, poverty, unbranded generics

Introduction

The World Health Organization (WHO) estimates that almost 30% of the world population lacks access to essential medicines and that the figure will rise to more than 50% in some countries of Africa and Asia.[1] The cost of the pharmaceuticals is the main factor that hampers access to medicines and the governments in poor countries seem to be doing very little to counter this problem. The public sector availability of essential medicines was less than 50% in most of the countries of Africa and Asia.[2] This is appalling in the face of increases in healthcare expenditure in most of the developing nations, mostly financed through secured loans by international development banks and consortia.

The situation in India is not very different than that of other developing nations. Healthcare expenditures have been growing in India, both in real terms and also when considered as a proportion of the Gross Domestic Product (GDP).[3] However, even with this recent increase in healthcare spending, India’s expenditure on health is nowhere near that of OECD (Organisation for Economic Cooperation and Development) nations.[4] The total public spending on healthcare in India accounted for only around 1.2% of GDP in 2012, with the per-capita spending on health around USD 160. This is a miniscule amount when compared against the OECD per-capita healthcare spending of USD 3,484 in 2012.[3,4] This shows that the healthcare spending in the country is set to rise further in the coming years and the healthcare industry is all set for a boom time.

The cost of medicines and pharmaceuticals as a percentage of total healthcare spending has also been rising worldwide.[5] It is the fastest-growing item in the healthcare budgets worldwide and it varies between 20-60% in various healthcare budgets of countries.[6] By 2020, the prescription drug market in United States of America is set to grow to USD 700 billion (B) and China will be USD 260 B.[5] Though no credible predictions about the Indian pharmaceutical industry are available, it is quite safe to assume that Indian pharmaceutical industry will also grow manifold. The growth of the pharmaceutical market worldwide and its increased share in total healthcare spending will reignite the age-old debate on how to balance the cost of innovation in drug research and universal access to the fruits of that research.[7]

Rise of Generics

The role of generic medicines in reducing the healthcare expenditure has been recognised for a long time. Multiple studies have proven that saving through substitution of originator brands by cheaper generic medicines, savings in the range of 10-90% can be achieved.[8] Most national governments have been encouraging the use of generic medicines worldwide and many healthcare systems have policies of substituting expensive branded original medications with generic medicines.[9] In the United States, generic substitution (GS) is an accepted practice and at the end of 2012, almost 80% of all the prescriptions were of generic medications. This has resulted in a substantial moderation of expenditure growth in widely used drugs and significant savings to the economy.[6] In the United Kingdom, GS is now a standard practice in hospitals operated by the National Health Service (NHS) and medical schools have included generic prescribing as a part of their medical training.[10]

In India, the procurement price of essential medicines is generally lower than the mean International Reference Pricing (IRP) but availability of these drugs in the public sector has always been a problem. The exorbitant cost of some of the commonly used medications in private pharmacies makes it inaccessible to majority of the poor.[11] Also, the difference between procurement prices and retail prices in case of some of the generic medicines, were as high as 28 times, which shows a very high margin of profit-taking in view of limited price control mechanisms.[11] It is in this light, that the government revised the National Pharmaceutical Pricing Policy in 2012. It gave methods to calculate ceiling prices for drugs which are under the National List of Essential Medicines (NLEM) which was modified in 2011. It gave a formula for deciding the ceiling prices for drugs under NLEM, using a market-based pricing (MBP) method, taking into account the prices of all manufacturers having a market share of more than 1% nationally.[12] The Drug Price Control Order of 2013 was a follow-up to the National Pharmaceutical Pricing Policy and gave the price ceiling for 348 drugs and over 600 formulations. However, the action was considered inadequate by many activists lobbying for cheaper drugs and they termed it as a sell-out to international pharmaceutical companies.[13]

Indian Pharmaceutical Industry

The multiplicity of brands and manufacturers makes it difficult to decipher the actual market dynamics and the structural issues in the Indian pharmaceutical industry. The complexity of the market and the intensity of the competition between companies in India have made the country a hub for manufacture of generic medicines, earning a sobriquet “pharmacy of the developing world.”[14] This, along with a favorable governmental stance has made India a powerhouse in this field, bringing it into direct confrontation with certain developed nations where most of the big multinational pharmaceutical companies are located[14] There have been many instances when the Indian Patents Office and the Supreme Court of India effectively used certain flexibilities of the Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement of the World Trade Organization and also the safeguards embedded in the Indian Patents Act. The compulsory licensing of Sorafenib, a drug used in treatment of advanced liver and renal cancer and the rejection of patent application for Imatinib, a drug used in the treatment of leukaemia, were considered as landmark decisions by many state and non-state organizations involved in pharmaceutical sector.[15,16]

Considering the Indian scenario, we can divide the brands into innovator brands (IB), most-selling generics (MSG), and least-priced generics (LPG).[17] The IBs will be at the highest price point, followed by MSGs and LPGs. A new category of generic drugs known as unbranded generics (UB) are also coming into the market now. These drugs are usually manufactured by not-for-profit organizations or are subsidised by certain non-governmental organizations (NGO).[18] Though the price points of these different categories of drugs are different, their efficacies are comparable. This fact has been proved by multiple studies all over the world and it belittles the reasoning which goes behind differential pricing of the same drug.[19,20] Even though it has been proved that there is not much difference in efficacy between the above categories of drugs, physicians tend to prescribe drugs manufactured by highly-reputed companies. Their trust is often misplaced as most of these leading companies market drugs manufactured by less-known manufacturers.[18]

A Model Community Pharmacy: Experiences from South India

Pushpagiri Medical College, which is a teaching hospital in Kerala state of India partnered with a social organization, Bodhana Social Service Society, involved in poverty alleviation and income generation programmes, to start an urban health center with an objective to improve patient accessibility to cost-effective medical care. The urban health center serves a population of 10,000, spread over 5 municipal wards of Tiruvalla municipality and was intended as a model for cost-effective primary care. A comprehensive population survey was carried out before the start of the project and the health center started functioning in September 2014. As a part of the initiative, a community pharmacy was opened to stock unbranded generic drugs manufactured by two non-governmental organizations. Low-Cost Standard Therapeutics (LOCOST), Baroda and Comprehensive Medical Supplies India (CMSI), Chennai were the two NGOs providing us with the drugs which were needed at the community pharmacy.[21,22] The drugs were provided to us at a nominal cost, after we provided an undertaking that the Pushpagiri Medical College is a charitable institution with no intention of making profits. Also, the physicians working at the health center made a collective decision to prescribe all the drugs generically and the pharmacist was advised to dispense the cheapest generic brand.

The drug inventory available with these not-for-profit manufacturers were fairly comprehensive when reviewed using the World Health Organization-Health Action International (WHO-HAI) tool for quantifying availability of essential medicines.[23] The WHO-HAI tool is a validated method for measuring availability of drugs in a health system and includes 30 core medicines: 14 essential medicines for global burden of disease and 16 medicines specific to the WHO region [Table 1].[24]

Table 1

Drug inventory of LOCOST, Baroda and CMSI, Chennai: Review using WHO-HAI tool for WHO South East Asian Region

The WHO-HAI tool showed a drug availability of 73.3% for LOCOST, Baroda and 43.3% for CMSI, Chennai. This is much better when compared to drug inventory in public hospitals in other parts of India, assessed using the same methodology.[11] There are a multitude of companies and NGOs manufacturing UB medicines and the drug inventory of a health system can be made comprehensive through a mixed purchase model where procurement is done from multiple vendors.[23]

Similarly, unbranded generic drugs offered significant savings to the health system in terms of costs involved for procurement. When reviewed against the MSBs, UB medicines were costing only a fraction of the maximum retail price (MRP) of MSPs [Table 2].

Table 2

Comparison of drug prices of most-selling brands and their generic counterparts: drugs identified by WHO-HAI tool for WHO South East Asian Region[17,25]

The community pharmacy has been in operation since September 2014, and stocks over 120 formulations manufactured by unbranded generic manufacturers. In addition, it also supplies LSG to augment the drug inventory of the pharmacy. There is a family physician and a general practitioner who run the center, apart from regular specialist visits from Pushpagiri Medical College Hospital. The urban health center has an outpatient load of 20-25 patients a day within 6 months of starting operations. The staff from the center is providing services to 3 old-age homes and a few surrounding schools and the drugs from the community pharmacy is being used for free supply during the medical camps conducted by the department of community medicine.

The patients and the physicians have responded positively to this novel initiative and the general acceptability has been found to be high, though objective studies to assess the same are yet to be done. Some physicians have suggested replicating this model in other similar health initiatives also. The financial sustainability of the model is still unproven, and the urban health center along with the community pharmacy is being sustained with large subsidies provided by Pushpagiri Medical College and Bodhana Social Service Society. The cost of setting-up such a facility was around INR 500,000, which includes the furniture, basic medical equipment, basic lab accessories, and first round of procurement for the community pharmacy and is exclusive of the capital expenditure on the building. The average monthly expenditure in running the health center, has been around INR 150,000 a month, including salaries, cost of consumables and medicines and exclusive of building rent and depreciation. The income earned by the center is around INR 40,000, and there is an excess of expenditure over income to the range of more than INR 100,000 a month, which is subsidised by Pushpagiri Medical College and Bodhana Social Service Society. Both the organizations are charitable societies run by a prominent religious group and the subsidies are meant to further their commitment to social causes.

The community pharmacy concept faced the following key challenges:

  • Absence of intermediaries for drug procurement results in inordinate delays in transit, mainly on account of the tardy services rendered by private logistics companies
  • Advance payment in full has to be remitted to the bank accounts of these NGOs for supply of drugs, which goes against the standard practice of procurement followed in hospitals. This has been an issue with the internal audit department
  • The difference between procurement price and the MRP is minimal and this is causing worries of long-term financial sustainability of the community pharmacy model
  • Packaging of the drugs is unattractive in some cases, resulting in difficulty to convince patients about the efficacy of the drug
  • We have faced difficulty in convincing some of the specialist doctors on the quality of the drug, despite providing ample literature proving the efficacy of unbranded generic drugs.

The Way Forward

Many studies have revealed apprehensions among physicians in prescribing UB medicines to their patients. Most of these apprehensions are related to quality of the product and the fear of losing patients.[26] Along with these unfounded concerns, poor patient acceptability due to various issues like poor packaging, lack of brand promotion initiatives, etc., are affecting the extend of penetration of UB drugs in the country, even though India is becoming a lifeline for all developing countries in the supply of generic medicines.[27] The government and the policy makers in India and other similar developing countries should focus on building the confidence of physicians and the patients regarding unbranded generic medications. The demand side management should include a multifaceted approach in which issues of different stakeholders are addressed and affirmative actions taken in favour of unbranded generic medicine manufacturers.[27] Another important issue is concerning the inherent deficiencies and implementation status of the Drug Price Control Order of 2013. The said order has been criticised extensively for being myopic in its approach, as the number of formulations included is less than 20% of the whole pharmaceutical market. Also, it gave ample space for pharmaceutical companies to tweak their marketing strategies by focussing on formulations and dosages not covered by the Drug Price Control Order. It also leaves out the important area of fixed-dose combinations (FDCs), a potential loop-hole for the pharmaceutical companies to exploit fully. It is indeed distressing to note that more than 90% of the diabetic drug market is out of the purview of this order.[13] The policy makers in the country needs to get a realisation that the share of drugs in out-of-pocket expenditure (OPP) is around 80% in India and a tighter regulatory framework is needed to protect the consumers against exploitation.[28]

In the future, we intend to do a study on the perception about generic drugs, among the treating physicians and the patients who form the clientele of the community pharmacy. This can help us to understand the issues which affect the actual stakeholders and find means to improve the acceptability and penetration of generic medicines. Also, after the yearly financial audit, we plan to do a cost-benefit analysis to objectively analyse the efficacy of the model in monetary terms.

References

1. The World Medicines Situation 2011. The World Health Organisation. [Last accessed on 2015 Mar 2]. Available from: http://apps.who.int/medicinedocs/documents/s18772en/s18772en.pdf .
2. Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: A secondary analysis. Lancet. 2009;373:240–9. [PubMed]
3. Health Expenditure, Total (% of GDP) | Data | Table. [Last accessed on 2015 Mar 2]. Available from: http://data.worldbank.org/indicator/SH.XPD.TOTL.ZS .
4. Microsoft Word-Briefing-Note-INDIA-2014-doc-Briefing-Note-INDIA-2014.pdf. [Last accessed on 2015 Mar 2]. Available from: http://www.oecd.org/els/health-systems/Briefing-Note-INDIA-2014.pdf .
5. Daemmrich A, Mohanty A. Healthcare reform in the United States and China: Pharmaceutical market implications. J Pharm Policy Pract. 2014;7:9. [PMC free article] [PubMed]
6. Hoffman JM, Li E, Doloresco F, Matusiak L, Hunkler RJ, Shah ND, et al. Projecting future drug expenditures–2012. Am J Health Syst Pharm. 2012;69:405–21. [PubMed]
7. Sax P. Spending on medicines in Israel in an international context. Isr Med Assoc J. 2005;7:286–91.[PubMed]
8. Cameron A, Mantel-Teeuwisse AK, Leufkens HG, Laing RO. Switching from originator brand medicines to generic equivalents in selected developing countries: How much could be saved? Value Health. 2012;15:664–73. [PubMed]
9. Hassali MA, Alrasheedy AA, McLachlan A, Nguyen TA, Al-Tamimi SK, Ibrahim MI, et al. The experiences of implementing generic medicine policy in eight countries: A review and recommendations for a successful promotion of generic medicine use. Saudi Pharm. 2014;22:491–503. [PMC free article][PubMed]
10. Duerden MG, Hughes DA. Generic and therapeutic substitutions in the UK: Are they a good thing? Br J Clin Pharmacol. 2010;70:335–41. [PMC free article] [PubMed]
11. Kotwani A, Ewen M, Dey D, Iyer S, Lakshmi PK, Patel A, et al. Prices and availability of common medicines at six sites in India using a standard methodology. Indian J Med Res. 2007;125:645–54.[PubMed]
12. Copy of f1.pdf – NPPPNotification.pdf [Internet] [Cited 2015 Mar 2, Last accessed on 2015 Mar 2]. Available from: http://www.nppaindia.nic.in/NPPPNotification.pdf .
13. Paying the Price – The Hindu. [Last accessed on 2015 Mar 2]. Available from: http://www.thehindu.com/opinion/op-ed/paying-the-price/article4912732.ece .
14. Kapczynski A. Engineered in India–patent law 2.0. N Engl J Med. 2013;369:497–9. [PubMed]
15. Bhaumik S. India’s rejection of Novartis’s patent is but a small step in the right direction. BMJ. 2013;346:f2412. [PubMed]
16. Lancet Oncology. Is India ready to lead the battle for fair access to medicines? Lancet Oncol. 2013;14:437. [PubMed]
17. Bhargava A, Kalantri SP. The crisis in access to essential medicines in India: Key issues which call for action. Indian J Med Ethics. 2013;10:86–95. [PubMed]
18. Amit G, Rosen A, Wagshal AB, Bonneh DY, Liss T, Grosbard A, et al. Efficacy of substituting innovator propafenone for its generic formulation in patients with atrial fibrillation. Am J Cardiol. 2004;93:1558–60. [PubMed]
19. Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, Lee JL, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: A systematic review and meta-analysis. Drugs. 2010;70:605–21. [PMC free article] [PubMed]
20. Asia Pacific Ecumenical News-News. [Last accessed on 2015 Mar 2]. Available from: http://apenews.org/newsread.asp?nid=163 .
21. LOCOST: Medicines within the Common Man’s Reach | The Alternative. [Last accessed on 2015 Mar 2]. Available from: http://www.thealternative.in/business/locost- affordable-medicine-drugscommon-man-reach .
22. Where Are We Now: Assessing the Price, Availability and Affordability of Essential Medicines in Delhi as India Plans Free Medicine for All. [Last accessed on 2015 Mar 2]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733775 . [PMC free article] [PubMed]
23. Madden JM, Meza E, Ewen M, Laing RO, Stephens P, Ross-Degnan D. Measuring medicine prices in Peru: Validation of key aspects of WHO/HAI survey methodology. Rev Panam Salud Publica. 2010;27:291–9. [PubMed]
24. Drug Price List. List of Generic Names in Alphabetical Order. [Last accessed on 2015 Mar 2]. Available from: http://www.medindia.net/drug-price .
25. Generic Index | DrugsUpdate India. [Last accessed on 2015 Mar 2]. Available from: http://www.drugsupdate.com/generic/listing .
26. Waning B, Diedrichsen E, Moon S. A lifeline to treatment: The role of Indian generic manufacturers in supplying antiretroviral medicines to developing countries. J Int AIDS Soc. 2010;13:35. [PMC free article][PubMed]
27. Shrank WH, Choudhry NK, Liberman JN, Brennan TA. The use of generic drugs in prevention of chronic disease is far more cost-effective than thought, and may save money. Health Aff (Millwood) 2011;30:1351–7. [PubMed]
28. Thakkar KB, Billa G. Light at the end of the tunnel: The Great Indian Pharmacoeconomics story. Front Pharmacol. 2013;4:153. [PMC free article] [PubMed]
Source:www.ncbi.nlm.nih.gov

