Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis—A randomised clinical trial

Journal of Hepatology 44 (2006) 784–790 www.elsevier.com/locate/jhep

Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis—A randomised clinical trial* Martin Phillips, Howard Curtis, Bernard Portmann, Nora Donaldson, Adrian Bomford, John O’Grady* Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK

See Editorial, pages 633–636 Background/Aims: Severe alcoholic hepatitis is associated with high morbidity and short-term mortality. Corticosteroids are the only widely used therapy but established contraindications to treatment or the risk of serious side-effects limit their use. The perceived need for alternative treatments together with the theoretical benefits of antioxidant therapy triggered the design of a randomised clinical trial comparing these treatment modalities. Methods: One hundred and one patients were randomized into a clinical trial of corticosteroids or a novel antioxidant cocktail with a primary endpoint of 30-day mortality. Results: At 30 days there were 16 deaths (30%) in the corticosteroid treated group compared with 22 deaths (46%) in the antioxidant treated group (PZ0.05). The odds of dying by 30 days were 2.4 greater for patients on antioxidants (95% confidence interval 1.0–5.6). A diagnosis of sepsis was made more frequently in the AO group (PZ0.05), although microbiologically proven episodes of infection occurred more often in the CS group (P!0.01). The survival advantage for corticosteroid treated patients was lost at 1 year of follow-up (PZ0.43). Conclusions: This study has shown that corticosteroids in the form of prednisolone 30 mg daily are superior to a broad antioxidant cocktail in the treatment of severe alcoholic hepatitis. q 2005 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Keywords: Acute alcoholic hepatitis; Corticosteroids; Antioxidants; Sepsis; Renal failure 1. Introduction Acute Alcoholic Hepatitis (AAH) is the most aggressive form of alcoholic liver disease with a short-term mortality as high as 65%, rising to 95% when complicated by renal failure [1]. Unlike other causes of liver failure, liver transplantation is not considered an option for these patients [2]. Most treatment modalities that have been studied in clinical trials in AAH have disappointed, including colchicine, propylthiouracil, Received 24 August 2005; received in revised form 24 October 2005; accepted 18 November 2005; available online 20 December 2005 * The authors who have taken part in this study declared that they have not a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. * Corresponding author. Tel.: C44 207 346 3252. E-mail address: john.o’[email protected] (J. O’Grady).

insulin and glucagon, anabolic steroids, and penicillamine [3–7]. Pentoxifylline, an inhibitor of TNF-a production, was associated with a significant short-term survival advantage in one study [8]. The most widely used therapy for AAH is corticosteroids and 14 randomized trials have been reported [6,9–21]. Five reported short-term survival benefit from corticosteroids but the largest trial was not confirmatory [6]. A similar conclusion is reached by meta-analyses (four published in full [22–25] and a fifth in abstract form [26]), The majority of studies excluded patients with sepsis, recent gastrointestinal bleeding, renal failure and pancreatitis, leading to concern that the results were not necessarily generalisable to patients with severe AAH. Concern over the safety of corticosteroids has tempered their widespread adoption in AAH despite the supportive data. Enthusiasm for the use of antioxidants in AAH is driven by the belief that oxidative stress plays a central role in the pathogenesis of AAH [27]. Oxidative stress is intimately

0168-8278/$32.00 q 2005 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. doi:10.1016/j.jhep.2005.11.039

M. Phillips et al. / Journal of Hepatology 44 (2006) 784–790

linked to pro-inflammatory cytokines, while reactive oxygen species activate the nuclear transcription factor NF-kB which in turn switches on pro-inflammatory cytokine production including interleukin-1, interleukin-6 and tumour necrosis factor-a (TNF-a) [28]. These cytokines are overproduced in AAH and plasma and hepatic levels are proportional to the severity of disease [29–33]. One trial of antioxidants in AAH studied 56 patients with moderate or severe disease in a placebo controlled trial of vitamin E 600 mg, selenium 200 mg, and zinc 12 mg [33]. Mortality was 6.5% in the antioxidant group compared to 40% in the placebo group. However, another study of 51 patients with mild to moderate AAH found no clinical benefit with vitamin E 1000 IUs daily [34]. Some benefit from N-acetylcysteine was detected with hepatorenal syndrome including patients with AAH [35]. This study tested the hypothesis that aggressive antioxidant therapy had a superior risk/benefit profile than corticosteroids in severe AAH resulting in improved 30-day survival rates.