Preoperative ACE and ARB: To hold or to withhold?


Treating physicians of patients undergoing (non-cardiac) surgery frequently decide to withhold both angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) before the operation, mostly out of concern regarding intraoperative hypotension. But does the continuing administration / withholding of these drugs really affect clinical outcomes? The current US-Canadian-British prospective cohort study says yes: Withholding ACE inhibitors and ARBs before surgery decreased the likelihood of 30-day all-cause mortality, stroke and myocardial injury by 18 percent.

The study was based on data from approximately 14,700 patients (including 4,800 ACE inhibitor / ARB users) who underwent non-cardiac surgery between 2007 and 2011. The primary composite outcome was all-cause death, stroke, or myocardial injury after non-cardiac surgery at 30 days; secondary outcomes included intraoperative and postoperative clinically important hypotension.

Compared to patients who continued their preoperative use of ACE-inhibitors and ARBs, the users who stopped their drugs in the 24 hours before surgery were less likely to experience the primary composite outcome (12.0 % versus 12.9 %; adjusted relative risk [aRR] 0.82; P = 0.01) and intraoperative hypotension (aRR, 0.80; P < 0.001). By contrast, both groups had a similar risk of postoperative hypotension (aRR, 0.92; P = 0.36).

Withholding ACE inhibitors and ARBs before major non-cardiac surgery is associated with a lower risk of death and postoperative vascular events, but a large randomized trial is required to confirm these findings. Until then, the authors recommend that patients withhold these two drugs in the 24 hours before undergoing surgery.

Abstract

Background: The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown.

Methods: In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes.

Results: Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery.

Conclusions: Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24 h before surgery.

What We Already Know about This Topic
  • Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are commonly withheld before surgery for concern over intraoperative hypotension, but whether this affects clinical outcomes is unclear

What This Article Tells Us That Is New
  • In a secondary analysis of 4,802 patients on these drugs in the Vascular events In noncardiac Surgery patIents cOhort evaluatioN prospective cohort study, those in whom the drugs were withheld in the 24 h before surgery were less likely to suffer a composite outcome of 30-day all-cause death, stroke, or myocardial injury (18% adjusted relative risk reduction)

MORE than 200 million people have major noncardiac surgery worldwide each year.1  Of those, millions die or suffer a major vascular complication during the perioperative period.2,3 Perioperative hypotension has been associated with myocardial infarction (MI), stroke, and death.2,4–6 
By blunting the effect of the sympathetic system on vascular tone, anesthesia may increase reliance on the renin–angiotensin and vasopressor systems to maintain blood pressure. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), which are commonly used in patients with a history of, or risk factors for, cardiovascular disease, block the physiologic renin–angiotensin response to hypotension.7 
Current guidelines from the American College of Cardiology and American Heart Association recommend continuing ACEI/ARBs in the setting of noncardiac surgery; these recommendations are based on data from small randomized trials and observational studies with significant risk of bias.8  By contrast, many anesthesia groups routinely withhold ACEI/ARBs on the day of surgery to avoid intraoperative hypotension.9,10  Without strong evidence, the practice of withholding ACEI/ARBs on the day of surgery appears to depend largely on provider preference and local policy.
The primary objective of this study was to test the hypothesis that withholding ACEI/ARBs (compared to continuing them on the day of surgery) is associated with a lower risk of the 30-day composite outcome of all-cause death, myocardial injury after noncardiac surgery (MINS), and stroke. Secondary objectives included determining the relationship between withholding ACEI/ARBs and perioperative clinically important hypotension and the association between perioperative clinically important hypotension and the 30-day risk of the composite outcome of all-cause death, MINS, and stroke.
Materials and Methods
Cohort
We conducted analyses in a sample from the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) study—a prospective international cohort study—that included 16,079 patients from 12 centers in eight countries (throughout North and South America, Australia, Asia, and Europe) recruited from August 2007 to January 2011 (ClinicalTrials.gov identifier: NCT00512109). The research ethics board at each site approved the protocol before patient recruitment.
Previous reports have described the VISION cohort study.11–13 Briefly, participants at least 45 yr old undergoing noncardiac surgery who required an overnight hospital admission with general or regional anesthetic were screened sequentially, and if eligible and consenting, they answered a series of questions regarding their past medical, surgical, and social history. Study personnel reviewed medical charts for additional history.
Outcomes
Our primary outcome was a composite of 30-day all-cause death, MINS,12  and stroke. These components were selected to fulfill the requirements for a valid composite outcome (i.e., including mortality avoided competing risks, each component could influence clinical practice as they all impact 30-day mortality, and one would anticipate that they would be affected by ACEI/ARBs similarly).14 MINS was defined as any peak non–high sensitivity cardiac troponin T (cTnT) value greater than or equal to 0.03 ng/ml resulting from myocardial ischemia (i.e., without evidence of a nonischemic etiology) that occurred within the first 30 days after surgery.12 Stroke was defined as a new focal neurologic deficit thought to be vascular in origin with signs and symptoms lasting more than 24 h.
Throughout each patient’s hospital stay, research personnel performed clinical evaluations and reviewed medical records. We measured cTnT using the Roche fourth-generation Elecsys assay (Germany) to assess for myocardial injury 6 to 12 h postoperatively and on the first 3 days after surgery. Research staff obtained other information on death and stroke from in-hospital follow-up, review of medical records, and a follow-up telephone interview conducted with the patients or their caregivers 30 days after surgery. If the patient interview indicated the occurrence of an outcome, their primary care physicians were contacted to obtain further documentation. Physicians experienced in perioperative medicine adjudicated death, MINS, and stroke.
Secondary outcomes of interest included clinically important intraoperative and postoperative hypotension, defined a priori as systolic blood pressure (sBP) less than 90 mmHg for any duration for which an intervention was initiated (including initiation or intensification of intravenous fluids, use of vasopressors or inotropes, blood transfusion, or intraaortic balloon pump therapy) that occurred during surgery (intraoperative hypotension) and during postoperative days 0 to 3 (postoperative hypotension).
Definitions for all variables are available in Supplemental Digital Content 1, http://links.lww.com/ALN/B326, under Variable Definitions.
Analyses
We performed the analyses using Stata (version 13.1 MP; Stata Corp, USA). All hypothesis tests were two sided; P < 0.05 denoted statistical significance.
Primary Objective
Relationship between Withholding versus Continuing Preoperative ACEI/ARBs and the Composite of Death, MINS, or Stroke.
Among patients who used ACEI/ARBs during the 7 days before surgery (i.e., baseline users), we compared outcomes of patients who did not take ACEI/ARBs within 24 h before surgery to the outcomes of those who did. We used multivariable modified Poisson regression15  to estimate relative risks adjusted for a large set of potential confounders (listed in table 1 and table S1 in Supplemental Digital Content 1, http://links.lww.com/ALN/B326), including patient characteristics, preoperative use of antihypertensive medications and antiplatelet agents or anticoagulants that may contribute to perioperative bleeding (use vs. no use 1 to 7 days before surgery), continuation, withholding, or new initiation of these medications on the day of surgery, and the type and the timing of surgery (elective vs. urgent or emergency surgery). We also accounted for potential center effects using a cluster-robust variance estimator16  with study centers as clusters. We used restricted cubic spline functions to model continuous variables (preoperative sBP, age, body mass index, and estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration equation).17  We did not study the effects of withholding ACEI/ARBs or other antihypertensive medications after surgery because the timing of postoperative medication use was not captured with sufficient precision in VISION.
Table 1.

Abridged Cohort Characteristics

Abridged Cohort Characteristics

Secondary Objectives
Effect of Preoperative sBP on the Relationship between Withholding of Preoperative ACEI/ARBs and the Composite of Death, MINS, or Stroke.
We tested whether the relationship between withholding versuscontinuing ACEI/ARBs and the primary outcome was consistent across different levels of preoperative sBP. We used tests of interaction in a multivariable fractional polynomial approach with the algorithm outlined by Royston and Sauerbrei18  to search for the optimal functional form of preoperative sBP that would significantly modify the effect of withholding ACEI/ARBs, where sBP was analyzed as a continuous variable.
Relationship between Clinically Important Hypotension and Withholding Preoperative ACEI/ARBs and Separately the Composite of Death, MINS, or Stroke.
We undertook multivariable modified Poisson regression analyses as the primary objective to explore the relationship between clinically important intraoperative and, separately, postoperative hypotension and withholding versus continuing ACEI/ARBs in the 24 h before surgery.
In all patients (not limited to ACEI/ARB users), we undertook similar multivariable modified Poisson regression analyses to study the relationship between intraoperative and, separately, postoperative clinically important hypotension and the composite of death, MINS, and stroke.
Variation in Withholding Preoperative ACEI/ARBs.
We estimated the proportion of variation in the practice of withholding or continuing ACEI/ARBs preoperatively that could be explained by study center, patient, and surgical factors. We first constructed a multivariable logistic regression model to predict the preoperative withholding of ACEI/ARBs with demographics, clinical factors, surgical factors, and the study center as independent variables. We next constructed a model that included only surgical factors and study center, and we compared it to the full model that also included demographics and clinical factors using a likelihood ratio test to determine whether clinical factors made a significant independent contribution to the explained variation. If the test was statistically significant, we estimated the independent contribution of clinical factors by subtracting the R2 of the model without clinical factors (calculated using the method of McKelvey and Zavoina19 ) from the full model. We repeated the same process for surgical factors and study center. We took variation that could not be explained by these factors as reflecting provider preference.
Sensitivity Analyses
To test for residual confounding, we performed tracer analyses with significant intraoperative bleeding that resulted in intraoperative blood transfusion and significant bleeding within 30 days that required transfusion of blood products or reoperation. These common outcomes were associated with increased risk of our primary outcome but are unlikely to be influenced by withholding ACEI/ARBs. Failing to detect these associations would lend support for a causal nature to our primary results.20,21 
We additionally looked for associations between withholding versuscontinuing other antihypertensive agents and our primary outcome. If withholding of several of these agents was associated with the primary outcome in the same direction as withholding of ACEI/ARBs, this may again suggest residual confounding.
We also conducted three post hoc sensitivity analyses in response to comments from peer reviewers. First, we repeated our main analyses using logistic regression in place of modified Poisson regression. Second, we repeated our main analyses based on the composite outcome of all-cause death, MI, and stroke at 30 days after surgery. Third, we examined the effect of progressively longer durations of intraoperative hypotension on the primary composite of death, MINS, or stroke at 30 days after surgery and performed a statistical test to assess for trend.
Approach to Missing Data
We excluded patients who did not have complete preoperative medication data or postoperative blood pressures recorded or (among those who did not die or experience a stroke) did not have a cTnT level measured or recorded correctly (e.g., recorded as less than 0.04 ng/ml instead of exact value). We imputed all other missing data using single stochastic conditional imputation with predictive mean matching for continuous variables22  and logistic regression for any other missing variables, both with fully conditional specification.23  We included all variables and outcomes in the imputation model.
Results
We analyzed data from 14,687 (91.3%) of the 16,079 recruited patients (fig. 1) of whom 1,409 (9.6%) died or suffered a nonfatal stroke or MINS; MINS occurred in 1,160 patients (7.9%), stroke in 90 (0.6%), and death in 302 (2.1%). We imputed missing baseline characteristics (mostly serum creatinine, height, and weight) for 10.3% of the included patients. The prevalence of most baseline characteristics differed among patients who suffered an event compared to those who did not (table 1 and table S1 in Supplemental Digital Content 1, http://links.lww.com/ALN/B326). Table S2 (Supplemental Digital Content 1, http://links.lww.com/ALN/B326) shows that the 8.7% of patients who were omitted from the analysis for missing data were similar to those included.
Fig. 1.
Participant flowchart. VISION = Vascular events In noncardiac Surgery patIents cOhort evaluatioN.

Participant flowchart. VISION = Vascular events In noncardiac Surgery patIents cOhort evaluatioN.

Six thousand eight hundred fifty-six (46.7%) patients were taking an antihypertensive agent at baseline (i.e., within 1 to 7 days before surgery); 4,120 (60.1%) used a single agent; 2,131 (31.1%) used two medications; and 605 (8.8%) used three or more. Four thousand eight hundred two patients took ACEI/ARBs at baseline; 2,275 of them (47.4%) were also using at least one other antihypertensive medication. Among all antihypertensive medication users, 1,794 (26.2%) had at least one of these medications withheld on the day of surgery (table 2). Typically only one antihypertensive agent was withheld (79.3% of patients), even in patients taking multiple agents at baseline. Patients with lower preoperative blood pressure were more likely to have their medications withheld on the day of surgery (table S3, Supplemental Digital Content 1, http://links.lww.com/ALN/B326).
Table 2.

Number of Antihypertensive Medications That Patients Were Using at Baseline and the Number and Proportion Withheld on the Day of Surgery

Number of Antihypertensive Medications That Patients Were Using at Baseline and the Number and Proportion Withheld on the Day of Surgery

Results for the Primary Objective
Patients in whom ACEI/ARBs were withheld (n = 1,245; 25.9%) were largely similar to those in whom ACEI/ARBs were continued but were less likely to have very high preoperative blood pressure, less likely to undergo major urogenital surgery, and more likely to undergo major general and urgent or emergency surgery.
Among the 4,802 patients who took ACEI/ARBs at baseline, withholding ACEI/ARBs on the day of surgery was associated with an 18% reduction in the relative risk of the composite outcome of death, stroke, or MINS (adjusted relative risk [aRR], 0.82; 95% CI, 0.70 to 0.96; P = 0.01) with the results qualitatively consistent across the component outcomes (fig. 2).
Fig. 2.
(A) Adjusted association between withholding versus continuing preoperative angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) with postoperative 30-day death from any cause, myocardial injury after noncardiac surgery (MINS), or stroke, intraoperative and postoperative (day 0 to 3) hypotension, and the exploratory outcome myocardial infarction (MI) in 4,802 patients taking these medications at baseline. (B) Association between hypotension and postoperative death and vascular events in all 14,687 patients. aRR = adjusted relative risk.

(A) Adjusted association between withholding versus continuing preoperative angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) with postoperative 30-day death from any cause, myocardial injury after noncardiac surgery (MINS), or stroke, intraoperative and postoperative (day 0 to 3) hypotension, and the exploratory outcome myocardial infarction (MI) in 4,802 patients taking these medications at baseline. (B) Association between hypotension and postoperative death and vascular events in all 14,687 patients. aRR = adjusted relative risk.

Results for Secondary Objectives
The relationship between withholding ACEI/ARBs and the primary composite outcome was consistent across preoperative sBP readings; the P value for interaction was nonsignificant (i.e.P > 0.2).
Withholding ACEI/ARBs was also associated with a 20% relative reduction in the risk of intraoperative hypotension (aRR, 0.80; 95% CI, 0.73 to 0.88; P < 0.001) but was not associated with postoperative hypotension (aRR, 0.92; 95% CI, 0.77 to 1.10; P = 0.36).
Among all patients (regardless of ACEI/ARB use), those who experienced clinically important hypotension during surgery (n = 4,162; 28.3%) were more likely to develop clinically important hypotension after surgery (aRR, 1.65; 95% CI, 1.48 to 1.84; P < 0.001). Adjusted for postoperative hypotension, intraoperative hypotension was not significantly associated with the composite outcome of death, MINS, or stroke within the 30 days after surgery (aRR, 1.11; 95% CI, 0.98 to 1.25; P = 0.09).
In total, 2,860 of 14,687 patients (19.5%) experienced at least one episode of clinically important postoperative hypotension; 2,728 (95.4%) of them experienced their first episode of postoperative hypotension by day 3 and the remainder between day 4 and discharge (fig. 3). Postoperative hypotension occurred in the postanesthesia care unit in 3.4% (n = 493) of patients; in the hours immediately after transfer out of the postanesthesia care unit in 6.3% (n = 931); and during the next day in 11.6% (n = 1,711). Patients who experienced clinically important hypotension by the third postoperative day (n = 2,728; 18.6%) were more likely to die or suffer a vascular event compared to their counterparts without postoperative hypotension (aRR, 1.68; 95% CI, 1.53 to 1.85; P < 0.001).
Fig. 3.
Clinically significant hypotension in the postoperative period. In total, 2,860 of 14,687 patients (19.5%) experienced at least one episode of clinically significant hypotension after their surgery; 2,728 (95.4%) of those patients experienced a hypotensive episode by postoperative day (POD) 3. OR = operating room; PACU = postanesthesia care unit.

Clinically significant hypotension in the postoperative period. In total, 2,860 of 14,687 patients (19.5%) experienced at least one episode of clinically significant hypotension after their surgery; 2,728 (95.4%) of those patients experienced a hypotensive episode by postoperative day (POD) 3. OR = operating room; PACU = postanesthesia care unit.

Only 6.62% of the propensity to withhold ACEI/ARBs on the day of surgery could be explained by available demographic and clinical information (explained 0.02%), surgical information (explained 0.6%), and center information (explained 6.0%). Figure S1 (Supplemental Digital Content 1, http://links.lww.com/ALN/B326) shows that the percentage of baseline ACEI/ARB users who had these medications withheld ranged from 9% to 44% across countries included in the study. Although these estimates are based on just 12 hospitals and relatively few patients, much variation likely reflects provider preference.
Sensitivity Analyses
Clinically significant bleeding during surgery occurred in 278 (5.8%) baseline ACEI/ARB users and was significantly associated with the composite of death and vascular events (aRR, 1.49; 95% CI, 1.13 to 1.97; P = 0.004) but not associated with withholding these medications (aRR, 0.94; 95% CI, 0.70 to 1.26; P = 0.69). Significant bleeding within 30 days of surgery occurred in 955 (19.9%) ACEI/ARB users and was significantly associated with the primary outcome (aRR, 2.05; 95% CI, 1.63 to 2.59; P < 0.001) but not associated with withholding these medications (aRR, 1.04; 95% CI, 0.92 to 1.18; P = 0.56). Withholding of other antihypertensive medications was not significantly associated with the primary outcome (fig. S2, Supplemental Digital Content 1, http://links.lww.com/ALN/B326), with wide CIs around the estimates. Both of these sensitivity analyses suggest that our primary results are specific to ACEI/ARBs and not explained by residual confounding.
A similar analysis suggested that some residual confounding affected the relationship between hypotension and the primary outcome, but the results remained qualitatively similar after adjusting for bleeding (Supplemental Digital Content 1, http://links.lww.com/ALN/B326, heading Sensitivity analysis for relationship between hypotension and the primary outcome).
The sensitivity analysis with logistic regression yielded results similar to our prespecified analyses (table S2, Supplemental Digital Content 1, http://links.lww.com/ALN/B326). The sensitivity analysis based on the composite outcome of death, MI, or stroke demonstrated similar results to the analyses based on the primary outcome. The association between withholding ACEI/ARB versuscontinuing these drugs before surgery and the composite outcome of death, MI, or stroke produced essentially the same point estimate of effect as seen with the primary composite outcome; however, the result in the sensitivity analysis was not statistically significant (aRR, 0.81; 95% CI, 0.62 to 1.03; P = 0.08). The sensitivity analysis had less power than the primary analysis because 205 (4.3%) baseline ACEI/ARB users suffered an MI, whereas 531 (11.1%) suffered MINS. The composite outcome of death, MI, or stroke was more likely to occur in patients who experienced intraoperative hypotension (aRR, 1.23; 95% CI, 1.03 to 1.47; P = 0.03) and postoperative hypotension (aRR, 2.01; 95% CI, 1.72 to 2.33; P < 0.001).
Figure S3 (Supplemental Digital Content 1, http://links.lww.com/ALN/B326) demonstrates a graded relationship between progressively longer durations of intraoperative hypotension and increasing risk of death, MINS, or stroke (P value for trend less than 0.001).
Discussion
One third of patients having major noncardiac surgery in this large prospective cohort study used ACEI/ARB on a regular basis. Of these patients, a quarter did not receive their ACEI/ARBs in the 24 h before surgery and had a lower adjusted risk of death or vascular events (aRR, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and of clinically important intraoperative hypotension (aRR, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The negligible association between clinical and surgical factors and the withholding of ACEI/ARBs suggests that clinician discretion, independent of patient characteristics, predominantly determined the decision to withhold.
Recent perioperative guidelines suggest continuing ACEI/ARBs before noncardiac surgery,8  citing a meta-analysis and a retrospective cohort study. The meta-analysis included three small randomized trials (20 to 30 patients per arm) limited to cardiac and vascular surgery and two retrospective observational studies (n = 434 patients) undergoing nonemergency surgery.24  The results suggested that patients given ACEI/ARBs before surgery were more likely to develop hypotension requiring a vasopressor during or shortly after induction of anesthesia (relative risk, 1.50; 95% CI, 1.15 to 1.96). The incidence of perioperative MI did not differ significantly in patients who continued or withheld ACEI/ARBs, but the CI was very wide and thus compatible with substantial benefit or harm (relative risk, 0.41; 95% CI, 0.07 to 2.53). A more recent meta-analysis arrived at similar conclusions.25 
In a cohort analysis that matched 9,028 baseline ACEI users to 9,028 nonusers on a propensity score for baseline ACEI use, ACEI use was not associated with either 30-day mortality (odds ratio, 0.93; 95% CI, 0.73 to 1.19) or the composite of in-hospital morbidity and mortality (odds ratio, 1.06; 95% CI, 0.97 to 1.15).26  The analysis had four limitations that we avoided in our analysis. First, patients who adhere to preventive medications (or placebo) have better health outcomes than those who have indications to take them but do not27–29 —a “healthy user” bias that may counteract an increase in risk associated with taking ACEI. In contrast, we limited our comparisons to patients who were already taking these medications at baseline. Second, outcomes were collected as part of routine care, whereas VISION employed central adjudication of the primary outcomes and active surveillance for myocardial injury with serial cTnT measurements. Third, the study was conducted in a single center, while VISION was a multicenter, international study. Finally, we obtained information on whether medication was withheld directly from patients and medication records.
We found that hypotensive episodes were common in the hours and days after surgery. Postoperative hypotension was independently associated with a greater risk of death or vascular events. Intraoperative hypotension was also common but was not significantly associated with mortality and vascular events after adjustment for postoperative hypotension.
Our findings regarding postoperative hypotension parallel the results from the 10,010-patient PeriOperative ISchemic Evaluation (POISE)-2 trial. In POISE-2, 37.1% of patients in the placebo arm experienced clinically important hypotension; hypotension was associated with perioperative MI (hazard ratio, 1.37; 95% CI, 1.16 to 1.62).30  The association between intraoperative hypotension and death or vascular events was not statistically significant in our analysis. Larger studies have reported an association between intraoperative hypotension, kidney and myocardial injury,4  and mortality.5  The difference from our findings may relate to these studies’ use of lower thresholds to define intraoperative hypotension, our adjustment for postoperative hypotension, or insufficient power in our study.
Study Strengths
We used prospectively collected data from a representative sample of patients undergoing a broad range of surgeries in several countries, actively monitored and centrally adjudicated outcomes, ensured minimal loss-to-follow-up, had a comprehensive approach to missing data, adjusted for a wide range of potential confounders, and had no evidence of substantial residual confounding in sensitivity analyses. Our study is the first to assess the effect of preoperative ACEI/ARB management on the incidence of a cardiovascular outcome that includes MINS distinct from MI. Only 15.8% of patients suffering MINS experience an ischemic symptom, and the remaining 84.2% of events would likely go undetected without systematic postoperative troponin monitoring.12 Accordingly, the third universal definition of MI consensus statement recommends monitoring perioperative troponin measurements in high-risk patients undergoing noncardiac surgery.31  Among baseline ACEI/ARB users, 205 (4.3%) suffered an MI, whereas 531 (11.1%) suffered MINS. Given the almost identical point estimate of apparent effect in the sensitivity analysis, this lower incidence of MI is almost certainly the reason that the association between withholding ACEI/ARBs versus continuing these drugs before surgery and the composite outcome of death, MI, or stroke was not statistically significant (aRR, 0.81; 95% CI, 0.62 to 1.03; P = 0.08).
Study Limitations
Residual confounding is possible in any observational study. We adjusted for many variables and failed to detect substantial residual confounding in sensitivity analyses. Patients in whom ACEI/ARBs were withheld were generally similar to those in whom they were continued in unadjusted comparisons of baseline characteristics but notably appeared more likely to undergo urgent or emergency surgery. Urgent or emergency surgeries were those performed within 72 h of the acute event that led to surgery. Patients were admitted more than 24 h before many of these surgeries during which time clinicians could withhold their blood pressure medications. After adjusting for the type of surgery and patient characteristics and accounting for center effects, patients who underwent urgent or emergency surgery were not significantly more likely to have their ACEI/ARBs withheld than patients who underwent elective surgery (P = 0.29).
We excluded 8.7% of patients due to missing data on cTnT, postoperative blood pressure, or preoperative medication use. Included and excluded patients had similar baseline characteristics. We imputed missing data for baseline characteristics in 10.3% of included patients. Our findings regarding withholding versuscontinuing ACEI/ARBs were likely robust to this small amount of missing confounder data because clinical variables explained very little of the variation in this practice (i.e., they were very weak confounders), and we made appropriate imputation efforts.
The need to control for many potential confounders and the correlation between them limited the statistical power of our analyses.32  We could not reliably estimate the effects of withholding antihypertensive medications other than ACEI/ARBs and of starting medications not already used before the day of surgery or study potentially relevant subgroups such as patients with heart failure or known cardiovascular disease. Sample size may also have limited our statistical power to detect differential effects of withholding ACEI/ARBs at different levels of preoperative blood pressure. Regression results demonstrated wide CIs for outcomes with a limited number of events (i.e., stroke and MI), but the direction of their point estimates was consistent with the composite outcome.
We relied on a crude dichotomous definition of hypotension (sBP less than 90 mmHg of any duration accompanied by intervention) rather than actual values. Our blood pressure threshold may have been too high, short durations of sBP slightly below 90 mmHg may not be prognostically significant, and the associations with death and vascular events may be driven by episodes with lower sBP or of a long duration. We relied on routine measurements commonly conducted at 4-h or longer intervals in the postoperative period and have likely missed some hypotensive episodes. Surveillance bias may have inflated the associations between postoperative hypotension and clinical outcomes because patients who develop complications are monitored more closely.
We could not evaluate renal outcomes in this subsample of VISION. Three randomized controlled trials totaling 64 patients studied renal outcomes of preoperative ACEI in cardiac and vascular surgery but detected no acute kidney injury events.33  A prospective cohort study of 1,594 cardiac surgery patients found a graded increase in the risk of acute kidney injury across three groups of preoperative ACEI/ARB exposure (none, 31%; held, 34%; continued, 42%; P for trend 0.03).34  The study suggested that, if anything, withholding of ACEI/ARBs is associated with a reduction in kidney injury.
We did not study the effects of withholding antihypertensive medications after surgery because the timing of postoperative medication use was not captured with sufficient precision in VISION.
Implications
We estimate that, if all patients who continue to take ACEI/ARBs on the day of surgery were to instead withhold them, 5.9% (95% CI, 1.2 to 10.1)—or over 500,000 patients per year—would avoid death, MINS, or stroke within 30 days of their operation. This estimate assumes that 100 million of the 200 million people who undergo major noncardiac surgery annually are at least 45 yr old,1,36 that 9.6% die or suffer an adverse perioperative vascular event, that our data accurately represents the international patient population and clinical practice, and that the relationship we observed is causal. Even if these assumptions are violated, our results have substantial global importance.