2. Methods 2.1. Patients The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the hospital’s ethics committee. Recruitment to the study commenced in 1997 and 1-year follow-up of all patients was completed in 2002. Written informed assent or consent was obtained from all patients (or their next of kin in encephalopathic or intubated and sedated patients). All patients had a history of heavy alcohol consumption defined as greater than 80 g alcohol per day for men, or greater than 60 g alcohol per day for women, prior to the onset of illness of at least 1-month duration. In such patients features considered consistent with a diagnosis of severe AAH were: (a) absence of alternative aetiology of liver disease, (b) serum bilirubin O100 mmol/L, (c) serum AST !300 IU/L, (d) serum IgA O5 g/L, (e) white cell count O20!109/L, (f) ultrasound evidence of hepatic fatty infiltration, (g) hepatomegaly (clinical or radiological). At the time of assessment, the presence of all of the first three features plus one of the remaining features was considered compatible with the diagnosis of severe AAH. Histological confirmation of AAH was not a prerequisite for entry to the trial as it was considered that this would delay randomisation and bias the study population to patients with less severe disease. Nevertheless, every effort was made to obtain histological confirmation during or after participation in the study. Exclusion criteria were as follows: (1) Active sepsis defined as positive microbiological culture, ascitic white cell count O500 cells/mL (or ascitic neutrophil count O250 cells/mL), or radiological appearances consistent with pneumonia. Patients were eligible for trial entry if treated with appropriate antibiotics for at least 48 h prior to randomisation. (2) Active significant gastrointestinal haemorrhage within the previous 48 h defined a requirement of R4 unit blood transfusion or haemodynamic instability (pulseO120/min or systolic blood pressure !100 mmHg). (3) Shock necessitating inotropic support. (4) Evidence of coexisting non-alcoholic liver disease. (5) Pregnant or lactating women. (6) Patients with a history of allergy to any component of the regimen.

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(7) Previous randomisation to the study. (8) Previous treatment with one of the trial drugs (within 12 months). (9) Patients clearly improving spontaneously prior to trial entry. Patients were stratified according to renal function at randomisation. Patients were divided into two groups—serum creatinine !200 mmol/L, and serum creatinine O200 mmol/L. Severity of AAH was assessed using the discriminant function (DF) first described by Maddrey DFZ4.6 (prologation in prothrombin time in seconds)Cbilirubin [(mmol/L)/17)] with a DF O32 indicative of severe AAH. All patients were treated with intravenous vitamin K 10 mg daily, intravenous multivitamins (Pabrinexw) once daily for 3 days and oral thiamine 300 mg daily. Nutritional status was assessed and energy and nitrogen requirements estimated using the Schofield equation [35,36]. Nutritional supplements were administered as sip feeds or nasogastric enteral feeding.

2.2. Treatment regimens Eligible patients were randomised to either corticosteroid therapy (CS) or antioxidant therapy (AO) as soon as possible, and preferably within 72 h of admission, using consecutive envelopes produced by computergenerated randomisation. CS therapy was given as oral prednisolone 30 mg once daily or methylprednisolone (24 mg) intravenously. Treatment was given for 28 days and then tapered over a 2 weeks period. The AO regimen administered is shown in Table 1 and this combination was given for 28 days. In addition, this group received 500 ml of 10% intralipid every 5 days as a membrane stabiliser.

2.3. Plasma samples Blood was drawn prior to study drug therapy and at weekly intervals up to 28 days in the fasting state. Blood samples were taken in EDTA tubes and lithium–heparin tubes and cooled immediately on ice, centrifuged at 3500 rpm for 10 min. Plasma was separated into three aliquots and frozen immediately at K80 8C until assay. Vitamins A and E levels were measured by high performance liquid chromatography [37]. Selenium levels were measured by atomic absorption spectrophotometry.

2.4. Endpoints The primary endpoint was 30 day survival. The secondary endpoint was 1-year survival.

2.5. Statistical analysis The trial set out to detect, with 80% power and 5% significance level, a change in the 30-day mortality from 50% in the CS group to 30% in the AO group. A conventional analysis with logistic regression required a sample size of 93 patients per group. A Cox’s regression model fitted to the times to death was also used to compare the efficacy of the two treatments. Sequential monitoring was also planned for this trial [38]. The power requirement of the sequential design yielded an expected sample size of 122 patients at termination. An interim analysis was triggered by clinical concern after a total of 101 patients were recruited. The accumulating Table 1 Antioxidant regimen (total daily doses) Antioxidant