Lung ultrasound to manage fluid volume in dialysis.


Volume overload is an important, but often hidden risk factor for all-cause and cardiovascular death in end stage renal disease (ESRD) patients. Monitoring lung water could be used as a biomarker for detecting and monitoring lung congestion in populations at risk for pulmonary edema, as substantial lung water accumulation may occur before clinical symptoms of heart failure and in other conditions appear, explains the author of the present Italian study. Until recently, measuring lung water meant using costly radioactive compounds, X-rays or placing catheter into the pulmonary artery. But as the present study shows, ultrasound (US) could also allow valid, reproducible estimates of lung water.

Why ultrasound? Water accumulates in the lung interstitium, thickening the interlobular septa and thereby generating visible bundles in the ultrasound. These bundles are a US equivalent of B lines (BL-US) detected in chest radiographs – which means that simply counting BL-US could offer an estimate of lung water. Studies have also shown that the number of BL-US is associated with parameters such as LV filling pressure, larger LV end-diastolic and end-systolic diameters, LV mass index, left atrial volume index, tricuspid regurgitation velocity and estimated pulmonary artery systolic pressure in heart failure (HF) patients. And: Ultrasound could also be particularly valuable in intensive care patients, where it could be used to discriminate moderate and severe lung congestion.

Ultrasound (US) is a well-validated technique that allows reliable estimates of lung water in the care of hemodialysis patients at high cardiovascular risk, summarizes the author.

 

Abstract

Volume overload is a hidden, pervasive complication in dialysis patients with dyspnea and pulmonary edema being its main clinical manifestations. Measuring lung water has clinical potential because it allows timely treatment of lung congestion at a preclinical stage. Chest ultrasound (US) is a novel, well-validated technique that allows reliable estimates of lung water in clinical practice. The application of this technique in dialysis patients has shown that an unsuspectedly high proportion of these patients have moderate to severe lung congestion which is usually asymptomatic. Furthermore, lung congestion in these patients is only loosely associated with fluid excess as measured by bioimpedance (BIA). Lung congestion is associated with a high death risk in dialysis patients and therefore represents a potential treatment target. The “Lung water by Ultra-Sound guided Treatment to prevent death and cardiovascular complications in high risk ESRD patients with cardiomyopathy” (LUST) study will provide important information about the clinical value of this technique in the care of hemodialysis patients at high cardiovascular risk.

Volume overload is considered a main, hidden risk factor for all-cause and cardiovascular death in end stage renal disease (ESRD) patients [1]. Observational studies support the hypothesis that chronic volume expansion is per se (i.e., above and beyond blood pressure and other risk factors) a strong, direct predictor of the risk of death in hemodialysis patients [2, 3]. A major reason hindering optimization of fluid volume status in dialysis patients is the almost universal presence of LVH and its associated LV diastolic and systolic dysfunction [4] which makes these patients hypotension-prone and unable to mount a successful counter-regulatory hemodynamic response to the volume removal at the UF rate applied in standard dialysis schedules.

Estimates of fluid volume in dialysis patients are being increasingly applied to guide the prescription of ultrafiltration and dietary sodium intake in dialysis patients. These estimates include the measurement of total and extracellular fluid volume by bio-impedance (BIA) [5], inferior vena cava diameter, plasma volume changes across dialysis by the Crit-Line system and circulating levels of cardiac natriuretic peptides. All these biomarkers still have a low evidentiary basis supporting their systematic use in ESRD. Though small trials based on surrogates seem to support the use of BIA [6, 7] we still lack trials based on clinical endpoints documenting the usefulness of this technique. Inferior vena cava diameter does not provide useful information for probing dry weight [8]. As with BIA, there are no clinical trials using valid clinical endpoints which test the value of this measurement in clinical practice. In a clinical trial testing the application of Crit-Line to guide UF, the Crit-Line Intradialytic Monitoring Benefit (CLIMB) study, adverse events in the active arm of the trial were significantly higher than in the control arm [9]. Finally, cardiac natriuretic peptides, ANP, BNP and Pro-BNP, largely reflect left ventricular (LV) myocardial mass and LV end-diastolic pressure rather than circulating volume [10, 11].

It should be noted that, however, reliable and accurate a technique might be, the derived estimates of global fluid volumes may be insufficient to guide clinical decisions about fluid volume optimization in ESRD patients. Fluid accumulation in critical organs like the lung is of particular importance. Until recently, no easily applicable method for measuring fluid accumulation in this organ was available. Overall, notwithstanding the large majority of nephrologists who have no doubt about the paramount importance of body fluid volume optimization in the care of dialysis patients, most dialysis centers have no established clinical policy for evaluating and monitoring fluid volume status [12].

Fluid Excess, Hemodynamic, and Pulmonary Congestion

Together with the heart, the lung is the organ where fluid excess poses the major health hazards. Accumulation of fluid in a dialysis patient’s lungs entails a high risk for pulmonary edema [13, 14]. Superficially, pulmonary edema might be equated with volume overload. However, fluid overload apart, lung water content also depends on two additional, quite relevant factors: left ventricular (LV) function and lung permeability. In both LV systolic and diastolic dysfunction, LV end-diastolic pressure and hence left atrial pressure are high; retrograde transmission of this pressure to pulmonary veins and lung capillaries results into high pulmonary capillary wedge pressure — “hemodynamic congestion”. Hemodynamic congestion sets the stage for extravasation of fluid into the lung interstitium and into the alveoli, resulting into “pulmonary congestion”.

Even though pulmonary congestion is, in most cases, attributable to high pulmonary capillary pressure concomitant with fluid overload, this alteration may also occur without fluid overload pointing to fluid redistribution triggered by systemic arterial and/or venous vasoconstriction. In this regard, it cannot be overemphasized that fluid removal in patients with decompensated heart failure has just a loose relationship with the improvement of dyspnea [15]. In the same vein, application of continuous intrathoracic impedance monitoring in these patients showed that pulmonary congestion may antedate by 2 weeks frank pulmonary edema in these patients. Of note, a high degree of tolerance to fluid accumulation in the lung without superimposed dyspnea is well-documented in patients with nephrotic syndrome where an estimated average lung water excess as high as 1.7 l can remain asymptomatic [16]. Yet, in the vast majority of cases, particularly in patients with LV disorders, congestion eventually triggers clinical lung congestion, i.e., dyspnea, a symptom most often leading to hospitalization.

The relevance of the second factor that may facilitate lung congestion in patients with kidney diseases, lung permeability, is obvious in acute kidney injury a condition where, independently of fluid overload, systemic inflammation may dramatically increase alveolo-capillary permeability and trigger life-threatening congestion [17]. Furthermore, pulmonary capillaries are recognized as a vulnerable segment of the cardiopulmonary circulation in patients with heart disease [18] which has obvious implications in dialysis patients, a population where cardiomyopathy is almost universal [4].

Measuring Lung Congestion

Because substantial lung water accumulation may occur before clinical symptoms in heart failure and in other conditions, monitoring lung water has prima facie credibility as a biomarker for detecting and monitoring lung congestion in populations at risk for pulmonary edema. However, until recently measuring lung water entailed either the use of costly radioactive compounds [19], exposure to X-rays [20] or the placement of a catheter into the pulmonary artery to apply the thermo-dilution technique [21]. The discovery that ultrasound (US) may allow valid, reproducible estimates of lung water as well as corollary information on other pulmonary alterations has been a breakthrough in pulmonary medicine [22].

The rationale for adopting ultrasound to measure lung water is that water accumulation in the lung interstitium thickens the interlobular septa. This thickening produces a reverberation of the US beam and generates visible bundles at narrow basis going from the probe to the edge of the echotomography screen. These bundles are a true US equivalent of B lines [BL-US] detected in chest roentgenograms and their simple count provides an estimate of lung water [23] (Fig. 1). The number of BL-US is associated with LV filling pressure [23] as well as with larger LV end-diastolic and end-systolic diameters, LV mass index, left atrial volume index, tricuspid regurgitation velocity and estimated pulmonary artery systolic pressure in heart failure (HF) patients with dyspnea as well as in those without overt cardiac decompensation [24]. Beyond heart failure, the technique is of particular value in intensive care patients where it is a powerful instrument to discriminate moderate and severe lung congestion (areas under the ROC curves of 0.94 and 0.96 respectively) [25].

Figure 1.

Ultrasound B lines in interstitial lung edema are generated because the US beam reverberates against the thickened (edematous) interlobular septa.

Lung Congestion in ESRD

Lung US has specifically been validated in ESRD patients where it holds high intra and interobserver reproducibility as well as high technical reproducibility, i.e. it provides reproducible results with different echo-tomography machines [26]. Measuring the degree of lung congestion in dialysis patients has clinical potential for various reasons. Lung congestion is common both in hemodialysis [26-28] and in peritoneal dialysis [29] patients where it is usually asymptomatic. There is a dose–response relationship in dialysis patients between the number of US B lines and both the risk of mortality and cardiovascular complications which is largely independent of other risk factors ([27, 28]). In addition, the number of US-B lines is strongly associated with various echocardiography parameters including left atrial volume, pulmonary artery pressure, Ee’ ratio (an index of diastolic function) and, particularly, with the ejection fraction; these associations hold true both predialysis and postdialysis implying that the relationships are largely independent of volume overload [26].

Lung auscultation to detect crackles at the lung bases is a cornerstone for the diagnosis and the monitoring of congestion in patients with heart failure and in those with chronic kidney failure [30]. However, as with several other time honored clinical signs [31], the reliability of auscultation for the diagnosis of lung congestion has not, until very recently, been specifically assessed in the dialysis population. Investigators of the “Lung water by Ultra-Sound guided Treatment to prevent death and cardiovascular complications in high risk ESRD patients with cardiomyopathy” (LUST) [32], a randomized trial testing whether the use of lung US in high risk hemodialysis patients may improve clinical outcomes and echocardiographic indicators of cardiomyopathy in these patients, adopted lung sonography as a reference test to examine the diagnostic reliability of crackles as a sign of pulmonary congestion [33] in over 1000 paired measurements of lung water by US with simultaneous standardized auscultation of the thorax. These analyses showed that crackles were quite insensitive in detecting interstitial lung edema found by lung US [26].

Lung congestion in heart failure is a gradual phenomenon and pulmonary edema may supervene after one or more weeks of insidious accumulation of fluid in the lung [34]. This is of particular relevance in dialysis patients, a population where lung water (as measured US-B lines) only weakly correlated with total body water (by BIA) and interdialysis weight gain10. Furthermore, dialysis patients have increased alveolo-capillary permeability [35] and the average estimated interstitial lung water in ESRD patients is about 1.2 l, an unsuspectedly high degree of pulmonary congestion [23].

The application of lung US has relevant clinical potential. However, its usefulness in patients needs to be tested in a randomized trial comparing a treatment policy guided by this technique with that using the standard approach. Currently, the usefulness of targeting asymptomatic lung congestion remains unproven. The CLIMB study is a cautionary tale about accepting on purely physiologic grounds the use of medical devices and the lack of proper trials testing their impact on clinical endpoints.

Lung US is a well-validated, simple and low-cost technique which can be easily applied by nephrologists at the bedside by using virtually all, old and new, US machines [36] including affordable hand-held US devices. The LUST study is currently testing whether the use of lung US by nephrologists may improve clinical outcomes in high risk dialysis patients. It will provide important information about the clinical value of this technique in the care of hemodialysis patients at high cardiovascular risk.

Source:http://onlinelibrary.wiley.com

Richard Lehman’s journal review.17 April 2017


NEJM  13 Apr 2017  Vol 376
Diabetes, death, and cardiovascular disease in Sweden
“Diabetes mellitus is a complex and heterogeneous group of chronic metabolic diseases that are characterized by hyperglycemia.” That’s a good intelligent sentence to begin a good intelligent analysis of outcomes in Sweden for people labelled with diabetes over the period 1998-2012.

Figure two summarises what happens to people with type 1 and 2 diabetes in a civilised country with decent modern healthcare. For cardiovascular outcomes, the story is one of steady improvement: events and hospital admissions for all patients with diabetes are falling compared with population controls. The main exception, however, is all cause death (per two year period) in people with the label of type 2 diabetes. This was going down up until 2008 and then something happened to stop it dropping. I would love to know why. Were the Swedes doing something right and then started doing something wrong? What non-cardiovascular factors are causing this anomaly? It should be very easy to check from the mortality registers on this database.

Diabetes in American youth
And now, with due foreboding, let’s fly to the US. Here the incidence of diabetes is rising, especially in the young. In this survey of Americans aged 10-19, the overall rise between 2002 and 2012 was 1.4% annually for type 1, and 7.1% annually (4.8% after adjustment) for type 2. But for two ethnic groups, the rise in T2DM was spectacularly larger than for white American youth: native Americans and black Americans. Early onset T2DM has a pretty terrible prognosis, even when ideally treated—and optimal treatment is unlikely to be affordable for many of those worst affected. Here is another driver towards ever greater health disparities by race in the US.

JAMA 11 Apr 2017  Vol 317
Middle life risk factors for later brain amyloid
Florbetapir: the word to remember this week. Florbetapir is a chemical that crosses the blood-brain barrier and attaches itself to amyloid. It is produced in a cyclotron in the morning and will have decayed by the evening, because the crucial ingredient is 19F, an isotope of fluorine with a half-life of 109 minutes. That’s just enough time to get your subject into a positron emission scanner and look for amyloid in the brain. Over two years, this was done to 322 participants in the Atherosclerosis Risk in Communities cohort, which was set up in 1987-9 and measured cardiovascular risk factors sequentially in US adults without overt cardiovascular disease at baseline. Now this is very impressive, but bear in mind that florbetapir uptake on positron emission tomography (PET) is just a surrogate for amyloid deposition, which in turn is just a surrogate for so called Alzheimer’s disease. This in turn has become a catch-all label for dementia, and is very different from the case described by Alzheimer in 1906. Florbetapir uptake is very common in older people: in this cohort of mean age 76, it was present in 31% of those with no CV risk factors in midlife and in 61% with two or more risk factors. So this study shows two things: florbetapir PET picks up a lot of brain amyloid that has no obvious clinical meaning, and amyloid deposition is associated strongly with traditional CV risk factors rather than being something which discriminates clearly between “vascular” and “Alzheimer’s” dementia.

Back pain & manipulation
When I get back pain I become tetchy and needy. I want somebody to take it away so that I can become the calm, amiable, easy to live with person I would like to be. Fortunately, I don’t often get back pain. Instead I find other excuses for being tetchy and needy. But if I got back pain all the time, I can see why I would be manipulated, although this systematic review provides a weak signal that spinal manipulation can help in acute episodes of back pain. As with so many kinds of symptom relief, it’s not the population effect I’d be looking for if I were the person with back pain, it’s what might work for me. That is why the world is full of manipulators for when you become tetchy and needy.

JAMA Int Med  Apr 2017  Vol 
Hospital based primary care is more wasteful
I’m a strong advocate of breaking down the barriers between primary and secondary care in Britain. It would be nice to think that the good features of general practice could spread into hospitals: a broader view of diagnosis, more continuity of care, acceptance of uncertainty, frugality with testing, give and take based on personal knowledge of patients. But there are dangers too, as this American survey shows. “Primary care” in the US is something else, and it is often co-located with hospital services that make money from doing things to patients. This large sample of primary care visits by Americans shows that those who go to hospital based clinics are more likely to be overinvestigated, especially using radiography and MRI, and referred needlessly to specialists. Primary care doctors can be infected by their environment. When the NHS is forced into its next phase of disintegration, it could easily happen here. And you will be paying a lot more for it.

US hospital initiative works
Just occasionally, incentives achieve what they set out to do. An example seems to be the Medicare Hospital Readmission Reduction Program in the US. This was a voluntary scheme, which provided financial incentives to reduce readmissions in participating hospitals. It had a number of components and it proved very popular. In 2010, none of the 2837 hospitals in this study were participating in the programs. By 2015, all of them were involved with some of the components. Using some sophisticated analytics, the investigators show that the degree of participation correlates with a fall in 30 day readmissions following myocardial infarction, heart failure, and pneumonia.

The Lancet  15 Apr 2017  Vol 389
Alcohol in England
Here is a wide ranging and well written survey of how alcohol affects the health of people in England. It is modestly billed as “A rapid evidence review of the effectiveness and cost-effectiveness of alcohol control policies: an English perspective,” but it is much more than that. It provides a panoramic survey of what is known about drinking in England and how public institutions assess its costs and harms. As for interventions, the evidence is sensibly summarised at the start: “Although there is variability in research design and measured outcomes, evidence supports the effectiveness and cost-effectiveness of policies that address affordability and marketing. An adequate reduction in temporal availability, particularly late night on-sale availability, is effective and cost-effective. Individually-directed interventions delivered to at-risk drinkers and enforced legislative measures are also effective. Providing information and education increases awareness, but is not sufficient to produce long lasting changes in behaviour.”

Death from breathing
Now from drinking to smoking, and from England to the world. A quarter of men around the world still smoke, which is a 28% reduction from 1990. Smoking has fallen everywhere since then, except for Congo and Azerbaijan (for men) and Kuwait and Timor-Leste (for women). Despite the absolute decline, the relative contribution of smoking to overall disease burden is growing, especially in lower income countries. There is no excuse for this. Nicotine addiction can be satisfied in safe ways, which don’t involve the inhalation of toxins. Selling combustible tobacco is mass murder.

There is slightly more excuse for air pollution, which is largely a legacy of our long dependence on burning hydrocarbons for energy. Another Gates funded global survey lists particulate air pollution as the fifth ranking mortality risk factor in 2015. Again, successes in rich countries are counterbalanced by increases in pollution in low to middle income countries. At least there is the general will to find technological solutions for this, based as much on a common fear of global warming as on concern for people inhaling toxic air.

Celecoxib vs naproxen in high risk patients
So here’s a fairly common clinical scenario: you have a patient who’s had a cardiovascular event for which aspirin is indicated. They also would like to take a non-steroidal anti-inflammatory drug (NSAID) for arthritis. But they have had an episode of upper gastrointestinal bleeding. So if you continue their present treatment, they will need to take a proton pump inhibitor. As for the NSAID, you could opt for naproxen, because of its greater cardiovascular safety, or celecoxib, because of its greater GI safety. Which is it to be? A hospital in Hong Kong collected 514 such patients over seven years and randomised them to one or the other, in addition to aspirin and esomeprazole. The title blazons the fact that this was an industry independent trial. Good. But it wasn’t sufficiently powered to determine cardiovascular events. It did, however, show that celecoxib was significantly less likely than naproxen to cause upper GI bleeds over an 18 month period.

The BMJ 15 Apr 2017  Vol 357
Quick-Wee
Attentive readers of The BMJ will remember reading about Quick-Wee in Minerva last September. And here is Quick-Wee again, in a biggish randomised trial rather than the earlier 40 baby series in the Emergency Medicine Journal. Infants were randomised to either gentle suprapubic cutaneous stimulation (n=174) using gauze soaked in cold fluid (the Quick-Wee method) or standard clean catch urine with no additional stimulation (n=170), for five minutes. The method resulted in a significantly higher rate of voiding within five minutes compared with standard clean catch urine (31% v 12%, P<0.001). I like the pee value. It means we can agree that Quick-Wee is a wee improvement in getting wee tots to pee when we see the need to test their wee.    

Short course steroids are not harmless
“A few days on pred to see them through” is a very common strategy in the US, as I’m sure it is here. In fact, one fifth out of a million and a half adults in an American commercial insurance plan were given prescriptions for short term use of oral corticosteroids during a three year period. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The absolute risk may be small, but these relative risks are pretty alarming, especially for sepsis.

Uncertain about adult tonsillectomy
It’s nice to see an Uncertainties article in this week’s BMJ, especially a meaty one with some good graphics. It covers the evidence base for tonsillectomy in adults with recurrent tonsillitis. There are some rather poor randomised trials and some good retrospective case series. The tables are good, but where is the decision tool to be used directly with patients? I hope that future articles will go the whole way and put The BMJ right at the forefront of shared decision making by turning evidence synthesis into adaptable, shareable infographics.

Plant of the Week: Koelreuteria paniculata “Coral Sun”
The Indian Golden Rain tree is named in honour of Joseph Gottlieb Kölreuter (1733 –1806), who spent most of his life doing experiments on hybridisation in plants. This form of it is not a hybrid but a natural mutation with red stems and coral-pink finely divided leaves in spring, which turn pale green in the summer and are then joined by sprays of yellow flowers. In autumn, red returns to the leaves and the flowers will have turned into interesting bladder-like fruits.

So here is a tree for all seasons: well, three seasons anyway. And in nurseries it is becoming commoner and cheaper by the year. When we saw one on sale for £12.99 the other day, we bought it at once, though we have no idea where to put it. Our garden is not very warm, and our life expectancy is not infinite, so we will be lucky to see it grow to 3m, perhaps. In a favoured spot, over a longer time, you could easily double that. I suspect that the further north in England you go, the less well this tree will perform. It likes sun. Somewhere above Nottingham, it will probably just get mardy* and die.

I haven’t yet seen this particular variety in a garden, but perhaps in time it will be as common a sight in our suburbs as laburnum. General practitioners of the future may look forward to its shrimpy leaves in April and its rain of golden flowers in August, as they drive along familiar town roads to familiar town patients. It will take a decade or more to tell if this is the kind of tree you want in your own front garden or would rather see in other peoples’.

*Mardy is a word of obloquy, which creeps in around Nottingham and Derby and is used sporadically in other places that Southern people rarely visit. It means sulky and unsociable. Often (but not necessarily) combined with “baby,” “bugger,” “bum,” or “pants.”

Management of the Crooked Nose- Study


The study has been published in International Journal of Head and Neck Surgery

Patients with crooked nose suffer from functional ailments, most significant nasal obstruction, as well as esthetic concerns which may impact their self-image as well as others’ perception of them. As such, management of the crooked nose is an especially challenging task in that it demands careful attention to both nasal function and appearance. There are a plethora of surgical technique..

Read more at Medical Dialogues: Management of the Crooked Nose- Study http://speciality.medicaldialogues.in/management-of-the-crooked-nose-study/

Citation: Scordino JW, Stucker FJ. Management of the Crooked Nose. Int J Head Neck Surg 2016;7(3):168-172.

Coca-Cola’s secret influence on medical and science journalists.


A series of journalism conferences on obesity received covert funding from Coca-Cola.

 Paul Thacker investigates

Industry money was used to covertly influence journalists with the message that exercise is a bigger problem than sugar consumption in the obesity epidemic, documents obtained under freedom of information laws show. The documents detail how Coca-Cola funded journalism conferences at a US university in an attempt to create favourable press coverage of sugar sweetened drinks. When challenged about funding of the series of conferences, the academics involved weren’t forthcoming about industry involvement.

For drinks manufacturers such as Coca-Cola the idea that consuming their products is fine as long as you exercise—reinforced with expensive advertising campaigns associated with sport—has been an important one. As Yoni Freedhoff, assistant professor of medicine at the University of Ottawa, told The BMJ, “For Coca-Cola the ‘energy balance’ message has been a crucial one to cultivate, as its underlying inference is that, even for soda drinkers, obesity is more a consequence of inactivity than it is of regularly drinking liquid candy.”

The six figure bill for funding these journalism conferences was more than repaid in favourable press coverage, say critics. Documented evidence of the industry’s covert influence on the media is rare. In 2004, researchers examined secret documents made public during tobacco litigation. Attempting to derail the effect of the US Environmental Protection Agency’s 1993 report on secondhand smoke, the tobacco industry successfully placed stories in major print publications about the report’s “scientific weakness” to help “build considerable reasonable doubt . . . particularly among consumers,” the researchers wrote.1 They concluded that even journalists can fall victim to well orchestrated public relations efforts, regardless of the quality of the science used in these PR exercises.

Source:bmj.com

Coca-Cola’s secret influence on medical and science journalists.


A series of journalism conferences on obesity received covert funding from Coca-Cola. Paul Thacker investigates

Industry money was used to covertly influence journalists with the message that exercise is a bigger problem than sugar consumption in the obesity epidemic, documents obtained under freedom of information laws show. The documents detail how Coca-Cola funded journalism conferences at a US university in an attempt to create favourable press coverage of sugar sweetened drinks. When challenged about funding of the series of conferences, the academics involved weren’t forthcoming about industry involvement.

For drinks manufacturers such as Coca-Cola the idea that consuming their products is fine as long as you exercise—reinforced with expensive advertising campaigns associated with sport—has been an important one. As Yoni Freedhoff, assistant professor of medicine at the University of Ottawa, told The BMJ, “For Coca-Cola the ‘energy balance’ message has been a crucial one to cultivate, as its underlying inference is that, even for soda drinkers, obesity is more a consequence of inactivity than it is of regularly drinking liquid candy.”

The six figure bill for funding these journalism conferences was more than repaid in favourable press coverage, say critics. Documented evidence of the industry’s covert influence on the media is rare. In 2004, researchers examined secret documents made public during tobacco litigation. Attempting to derail the effect of the US Environmental Protection Agency’s 1993 report on secondhand smoke, the tobacco industry successfully placed stories in major print publications about the report’s “scientific weakness” to help “build considerable reasonable doubt . . . particularly among consumers,” the researchers wrote.1 They concluded that even journalists can fall victim to well orchestrated public relations efforts, regardless of the quality of the science used in these PR exercises.

Coca-Cola funding at the University of Colorado

The story begins with articles last year in the New York Times and Associated Press on the Global Energy Balance Network, a now defunct “science based” collaboration between Coca-Cola and university scientists to tackle the obesity crisis.2 The company donated $1m to the University of Colorado, home institution of the Global Energy Balance Network’s president, James Hill, a professor of paediatrics. After experts criticised the network as a Coca-Cola ploy to shift the public’s perception of the causes of obesity from diet and consumption of sugary drinks to lack of exercise, the network shut down in December 2015. The University of Colorado later returned the money to Coca-Cola, and the company now declares its funding to external organisations on a website.

Not yet reported are several journalism conferences the University of Colorado ran with funding from Coca-Cola. Emails and documents obtained by The BMJ under freedom of information laws show that Coca-Cola began approaching professors at the university in early 2011 in an attempt to sway journalists. The tactic bore fruit. In one example, a CNN reporter attended the 2014 journalism conference and later contributed to a story that argued that obesity’s cause could be lack of exercise, not consumption of sugary soft drinks. Critics told The BMJ that Coca-Cola’s $37 000 support for that particular conference and the resulting story was a better bargain than an advertisement placed on CNN’s website.

Emails between Hill and Coca-Cola in 2011 detail the planning for a journalism conference that took place in early February 2012. Almost 20 journalists attended the conference, with assistance from the non-profit, Washington DC based National Press Foundation.

Some months after the event, Hill emailed a Coca-Cola executive and described the conference as a “home run,” adding, “The journalists told us this was an amazing event and they generated a lot of stories.” Hill continued, “You basically supported the meeting this year . . . I think we can get many more sponsors involved next year.”

Months later, the company agreed to send $45 000 to the University of Colorado Foundation for further support.

In August 2013 Hill emailed Coca-Cola about another journalism conference on obesity held with the National Press Foundation. Emails and questions to the foundation suggest that it did not know about these conversations with Coca-Cola. Hill wrote to the company: “The conference was a great success and even better than last year. These journalist[s] came away with a much more realistic understanding of obesity. Thanks again for your support.” Hill apparently attached a report of the conference, as a Coca-Cola executive responded, “Have read the entire [report]—excellent. Count us in for next year.”

Journalist complains

But one journalist, Kristin Jones, became concerned about how these conferences were funded and complained to the National Press Foundation. The foundation’s president, Bob Meyers, passed on her concerns to Hill and fellow professor John Peters. Meyers told the professors that Jones was upset to hear that Coca-Cola provided $10 000 for the 2014 journalism conference, which she attended, and added that he had told Jones “that all we know about funding is that it came from the University of Colorado Foundation.”

Peters then told the National Press Foundation by email, “The funding for this came from our general educational grant resources.” Months later, Peters emailed Coca-Cola executives a report on the 2014 journalism conference, thanking them for the “educational grant that supported this work.”

“I feel like I was lied to,” Jones told The BMJ. Jones no longer works as a journalist but said that she would not have attended the conference had she known of Coca-Cola’s funding.