Route

Dose

b-Carotene Vitamin C (ascorbic acid) Vitamin E (D-a-tocopherol) Selenium Methionine Allopurinol Desferrioxamine N-Acetylcysteine

Oral Oral Oral Oral Oral Oral Parenteral Intravenous

12 (mg) 1100 (mg) 388 (mg) 300 (mg) 1600 (mg) 300 (mg) 30 (mg/kg) 150 (mg/kg)

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evidence of the advantage of AO was summarized in terms of the odds ratio. The triangular design was used for the sequential monitoring to detect no difference between the treatments. The estimation of the odds ratios and their significance is adjusted for the sequential nature of the trial. The computer package SPSS v.10 is used for the computations of the conventional methods and derivation of the stopping boundaries and adjustments to account for the sequential analyses were obtained using the computer package PEST3, developed by the Planning and Evaluation of Sequential Trials project at the University of Reading [39]. Survival analyses were performed on an ‘intention to treat’ (ITT) and ‘per protocol’ bases.

3. Results 3.1. Patient characteristics At the time of analysis 213 patients had been referred for consideration of trial entry, 112 were excluded and 101 patients were enrolled with 48 patients (32 men and 16 women) randomised to AO and 53 patients (28 men and 25 women) to CS (Fig. 1). Demographic and clinical characteristics were similar for both treatment groups at randomisation (Table 2). Liver histology was available for 29 (60%) of the AO group and 36 (68%) of the CS group and cirrhosis was present in 94%. Median time to biopsy was 14 days after randomisation (7.5 days in the AO group and 17 days in Assessed for eligibility (213)

Excluded (112) not AAH (62) AAH (44) no consent (1) spontaneous improvement (6) pre-treatment with trial drug (14) other exclusions (23)

Randomised (101)

Table 2 Baseline clinical characteristics of patients at randomisation

Male Age (years) Days to randomisation Hepatic encephalopathy Recent GI haemorrhage Recent sepsis Renal impairment (CreatinineO 200mmol/L)

Antioxidants (48)

Corticosteroids (53)

P

32 (67%) 45 (25–71) 3 (1–13)

28 (53%) 43 (26–76) 3 (0–13)

0.16 0.66 0.26

12 (26%)

17 (32%)

0.43

5 (10%)

12 (23%)

0.10

2 (4%) 9 (19%)

4 (8%) 13 (25%)

0.68 0.48

Values shown as median (range), or value (%).

the CS group). 53 patients (84%) were biopsied within 60 days of randomisation AAH was confirmed in 52 patients (98%) and was histologically severe in 35 patients (66%). Many biopsies showed evidence of mild or moderate iron deposition (grades 1 and 2) on Perls stain, but two had grade 3 or 4 siderosis. Median duration of treatment was 14 days for AO treated patients and 18 days for CS treated patients. Treatment was completed (either 28 days of therapy or a clinical response justifying premature termination of therapy) in 13 patients on AO therapy and 33 patients on CS therapy. Treatment was prematurely discontinued in three patients (two patients on AO and one patient on CS). Three patients were withdrawn from the study because of protocol violation (two patients in the AO group had positive hepatitis C serology and one patient in the CS group had co-existing carcinoma of the head of the pancreas). In the AO group two patients were intolerant of treatment due to painful phlebitis. In the CS group one patient developed severe psychosis on day 9 after randomisation triggering withdrawal of therapy. In six other patients on CS treatment was withdrawn due to clinical sepsis, four within 4 days of randomisation and Table 3 Laboratory parameters at randomisation

Allocated AO (48) Received AO (46) Withdrew consent (2)

Allocated CS (53) Received CS (53)

Discontinued AO; withdrew consent (4) painful phlebitis (2) protocol violation (2)

Discontinued CS; withdrew consent (1) psychosis (1) sepsis (6) protocol violation (1) lost to follow up (1)

Analysed (n=48)

Analysed (n=53)

Fig. 1. Trial profile.

Haemoglobin (g/dL) White cell count (!109/mL) Platelets (!109/mL) INR Creatinine (mmol/L) Albumin (g/dL) Bilirubin (mmol/L) AST (IU/dL) Child-pugh score Discriminant function

Antioxidants (48)

Corticosteroids (53)

P

10.5 (7.3–14.3) 14.9 (4.0–47.0)

10.2 (7.0–13.7) 14.3 (3.9–46.5)

0.68 0.97

150 (36–524) 1.63 (1.00–2.90) 98 (55–522) 26 (15–35) 422 (106–744) 104 (43–345) 12 (7–15) 61.1 (7.3–163.5)

127 (45–354) 1.51 (1.00–3.64) 109 (46–1774) 27 (15–38) 473 (104–786) 101 (45–346) 12 (8–15) 60.7 (14.7–199.6)

0.45 0.20 0.36 0.07 0.08 0.59 0.97 0.13

Values shown as median (range).

M. Phillips et al. / Journal of Hepatology 44 (2006) 784–790

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Table 4 Stratified analysis and estimation of the 30 days survival (adjusted for sequential monitoring and stratified for renal failure) Group

Patient number

Deaths

Mortality rate

Odds ratio

95% confidence interval

P

Steroids Antioxidants Total

53 48 101

16 22 38

0.27 0.47

2.4

(1.0, 5.6)

0.05

3.2. Laboratory parameters Laboratory parameters at randomisation are shown in Table 3. There were no statistically significant differences between the two groups. By day 7, the median serum bilirubin had fallen to 349 mmol/l in the AO group and 321 mmol/l in the CS group. This early fall in serum bilirubin was seen in 71% of the AO group and 66% of the CS group. Serial evaluation of the laboratory parameters at 7 day intervals revealed no differences between the two groups with the exception of serum albumin at day 7 (AO 25 vs CS 28 g/l, PZ0.01) and white cell count at day 28 (AO 12.2 vs 17.4, PZ0.05). 3.3. Morbidity and survival At 30 days there were 22 deaths (46%) in the AO group and 16 deaths (30%) in the CS group (PZ0.05). The odds of dying by 30 days were 2.4 greater for patients on AO (95% confidence interval 1.0–5.6) (Table 4). The sample path of the triangular design crossed the boundary towards no treatment difference. AO did not prove to be superior to CS. Cox’s regression analysis adjusted for renal failure and gender (but unadjusted for the sequential analysis) showed that the most important determinants of 30 day mortality were baseline bilirubin, white cell count, and the presence of encephalopathy (Table 5). After adjusting for these variables, the treatment difference remains significant with the hazard of dying within 30 days whilst on AO therapy being over three times that for patients treated with CS (PZ0.003; hazard ratio 3.22, 95% CI, 1.48–7.03). The Kaplan–Meier survival curves assessing 30 day Table 5 Cox regression analysis (stratified by renal function) for 30 day survival

Age Male sex INR Bilirubin Encephalopathy WCC Treatment

Hazard ratio

CI

P

1.02 1.98 1.77 1.0 2.53 1.05 3.22

0.99–1.05 0.93–4.19 0.89–3.49 1.0–1.01 1.13–5.66 1.01–1.10 1.48–7.03

0.18 0.08 0.10 0.03 0.02 0.03 0.003

mortality and utilising an ITT analysis are shown in Fig. 2. Similar data based on a ‘per protocol’ analysis showed greater divergence of the curves with 41.2% survival in the AO group at 30 days (14 patients ‘at risk’) as compared with 76.7% in the CS group (33 patients ‘at risk’). Causes of death are outlined in Table 6 and there was no significant difference between the groups (PZ0.96). Eleven patients had a total of 15 gastrointestinal bleeds during the study but varices were the site of haemorrhage in only four patients (two in each group) and all were managed with band ligation. Renal stratification divided the group so that nine patients (19%) in the AO group had renal impairment at randomisation, as compared to 13 patients (25%) in the CS group. The 30 day survival in patients who did not exhibit renal impairment at the time of randomisation was 62% in the AO group and 80% in the CS group (PZ0.07). Five of these patients in the AO group and eight patients in the CS group received renal replacement therapy. Renal failure developed during the study period in 17 patients, 11 treated with AO and six treated with CS and all but one of these patients died. In total, four patients received terlipressin for hepatorenal syndrome (AO 1, CS 3). At 30 days only two patients in the AO group were still alive, whereas five patients survived in the CS group (PZ0.42). There were 108 episodes of sepsis within the first 30 days of randomisation in 59 patients (Table 9).

cumulative survival

two after 16 and 19 days of treatment. Eight patients withdrew consent after randomisation.

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

p=0.05

Antioxidants Corticosteroids 0

5

10

15

20

25

30

Days since randomization No. at risk

53 48

50 45

49 38

46 35

42 29

39 27

37 (Survival 69.8%) 26 (Survival 54.2%)

Fig. 2. 30 day survival of patients with severe alcoholic hepatitis treated with antioxidants or corticosteroids.