The National Press Foundation’s detailed report of the 2014 conference included comments from reporters who attended and listed stories they later wrote. At the top of the report is a prominent quote from reporter Jen Christensen of CNN: “You had all the rock stars of the obesity topic—the quality of the speakers you chose was incredible. Never have I been to such a helpful fellowship.” The report notes that, months after the conference, Christensen contributed to a CNN story titled, “Soda makers want to cut calories, but is diet really better?”3

Christensen did not return repeated requests to comment for this story, nor did a reporter from National Public Radio who also attended.

“Great business”

Ottawa University’s Yoni Freedhoff commented, “It’s great business for Coca-Cola to fund the indoctrination of journalists in Coca-Cola friendly dogma, a fact I’d wager was clear to those experts who helped Coca-Cola to hide their involvement.”

The organiser of the conferences for the National Press Foundation was Bob Meyer, who has left the group. He did not respond to requests for comment. The foundation is now run by Sandy Johnson, who said by email that “a more appropriate sponsor of a journalist training program would be an organization such as Mayo Clinic, which did just that in February 2016.”

After reviewing several of the documents obtained by The BMJ, including the final 2014 report, Marion Nestle, professor of nutrition and public health at New York University, said that journalists should have realised that the programme was an industry event because of the choice of speakers and topics covered. One panel, for instance, featured representatives from McDonald’s and Coca-Cola discussing their corporate initiatives on obesity. Journalists appear to have been misled, but they should not have been so gullible, Nestle added. “Overall, this looks like an industry meeting framed as science, and the journalists bought into it. Coca-Cola got its money’s worth on this one.”

A Coca-Cola representative said that in September 2015 the company disclosed on its website the $45 000 funding to the University of Colorado for the journalism training programme in the spring of 2012. Before 2015 it wasn’t clear where the funding for the journalism programme was coming from. The University of Colorado told The BMJthat the university funded the 2014 journalism conference with $37 500 provided primarily by Coca-Cola Company for the Global Energy Balance Network. A university spokesperson told The BMJ, “Essentially funding for the conference came from a gift from Coke.”

Hill and Peters have not responded to The BMJ’s requests for comment.

References

Source:BMJ

Impact of total knee replacement practice: cost effectiveness analysis of data from the Osteoarthritis Initiative 


Abstract

Objectives To evaluate the impact of total knee replacement on quality of life in people with knee osteoarthritis and to estimate associated differences in lifetime costs and quality adjusted life years (QALYs) according to use by level of symptoms.

Design Marginal structural modeling and cost effectiveness analysis based on lifetime predictions for total knee replacement and death from population based cohort data.

Setting Data from two studies—Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study (MOST)—within the US health system.

Participants 4498 participants with or at high risk for knee osteoarthritis aged 45-79 from the OAI with no previous knee replacement (confirmed by baseline radiography) followed up for nine years. Validation cohort comprised 2907 patients from MOST with two year follow-up.

Intervention Scenarios ranging from current practice, defined as total knee replacement practice as performed in the OAI (with procedural rates estimated by a prediction model), to practice limited to patients with severe symptoms to no surgery.

Main outcome measures Generic (SF-12) and osteoarthritis specific quality of life measured over 96 months, model based QALYs, costs, and incremental cost effectiveness ratios over a lifetime horizon.

Results In the OAI, total knee replacement showed improvements in quality of life with small absolute changes when averaged across levels of confounding variables: 1.70 (95% uncertainty interval 0.26 to 3.57) for SF-12 physical component summary (PCS); −10.69 (−13.39 to −8.01) for Western Ontario and McMaster Universities arthritis index (WOMAC); and 9.16 (6.35 to 12.49) for knee injury and osteoarthritis outcome score (KOOS) quality of life subscale. These improvements became larger with decreasing functional status at baseline. Provision of total knee replacement to patients with SF-12 PCS scores <35 was the optimal scenario given a cost effectiveness threshold of $200 000/QALY, with cost savings of $6974 ($5789 to $8269) and a minimal loss of 0.008 (−0.056 to 0.043) QALYs compared with current practice. These findings were reproduced among patients with knee osteoarthritis from the MOST cohort and were robust against various scenarios including increased rates of total knee replacement and mortality and inclusion of non-healthcare costs but were sensitive to increased deterioration in quality of life without surgery. In a threshold analysis, total knee replacement would become cost effective in patients with SF-12 PCS scores ≤40 if the associated hospital admission costs fell below $14 000 given a cost effectiveness threshold of $200 000/QALY.

Conclusion Current practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life and QALYs at the group level. If the procedure were restricted to more severely affected patients, its effectiveness would rise, with practice becoming economically more attractive than its current use.

 

Abstract

Objectives To evaluate the impact of total knee replacement on quality of life in people with knee osteoarthritis and to estimate associated differences in lifetime costs and quality adjusted life years (QALYs) according to use by level of symptoms.

Design Marginal structural modeling and cost effectiveness analysis based on lifetime predictions for total knee replacement and death from population based cohort data.

Setting Data from two studies—Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study (MOST)—within the US health system.

Participants 4498 participants with or at high risk for knee osteoarthritis aged 45-79 from the OAI with no previous knee replacement (confirmed by baseline radiography) followed up for nine years. Validation cohort comprised 2907 patients from MOST with two year follow-up.

Intervention Scenarios ranging from current practice, defined as total knee replacement practice as performed in the OAI (with procedural rates estimated by a prediction model), to practice limited to patients with severe symptoms to no surgery.

Main outcome measures Generic (SF-12) and osteoarthritis specific quality of life measured over 96 months, model based QALYs, costs, and incremental cost effectiveness ratios over a lifetime horizon.

Results In the OAI, total knee replacement showed improvements in quality of life with small absolute changes when averaged across levels of confounding variables: 1.70 (95% uncertainty interval 0.26 to 3.57) for SF-12 physical component summary (PCS); −10.69 (−13.39 to −8.01) for Western Ontario and McMaster Universities arthritis index (WOMAC); and 9.16 (6.35 to 12.49) for knee injury and osteoarthritis outcome score (KOOS) quality of life subscale. These improvements became larger with decreasing functional status at baseline. Provision of total knee replacement to patients with SF-12 PCS scores <35 was the optimal scenario given a cost effectiveness threshold of $200 000/QALY, with cost savings of $6974 ($5789 to $8269) and a minimal loss of 0.008 (−0.056 to 0.043) QALYs compared with current practice. These findings were reproduced among patients with knee osteoarthritis from the MOST cohort and were robust against various scenarios including increased rates of total knee replacement and mortality and inclusion of non-healthcare costs but were sensitive to increased deterioration in quality of life without surgery. In a threshold analysis, total knee replacement would become cost effective in patients with SF-12 PCS scores ≤40 if the associated hospital admission costs fell below $14 000 given a cost effectiveness threshold of $200 000/QALY.

Conclusion Current practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life and QALYs at the group level. If the procedure were restricted to more severely affected patients, its effectiveness would rise, with practice becoming economically more attractive than its current use.

Introduction

Osteoarthritis is a leading cause of disability worldwide,1 resulting in pain, structural changes in the bone and joint space, and limitation of motion. Disease onset is gradual and usually begins after the age of 40. Osteoarthritis of the knee has a variable prognosis. Once present, improvement of joint structure is rare when assessed by radiography, but abatement of joint pain and disability occurs frequently.2 About 12% of adults in the US are affected.3 The annual rate of total knee replacement in the US has doubled since 2000, especially in those aged 45-64.45 This disproportionate increase in this practice has been attributed to expansion of eligibility to people with less severe symptoms.6 The total number of procedures performed each year now exceeds 640 000, at a total annual cost of about $10.2bn (£8.3bn, €9.6bn).5

The potential benefit of total knee replacement in patients with knee osteoarthritis should outweigh the associated costs. A recent randomized controlled trial looked at replacement compared with non-surgical management alone in 95 patients and showed large improvements in pain and physical limitations and significant increases in quality of life at 12 months.7 The trial population predominantly included patients with severe preoperative symptoms, as shown by low mean quality of life utility values at baseline.7 Many previously published uncontrolled before-after studies showed similarly large effects.89 In particular, the systematic review by Shan and colleagues described 19 studies that showed substantial improvements from baseline status, both in the intermediate and long term, for disease specific and generic health related quality of life across a broad range of domains.9 It is estimated, however, that up to a third of recipients of total knee replacement experience chronic pain postoperatively,1011 and the health benefits of the procedure are assumed to be higher in those with poor physical functioning before surgery.121314 This would imply that patients undergoing the procedure because of the recently expanded practice in the US might show less significant improvement in symptoms. Yet, the effectiveness of total knee replacement has been understudied in patients who are representative for the current practice population.1011

We used data from the Osteoarthritis Initiative (OAI) to estimate the effect of total knee replacement according to patients’ functional status by looking at longitudinal health outcomes of patients with knee osteoarthritis with heterogeneous symptoms who underwent the procedure compared with those who did not.15 We subsequently performed a decision modeling study to evaluate the impact of the procedure on lifetime costs and quality adjusted life years (QALYs) while varying its use by level of symptoms.

Methods

Study populations

We obtained the data for our analysis from the Osteoarthritis Initiative (OAI) database, which is available for public access at http://www.oai.ucsf.edu/. The OAI is a multi-center cohort study of 4796 individuals with knee osteoarthritis or at risk for knee osteoarthritis who were recruited from the general population in 2005-06 across four US centers. Study participants were aged 45-79 at enrolment and were tracked with repeated follow-up evaluations for nine years. These evaluations included physical examinations, radiographs of both knees, and questionnaires on risk factors, symptoms, medical history, and quality of life. Knee osteoarthritis was defined as the patient having pain, aching, or stiffness in or around the knee on most days for at least one month during the past 12 months, and radiographically confirmed tibiofemoral osteophytes of grades 1-3 according to the Osteoarthritis Research Society International (OARSI) atlas.1617 Patients eligible for the current analysis were those included in the outcomes dataset released 11 October 2015 (n=4796). To develop a decision model for estimating lifetime outcomes, we excluded participants who had already undergone TKR at baseline, confirmed by radiography (n=62) and participants from the low osteoarthritis risk, “non-exposed” control group (n=122) who had no established risk factors, symptoms or radiographic findings of knee osteoarthritis.18 This resulted in a development sample of 4498 (table 1). OAI participants classified as having knee osteoarthritis at baseline (n=1327), as opposed to participants who were at high risk for knee osteoarthritis,were defined as the study population for estimation of the effect of total knee replacement on quality of life and use ofnon-surgical treatment for osteoarthritis pain, and for the base case cost effectiveness analysis. To validate the effect estimates, we repeated similar analyses with 30 months’ follow-up data on 965 participants with knee osteoarthritis at baseline of the Multicenter Osteoarthritis Study (MOST).23 To show generalizability of the base case cost effectiveness analysis, we performed a scenario analysis using the 965 MOST patients.

Modeling effect of total knee replacement on quality of life and use of non-surgical treatment

Outcomes were defined as the SF-12 physical component summary (PCS) score, the SF-12 mental component summary (MCS) score, the SF-6D utility index, the Western Ontario and McMaster Universities arthritis index (WOMAC), the quality of life subscale on the knee injury and osteoarthritis outcome score (KOOS), and self reported use of pain medication for osteoarthritis, all measured at 12, 24, 36, 48, 72, and 96 months. We evaluated the effect of total knee replacement on use of non-pharmacological treatments with measurements at 24, 48, and 96 months, as questions on these treatments were not included at the other study visits. The SF-12 instrument is a single page questionnaire measuring generic quality of life.24 To estimate this, we calculated the SF-6D utility index, which can be directly derived from SF-12 by using a previously published algorithm.25 The KOOS and WOMAC instruments are validated questionnaires measuring quality of life, pain, stiffness, and functionality specific for osteoarthritis.242627 We chose to use only the KOOS quality of life subscale, which measures knee related quality of life and mental and social aspects such as awareness and lifestyle changes. These items are not well captured by the WOMAC total score, which focuses on knee symptoms and functioning. The Pearson product moment correlation coefficient for the two scores in the 1327 OAI participants with knee osteoarthritis was −0.67. Osteoarthritis pain medication included acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs (NSAIDs), and cyclo-oxygenase-2 (COX-2) inhibitors. Non-pharmacological treatments included massage, chiropractic, acupuncture treatments, and other less commonly used complementary treatment options such as acupressure, chelation therapy, folk medicine, and homeopathic treatment.

To estimate the effect of total knee replacement on these longitudinally measured outcomes compared with no/delayed procedure, we used marginal structural models for repeated measures defined as weighted generalized estimating equations (GEEs) with each outcome as the dependent variable.28 Marginal structural models are warranted when outcome values can vary over time and can predict future treatment assignment along with other time varying confounders. For example, an increase in use of osteoarthritis pain medication could be associated with a higher likelihood of receiving total knee replacement. Each GEE included a treatment variable for the procedure, which was set to one after performance, a study visit indicator, the outcome’s baseline value, and other baseline variables including age, sex, race, income, education, knee injury in medical history, knee surgery in medical history, body mass index (BMI), Charlson comorbidity score,29 use of osteoarthritis pain medication, doctor’s diagnosis of knee osteoarthritis, Kellgren-Lawrence radiographic grade, SF-12 scores, WOMAC total score, and KOOS quality of life. To evaluate the effectiveness of total knee replacement according to preoperative physical functioning, we included an interaction term for the procedure with baseline SF-12 PCS.3031 Within these GEEs, we included weights for treatment propensity (that is, the likelihood of having received total knee replacement) for each study visit. Weights were estimated by logistic regression models pooled for study visits with the above mentioned baseline variables, study visit, longitudinally measured BMI, Charlson comorbidity score, doctor’s diagnosis of knee osteoarthritis, Kellgren-Lawrence radiographic grade, and all outcome variables. The main treatment effect estimate obtained from the marginal structural modeling should be interpreted as a “time averaged” causal effect.28

Missing values were imputed 20 times with a flexible additive model including status variables and the Nelson-Aalen estimator of the cumulative hazard for total knee replacement and death. To estimate parameter uncertainty, we re-fitted imputation, pooled logistic regression, and GEE models in 500 bootstrap datasets. We used the 2.5th and 97.5th centiles of bootstrap effect estimates for uncertainty interval limits. To validate the effect estimates from models developed with OAI patients, we performed multivariable adjusted analyses for SF-12 scores, SF-6D utility index, WOMAC, and use of osteoarthritis pain medication using 30 months’ follow-up data on 965 MOST participants with knee osteoarthritis at baseline. All statistical analyses were performed with R version 3.2.0 (2015, R Foundation for Statistical Computing). For more information on these statistical analyses see appendix 1.

Modeling of lifetime outcomes and cost effectiveness of total knee replacement

We developed the KOSMOS (Knee OSteoarthritis MicrOSimulation) model to simulate the virtual life course of 1327 OAI patients by modeling the occurrence of primary total knee replacement, revision procedure, and death up to age 100. Rates of primary total knee replacement and death were modeled by cause specific multivariable Cox regression with chronological age as time scale. Revision rates were based on the literature19 using the log cumulative hazard of revision procedure as reported for different age groups, which was modeled as a linear function of log time since the primary procedure. Health related SF-6D utility scores, use of osteoarthritis pain medication, and use of non-pharmacological treatment were based on the patients’ baseline and predicted 96 month values taken from the output of the GEEs with and without total knee replacement. We used linear interpolation to calculate patients’ values through eight years. We estimated SF-12 PCS, SF-12 MCS, and SF-6D scores for patients alive longer than eight years by linear extrapolation, based on the observed steady changes over time (figs A-C in appendix 3). Use of osteoarthritis pain medication and non-pharmacological treatments was assumed to remain stable after eight years (figs F and G in appendix 3), and the predicted 96 month probability of use was carried forward.

For simulated patients who survived each cycle of the model, we calculated an undiscounted QALY as the predicted SF-6D score multiplied by one year, thus resulting in a different QALY outcome for patients receiving total knee replacement in that cycle. Patients could accrue QALYs in the model until death or age 100. We calculated effect modification of procedure by SF-12 PCS scores using the latest predicted score, which was updated every eighth year until total knee replacement. We assumed that with revision procedure a beneficial effect on SF-12 PCS, use of osteoarthritis pain medication, and non-pharmacological treatment would be cancelled out by deterioration and improvement before and after the revision.3233

Costs associated with care of knee osteoarthritis and total knee replacement procedures were estimated from a US health system perspective (table 2) and were either applied for each model cycle (annual costs associated with pharmacological and non-pharmacological treatment, physician office visits, and imaging) or as a one off cost penalty (costs associated with primary and revision procedures and rehabilitation including physiotherapy). All costs were expressed in 2013 $, with inflation rates reported in the US healthcare consumer price index.34 We recalibrated the average life expectancy predicted by the KOSMOS model for the modeled patient cohort to reflect the average life expectancy as predicted by age and sex specific US 2011 life tables and validated the KOSMOS model’s predictive performance in OAI and MOST data. More details on the development and validity of the KOSMOS model are provided in appendix 1.

For the base case analysis, we modeled 10 scenarios, ranging from current practice with rates as observed in the OAI, to lower rates of practice in which the procedure was performed only in individuals with lower SF-12 PCS levels (from <55-<20), to a scenario without total knee replacement. In the restricted scenarios, the underlying annual rate was kept the same as modeled for the current practice scenario, but no effects on quality of life, use of non-surgical treatment, and costs, and no procedural mortality rates were incorporated if the preceding SF-12 PCS level was greater than or equal to the threshold value.

For each scenario, we performed microsimulation of 1327 individuals for each set of 500 bootstrap equations and calculated the accrued QALYs and costs using the recommended 3% discount rate.35 We calculated 95% uncertainty intervals by using the 2.5th and 97.5th centiles of 500 modeled outcomes, each averaged across 1327 individuals. We calculated incremental cost effectiveness ratios (ICERs), defined as the difference in average costs divided by the difference in average QALYs, after ranking scenarios according to increasing costs and exclusion of dominated scenarios. Dominated scenarios were defined as programs less effective and more costly than the previous program (absolutely dominated) and programs with a larger incremental cost effectiveness ratio than the next not dominated program (extendedly dominated). We considered cost effectiveness thresholds of $50 000, $100 000, and $200 000 per QALY for decision making.36

Sensitivity analyses

In threshold analyses, we varied the hospital admission costs of primary and revision total knee replacement and used various percentages up to 100% for a further decline in quality of life (SF-12 PCS, SF-12 MCS, and SF-6D) in patients who were simulated to receive the procedure in the current practice scenario but were modeled to not receive the procedure in the other scenarios. For modeling the additional decline, we multiplied the main effect of follow-up time by values from 1 to 2. We used a time lag of four years after total knee replacement (equal to the difference in last follow-up measurement and median time to the procedure), so that the further decrease would reflect a long term effect of total knee replacement that we could have missed using OAI data.

We performed a scenario analysis using the 965 MOST patients after recalibration of hazard rates for total knee replacement and an analysis using EuroQol (EQ)-5d utility values as a substitute for SF-6D values by conversion of SF-12 MCS and PCS scores by a published equation.373839 In additional analyses, we modeled an increased rate of primary total knee replacement up to 30% to investigate the impact of a further increase in procedure rates as observed in the US after 2006.5 We also increased the background mortality rate based on findings that patients with osteoarthritis might have an excess all cause mortality compared with the general population by multiplying mortality rates by standardized mortality ratios sampled from a lognormal distribution (mean 1.55, 95% confidence interval 1.41 to 1.70).40 Finally, we performed an analysis exploring the potential influence of non-healthcare costs and loss of productivity not captured by a decrease in health utility,41 through inclusion of costs due to work time lost by patients and cost of informal caregiving. More details on these sensitivity analyses are provided in appendix 1.

Patient involvement

No patients were involved in developing plans for recruitment, design, or implementation of the studies, nor were they involved in developing the research questions and outcome measures. No patients were asked to advice on interpretation or writing up of results. Plans are in place for dissemination of the results of the research to the patient community. These plans include providing manuscript summaries to media sources, osteoarthritis charities, provider bodies, and patient organizations, in addition to social media announcements and institutional provision of pamphlets in health system waiting areas.

Results

Study populations

The 1327 OAI participants with knee osteoarthritis at baseline had worse SF-12 PCS, SF-6D, and osteoarthritis specific quality of life scores than the 3171 at high risk for knee osteoarthritis (P<0.001, table 1). There were 382 total knee replacements, of which 319 were done before the 96 month visit, and 255 were in the 1327 with knee osteoarthritis at baseline. In the MOST cohort (table A, appendix 2), 135 total knee replacements were performed in 965 participants with knee osteoarthritis at baseline, and 16 were performed in 1719 individuals at high risk of knee osteoarthritis, all before the 30 month visit.

Effect of total knee replacement on quality of life and use of non-surgical treatment

Figures A-G in appendix 3 show time trends of SF-12 PCS, SF-12 MCS, SF-6D, WOMAC, KOOS quality of life, use of osteoarthritis pain medication, and non-pharmacological treatments, specified for those who did and did not undergo total knee replacement. After adjustment for baseline and time varying confounders, the main effects of total knee replacement (that is, treatment effects averaged across confounding variable levels and follow-up time) comprised an absolute improvement of 1.70 points (95% uncertainty interval 0.26 to 3.57) on SF-12 PCS, and changes in SF-12 MCS of −0.22 (−1.49 to 1.31) and SF-6D of 0.008 (−0.008 to 0.028) point. For each unit decrease in baseline SF-12 PCS, the effect on SF-6D increased and could be calculated as 0.098−0.002×(SF-12 PCS), suggesting that total knee replacement would become more effective if it was restricted to patients with SF-12 PCS scores <50. For osteoarthritis specific measures of quality of life, the procedure’s main effects included improvement of the WOMAC score by 10.69 (8.01 to 13.39) and KOOS quality of life of 9.16 (6.35 to 12.49) points. Total knee replacement reduced the odds of use of medication for osteoarthritis pain, but this effect was uncertain, with an odds ratio of 0.81 (0.55 to 1.12). Use of non-pharmacological treatment did not significantly seem to change with total knee replacement (0.91, 0.55 to 1.77). These effects were generally consistent with those obtained from multivariable adjusted analyses of MOST data, although in MOST the effect on SF-12 MCS was positive in contrast with the effect in OAI (table 3).

Table 3

Changes in quality of life measures and use of non-surgical treatment after total knee replacement (TKR) in four models*. Figures are effect estimates with 95% uncertainty intervals based on refitting all modeling steps in 500 bootstrap datasets given for 1327 Osteoarthritis Initiative (OAI) participants with knee osteoarthritis at baseline who were repeatedly followed up until 96 months v 965 Multicenter Osteoarthritis Study (MOST) participants with knee osteoarthritis at baseline who were followed up until 30 months

 Lifetime outcomes and cost effectiveness of total knee replacement practice

In the current practice scenario, the lifetime likelihood of undergoing total knee replacement, as predicted for OAI, was 39.9% (95% uncertainty interval 34.5 to 45.3), and the average undiscounted life expectancy was 22.39 years (21.13 to 23.85 years). Modeled quality of life values and proportions of use of non-surgical treatments over time were generally most favorable in the current practice scenario, except for SF-12 MCS scores (figs I-M, appendix 3). The mean discounted QALYs in the current practice scenario were 11.18 (10.66 to 11.70) and costs were $17 168 ($15 307 to $19 124).

In the base case cost effectiveness analysis, only the ICER of total knee replacement for those with SF-12 PCS <20 fell below $100 000/QALY. The optimal scenario given a cost effectiveness threshold of $200 000/QALY was surgery for those with SF-12 PCS scores <35; surgery for those with SF-12 PCS <40 was borderline cost effective. Compared with current practice, restriction of surgery to those with SF-12 PCS <35 would decrease the lifetime likelihood of total knee replacement to 10.2% (95% uncertainty 8.1 to 12.4), and would save $6974 ($5789 to $8269) per patient, whereas the effectiveness would be only slightly lower at −0.008 (−0.056 to 0.043) QALYs. The ICER of this strategy compared with the previous best scenario was $160 974/QALY (table 4 and fig 1). The current practice scenario was less effective and more expensive than the more restrictive scenarios with SF-12 PCS threshold values of 40-55 and therefore dominated. None of the ICERs fell below the $50 000/QALY threshold. The likelihood that the current practice scenario would be considered to be cost effective was low for cost effectiveness thresholds below $200 000/QALY (fig N, appendix 3).

Table 4

Lifetime cost effectiveness outcomes for different scenarios for determining which patients are eligible for undergoing total knee replacement (TKR) with 95% uncertainty intervals based on 500 bootstrap datasets for simulations of 1327 participants from the Osteoarthritis Initiative (OAI) with knee osteoarthritis at baseline

 

Fig 1 Base case analysis cost effectiveness at different levels of SF-12 PCS (physical component summary). Costs ($) and QALYs are means in OAI study population. Incremental cost effectiveness ratios (ICERs) not shown for dominated scenarios

“>Figure1

Fig 1 Base case analysis cost effectiveness at different levels of SF-12 PCS (physical component summary). Costs ($) and QALYs are means in OAI study population. Incremental cost effectiveness ratios (ICERs) not shown for dominated scenarios

 Sensitivity analyses

With a cost effectiveness threshold of $200 000/QALY, restriction of surgery to those withSF-12 PCS <40 became attractive if the hospital admission costs of primary total knee replacement fell below $14 000. If the admission costs of primary total knee replacement fell below $8000, restriction of surgery to those withSF-12 PCS <30 would become economically attractive given a cost effectiveness threshold of $100 000/QALY. Cost effectiveness outcomes were not sensitive to the admission costs of revision procedures.

Simulation of the MOST population with knee osteoarthritis provided much higher lifetime likelihoods of total knee replacement, but similar ICERs, although restriction of surgery to those withSF-12 PCS <40 now became the optimal scenario at a cost effectiveness threshold of $200 000/QALY (table E in appendix 2). Use of EQ-5D utility values improved ICERs, with the ICER of restriction of surgery to those withSF-12 PCS <40 now amply falling below $200 000/QALY (table F in appendix 2). Increasing rates of primary total knee replacement or background mortality only minimally affected incremental cost effectiveness outcomes, and restriction of surgery to those withSF-12 PCS <35 remained the optimal scenario at a cost effectiveness threshold of $200 000/QALY (tables G and H in appendix 2).

Inclusion of costs associated with work days lost (see table D in appendix 2) and informal caregiving did not have a major impact on the cost effectiveness results: again restriction of surgery to those withSF-12 PCS <35 was the optimal scenario at a cost effectiveness threshold of $200 000/QALY (table I in appendix 2). If patients who would receive total knee replacement in current practice, but not in the more restrictive scenarios, experienced an additional decline of 50% in quality of life over the long term, all scenarios of performing total knee replacement including current practice became economically attractive given a cost effectiveness threshold of $200 000/QALY and with an additional decline of 80% given a cost effectiveness threshold of $100 000/QALY.

Discussion

Principal findings

We evaluated the effectiveness of total knee replacement on quality of life and use of non-surgical treatment in a recent US cohort of patients with knee osteoarthritis. Compared with patients who did not undergo total knee replacement, generic quality of life scores (on SF-12 physical) and those related to osteoarthritis improved with performance of the procedure, with larger improvements generally in those with a lower SF-12 physical score at baseline. Changes in use of osteoarthritis pain medication and SF-12 mental scores were small and heterogeneous across the two cohorts. In a cost effectiveness analysis modeling the life courses of OAI patients with knee osteoarthritis with inclusion of utility values derived from the SF-12, current practice was more expensive and in some cases even less effective compared with scenarios in which total knee replacement was performed only in patients with lower physical functioning. At the group level, the economically most attractive strategy was performing the procedure in those with a SF-12 PCS <35, assuming a cost effectiveness threshold of $200 000 per QALY. These findings were reproduced among knee osteoarthritis patients from the MOST cohort. Extension of the use of total knee replacement to those with a SF-12 physical score of ≤40 would become financially attractive if the hospital admission costs fell below $14 000.

Comparison with other studies

Scenarios of total knee replacement restricted to those with lower SF-12 PCS scores provided higher QALYs in our cost effectiveness analysis because small improvements in quality of life after the procedure became more prominent in people with lower baseline scores. A recently published randomized controlled trial showed larger effects of total knee replacement on quality of life measures than we found. 7 The OAI patient population undergoing total knee replacement, however, had on average less severe symptoms before surgery compared with the population from that randomized controlled trial, and the mean follow-up duration was longer in the OAI. Moreover, measures of quality of life were assessed independently of care providers in the OAI, contributing to a more limited potential for reporting desirable answers on quality of life scores before and after surgery.4243 Recent uncontrolled before-after studies have also shown larger effects of total knee replacement, generally including improvements in SF-12 PCS scores of 5-15 points.3244454647484950515253 In these studies, changes in SF-12 MCS were heterogeneous and varied from no improvement to 5 points.4749 Similar to SF-12 PCS, larger effects have been shown in before-after studies for quality of life measures specific to osteoarthritis.1332445455 As with the study population in the randomized controlled trial, however, the preoperative quality of life scores for these studies were on average worse than those of our study population and the duration of follow-up was generally shorter, possibly explaining the larger effects.

In addition to our analysis, three observational studies have compared quality of life outcomes in patients who did and did not undergo total knee replacement.125657 Two of these studies were not designed to prospectively collect data on generic and osteoarthritis related quality of life measures in people who did not and did undergo the procedure.1256 In a single hospital prospective cohort study (n=174) including 30 patients who received total knee replacement, there were large improvements in SF-12 PCS (9.6 points) and total WOMAC (24.2 points) scores at 12 months after joint replacement. The effect estimation, however, included effects of hip replacements (n=21), which generally have much larger effects than knee replacements.4749 Modeling studies that investigated the cost effectiveness of total knee replacement all used effects from before-after studies with larger marginal effects on quality of life, contributing to much lower estimated ICERs than we found.135859

Strengths and limitations of study

We estimated the effectiveness of total knee replacement versus no or delayed surgery in a large population based sample, the OAI cohort study, adjusting for baseline and time varying variables using marginal structural models. Marginal structural modeling has been shown to produce unbiased estimates of causal treatment effects.28 The larger number of procedures in our analysis enabled us to evaluate effect modification by baseline symptoms. Effect estimates and modification by baseline physical functional scores obtained in OAI were generally consistent with those found in the MOST population. Nevertheless, our findings should be interpreted in light of several limitations. First, the knee osteoarthritis populations of the OAI and MOST might not be representative of the current total population of patients with knee osteoarthritis in the US, limiting the generalizability of our findings. For example, younger patients might have been under-represented, contributing to fewer lower quality of life values from symptoms affecting work and other regular activities. Yet, both studies recruited participants from the general population across different regions in the US and obtained detailed information on risk factors, total knee replacements, and outcome measures independently from the hospital in which procedures were performed. Furthermore, our conclusions were unaffected by an increase in the rate of total knee replacement, resembling the most recent increase in use on a national level. Second, the study visits performed within OAI and MOST did not allow for measurement of outcomes immediately before procedures, and ignoring worsening symptoms just before could cause an underestimation of the true effect. We, however, adjusted for differences in 12 month changes in use of osteoarthritis pain medication, Kellgren-Lawrence radiographic grade, and quality of life scores assessed at the visit preceding total knee replacement. In addition, no changes in quality of life are observed at 12 months before procedures versus at one month before,50 and an immediate worsening of symptoms as a reason for undergoing total knee replacement is not likely as patients generally defer surgery for years before finally proceeding.606162 Third, as our study was based on analyses of non-randomized data without an intention to treat principle, residual confounding by indication and selection bias could be possible. Fourth, the self reported outcomes available in the retrospective data, such as use of osteoarthritis pain medication and loss of productivity, could potentially have influenced outcomes because of reporting bias or non-differential overestimation and underestimation. Finally, we made several assumptions in our cost effectiveness analysis. In any modeling study, a trade-off must be made between comprehensively including consequences of each strategy and their relevance to the decision problem at hand. We developed our decision model using individual level data on quality of life, treatment use, and survival, which allowed us to incorporate correlation between the model parameters while assessing uncertainty. Unfortunately, the OAI and MOST studies did not include collection of cost data. We therefore had to estimate costs using the best available external data sources, which might not have been representative for our patient cohort.

Conclusions and policy implications

Improvements in quality of life with total knee replacement were on average smaller than previously shown. Given its limited effectiveness in individuals with less severely affected physical function, performance of total knee replacement in these patients seems to be economically unjustifiable. Considerable cost savings could be made by limiting eligibility to patients with more symptomatic knee osteoarthritis. Only one randomized controlled trial has so far been published evaluating total knee replacement as an adjunct treatment to optimized non-surgical treatment, but it did not include results according to symptom status.7 Our findings emphasize the need for more research comparing total knee replacement with less expensive, more conservative interventions, particularly in patients with less severe symptoms, and research aiming to develop individualized prediction models for a better selection of patients with a predicted large net benefit from the procedure. These interventions can then be compared within cost effectiveness analyses, for which non-US data sources should be considered as well. In conclusion, the practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life. If the procedure were restricted to patients with more severe functional status, however, its effectiveness would rise, with practice becoming economically more attractive.

What is already known on this topic

  • Rates of total knee replacement in the US have more than doubled since 2000, primarily because of expanding eligibility to patients with less symptomatic knee osteoarthritis

  • Up to a third of recipients of total knee replacement experience chronic pain postoperatively, and health benefits are assumed to be higher in those with poor preoperative physical functioning

What this study adds

  • Quality of life outcomes generally improve after total knee replacement, with small effects becoming larger with decreasing preoperative functional status

  • The practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on QALYs at the group level and was found to be economically unattractive

  • Total knee replacement practice, however, could be considered cost effective if the procedure were restricted to patients with more severely affected functional status.

Soure: BMJ

Richard Lehman’s journal review.


The longer you give anticoagulants to people following venous thromboembolism, the fewer subsequent thromboembolic events they will have. At some point you have to decide whether to go on or to stop, and this Bayer-funded trial has recruited participants who “had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation.” Bayer produces the direct oral anticoagulant rivaroxaban which has plenty of patent time left and costs about £800 per patient per year in the NHS. The trial compared fixed doses of rivaroxaban (10mg and 20mg) with 100mg of aspirin daily. Not surprisingly, rivaroxaban proved better at preventing recurrent VTE over the course of a year than aspirin: absolute rates were 1.5% (20mg), 1.2% (10mg) and 4.4% for aspirin. It was a typical industry trial involving 3396 patients from 244 sites in 31 countries with Bayer as the data holder and main analyst. But that’s not my beef today: what puzzles me is the lack of a definition of the “equipoise” that these patients were supposed to be in. This isn’t specified in the article or the supplement, and the table of patient characteristics shows a very heterogeneous picture. I do hope Bayer will make the individual participant data available without delay.

Quadrivalent HPV vaccine & pregnancy outcomes

A few weeks ago, I unintentionally strayed into a minefield on the subject of the safety of quadrivalent vaccines to prevent human papillomavirus infection. This time I will tiptoe around the circumference very carefully. In a nationwide case-control study from Denmark, women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. In these matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect, spontaneous abortion, preterm birth, low birth weight, small size for gestational age, or stillbirth.

Inotropic “support” during cardiac surgery

When people with heart failure are given drugs to stimulate the heart, they tend to die faster. If they feel better in the meantime, I would say that the choice should be theirs. But in this trial of levosimendan the patients were mostly asleep. The inotrope was given to patients just before heart surgery and the hope was that it would help to reduce post-operative low cardiac output syndrome. The composite end-point of the trial was a very generous mix, but despite that and a well-powered design, levosimendan failed to make any difference.

How open data gets used

Five years ago, when I had the amazing fortune to be in at the start of the Yale University Open Data Access project, data sharing was a bold and threatening idea which provoked much overt and covert opposition. Now it has become motherhood-and-apple-pie, and the best that its opponents can come up with is that mothers are nice and so are apple pies, but do we really need to divert so much attention to them when mum is in a comfy nursing home and there are so many other pies on the supermarket shelves. Let’s not forget that even now, many pharmaceutical companies only allow very limited access to their data and very few academics show enthusiasm for sharing. And interest in working on full data sets is relatively limited as yet, since it’s not a major draw for funders. But a survey of data requests made to the US National Heart, Lung, and Blood Institute data repository shows what I hope is the beginning of a surge. From January 2000 through May 2016, a total of 370 investigators requested data from 1 or more clinical trials. Requests for trial data have been increasing, with 195 investigators (53%) initiating requests during the last 4.4 years of the study period. Although I would argue that every trial with important consequences for clinical practice and/or health spending should undergo independent individual participant analysis, very few people are doing this. “Demand for trial data for secondary analysis has been increasing. Requesting data for the a priori purpose of reanalysis or verification of original findings was rare.” Just look back at that Bayer trial of rivaroxaban—wouldn’t it be good to delve into the individual data before committing to spending £800 per patient per year for hundreds of thousands of people?

JAMA 28 Mar 2017  Vol 317

Vit D & calcium: no effect on cancer incidence in older women

There is so much conflicting observational evidence about vitamin D that I felt I had to give honourable mention to this randomised controlled trial, even though it tells us little. Here is what: Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years.

Hysterectomy type in early endometrial cancer

Surgical triallists are among my heroes, and I follow their work from time to time in these reviews, and sometimes by chatting with Peter McCulloch about his wonderful IDEAL Collaboration. Here’s a classic example of a trial which directly informs clinical practice: the Laparoscopic Approach to Cancer of the Endometrium (LACE) trial. It was conducted between 7 October 2005, and 30 June 2010, in 20 tertiary gynaecological cancer centres in Australia, New Zealand, and Hong Kong. 760 women with stage I endometrial cancer to either total laparoscopic hysterectomy or total abdominal hysterectomy, and follow-up ended on March 2016. So over 12 years from setting up the trial to publication in JAMA. The two methods of hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival.

Plumbing the effects of lead in children

The city of Dunedin in the South Island of New Zealand was mapped out in advance using rulers on a map in Edinburgh (syn Dunedin), prior to mass migration there by members of the Free Church of Scotland. Presbyterian rulers are hard and straight, and so in consequence were the roads of Dunedin NZ, which take no account of local topography. Anyone who has tried to drive in Dunedin will know what I mean. Chugging and stalling on the nearly vertical slopes, the cars and lorries of yesteryear would have belched out the fumes of barely combusted leaded petrol. Children gasping up these mountains inhaled measurably more lead than those in most other cities. Although the dangers were known at the time, amelioration came too late for many. In a cohort of just over 1000 children whose lead levels were tested at the age of 11 in 1972-3, high exposure was associated with lower cognitive function and socioeconomic status at age 38 years, and with declines in IQ and downward social mobility.

JAMA Intern Med  Mar 2017  Vol

Does acid suppression increase C diff recurrence?

Like many doctors, I’ve been told that gastric acid suppression increases the risk of recurrent Clostridium difficile infection. This systematic review shows how weak the basis for that assertion is. Nobody has done a prospective randomised trial. OK, that would be difficult, but our knowledge at present is derived from 16 heterogeneous observational studies with a total of 7703 patients with CDI, of whom 20% developed recurrence. The rate in patients taking acid suppressors was 22.1% compared with 17.3% in those who were not. Taken at face value, that’s a statistically significant difference, but there is so much scope for bias and residual confounding that I wouldn’t attach any meaning to it.

The Lancet  1 Apr 2017  Vol 389

Multiple sclerosis

Finding little to tempt me in the research papers of this week’s print Lancet or the website, I decided to dive in to their reviews sections on multiple sclerosis. Let me test your patience with my reflections on MS over 45 years. The positives first: diagnosis has improved immeasurably. Classification has improved a little. Treatments abound, but the choice is difficult in relapsing/remitting MS and non-existent for progressive MS. The thing that has improved most is personal care for patients, thanks to community specialist nurses and dedicated MS centres.

Now for the negatives. MS still leads to severe disability in 80% of patients, with a mean loss of 10 years of life. Although there is now a choice of 14 drug treatments, they all work on inflammatory pathways and cause a variety of serious or lesser adverse effects, roughly in proportion to their efficacy. The progressive forms of MS are probably driven by other mechanisms and no adequately tested therapy has shown any effect.

These would be good teaching papers for any course on the shared understanding of medicine, should such a course ever be offered. The diagnosis paper illustrates all the dilemmas of real-life diagnostic pathways and how we should conceptualise and communicate about them. The treatment paper shows how difficult it is to avoid excessive reliance on surrogate outcomes which relate very poorly to clinical outcomes. How can you do conventional shared decision making when you have an offer of 14 variously tested drugs, plus non-drug interventions like bone marrow transplantation? Can we expect patients to understand these when we don’t fully understand them ourselves? How much should be left to clinical expertise, and how can we bring kindness into the equation?

The BMJ  1 Apr 2017  Vol 356

Steroids in pregnancy

Antenatal corticosteroids gave birth to evidence-based medicine as we know it. They are also good for premature babies. Forty years since Iain Chalmers began his transformative work in this area, here is a prospective cohort study of the effect of corticosteroids on infant outcomes, based on data from 300 neonatal intensive care units in the United States. “The effect on mortality and survival without major morbidities of exposure to antenatal corticosteroids seems to be largest in infants at the lowest gestations, including infants at 23 weeks’ gestation who were not included in randomized controlled trials.” The study also found that antenatal exposure to corticosteroids was associated with lower rates of mortality and major hospital morbidities at most gestations for which steroids are currently recommended. This study supports the administration of antenatal corticosteroids in women with threatened preterm labor from 23 to 34 weeks’ gestation.” (As usual with The BMJ, American spellings remain in American papers.)

Fewer antimalarials, more antibiotics?

I have never worked in Africa, but those who have tell of moribund feverish children carried for hours or days to remote medical centres, where many of them die. What would you do in that situation? I’m sure I would give them a cocktail of whatever antimalarials and antibiotics happened to be in the cupboard, plus fluids by whatever route was feasible. How deplorable this sounds in the comfort of air-conditioned offices thousands of miles away. Here’s a paper by nearly 40 authors which assesses the effect of introducing near-patient rapid malaria testing in 8 randomised trials and one observational study, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda. In 522 480 children and adults with acute febrile illness, use of antimalarials fell, but antibiotic use remained high at 69% of those with a negative malaria test and 40% of those with a positive test. The authors state that this “probably represents overprescription. This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings.” Perhaps. But first prove that attempts to reduce antibiotic prescribing do not lead to more dead children and adults in these settings.

Insulin: pumping vs injecting

“Adding pump treatment to structured training in flexible intensive insulin treatment did not substantially enhance educational benefits on glycaemic control, hypoglycaemia, or psychosocial outcomes in adults with type 1 diabetes.” That’s really all you need to know about the REPOSE trial. You might like to send this paper to your local diabetes centre the next time they prescribe a pump to one of your patients. You might also like to find out if they receive money from a manufacturer of these pumps.

Plant of the Week: Pulmonaria Opal “Ocupol”

Early spring is the time for plants which are named after internal organs. If you are lucky, you will have enjoyed the dainty flowers of hepaticas over recent weeks, and will now be admiring your pulmonarias. In each case, the leaves are what caused our forefathers to call these plants liverworts and lungworts, or their equivalents in Latin: the old leaves of hepaticas are a liverish colour and shape, while pulmonarias have leaves that are spotted like cut lungs.

Pulmonarias come in a patriotic range of reds, whites, and blues. Left to their own promiscuous devices, they tend to have baggy leaves and flowers that vary between pink and blue on the same stem. But selectors and hybridizers have done sterling work over the last 15 years and there are now some wonderful pulmonarias available in every garden centre. “Opal” is one of them. The leaves are positively emphysematous, with more white than green, but all the more beautiful for that, while the flowers are open and of the softest clear blue.

All pulmonarias are tough native perennials by nature, though I have found that the red ones don’t like hard winters. You can split them at will, and now that there are so many good clones, I would suggest you stick with doing that, while banishing any miscegenous seedlings to the further reaches of your garden or your compost bin.

Source:BMJ