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Cause of death

Antioxidants

Corticosteroids

Deaths within 30 days Number of deaths 22 Sepsis 11 Hepatorenal 7 syndrome GI haemorrhage 3 Progressive liver 1 failure Deaths between 30 days and 1 year Number of deaths 7 Sepsis 2 Hepatorenal 0 syndrome GI haemorrhage 1 Progressive liver 4 failure Other 0

16 7 5

PZ0.96

3 1

PZ0.353

2 2

Steroids Anti oxidants Total

Corticosteroids

p=0.43

No at risk 53 48

60 120 180 240 300 Days since randomisation 37 26

32 24

28 22

26 21

26 20

26 19

360

26 (Survival 49%) 19 (Survival 40%)

4

Deaths

Mortality rate

Odds ratio

95% confidence interval

P

53 48

27 29

0.51 0.60

1.4

(0.6, 3.2)

0.43

101

56

Table 8 Cox regression analysis (stratified by renal function) for 1 year survival

Renal failure Treatment

Antioxidants

Fig. 3. 1-year survival of patients with severe alcoholic hepatitis treated with antioxidants or corticosteroids.

Table 7 Stratified analysis and estimation of the 1 year survival, adjusted for sequential monitoring Patients

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

13 3 2

A diagnosis of sepsis was made more frequently in the AO group but microbiologically proven episodes of infection occurred more often in the CS group. A diagnosis of sepsis without microbiological confirmation was mainly due to cellulites, suspicious chest radiology or spontaneous bacterial peritonitis (SBP) diagnosed on the ascitic white cell count. At 1 year there had been 29 deaths (60%) in the AO group and 29 deaths (55%) in the CS group (PZ0.43) (Table 7). The sample path crossed the boundary of no treatment difference in the triangular design. The odds of dying before 1 year appear to be, on average, 40% greater for the AO group. This indicates conclusive evidence of no difference in the 1-year survival between AO and CS. Cox’s regression analysis, adjusted for renal failure status and gender (but unadjusted for the sequential analysis) indicated the hazard of death by 1 year was three times

Group

Cumulative Survival

Table 6 Causes of death

Hazard ratio

CI

P

3.0 1.5

1.7–5.3 0.9–2.5

!0.001 0.15

greater for patients with renal impairment at randomisation (Table 8). The Kaplan–Meier survival curves are presented in Fig. 3. Six patients in each group resumed alcohol consumption after discharge from hospital while 10 AO patients and 12 CS patients remained abstinent. The drinking pattern is unknown for seven patients (Table 9). 3.4. Antioxidant levels Vitamins A and E, and selenium levels in plasma were assayed in paired plasma samples from 38 patients, 19 patients from each treatment group, at the time of randomisation and 7 days after commencement of treatment. Baseline antioxidant levels were also compared to 11 normal volunteer controls. Plasma vitamins A, E and selenium levels were all significantly depressed in the trial patients at randomisation (Table 10). At randomisation there were no differences in antioxidant levels between the groups. Plasma vitamin E levels, adjusted for lipid levels, increased significantly after 7 days of AO treatment (p! 0.001) to that of the normal controls, but were unchanged Table 9 Episodes of sepsis during treatment

Patients with sepsis Deaths from sepsis Episodes of sepsis Microbiologically proven

Antioxidants (48)

Corticosteroids (53)

PZ

35 9 (31.4%) 54 21 (38.9%)

24 12 (45.8%) 54 42 (77.8%)

0.05 0.63

Site of microbiologically proven sepsis Septicaemia 8 Pneumonia 4 SBP 3 Urine 4 Intravenous line 0 Stool 1 Other 1

12 5 10 4 5 2 4

!0.001

0.492

M. Phillips et al. / Journal of Hepatology 44 (2006) 784–790 Table 10 Plasma antioxidant levels at randomisation (day 0) and after 7 days treatment (day 7)

AO group (nZ19) Day 0 Day 7 CS group (nZ19) Day 0 Day 7 Controls (nZ11)

Vitamin E/total lipids

Vitamin A (mmol/L)

Selenium (mg/L)

8.41 16.21 P!0.001

0.6 0.55 PZ0.296

34.5 78* P!0.001

7.67 9.08 PZ0.904 17.11**

0.56 1.15 P!0.001 2.78#

34 47* PZ0.001 84#

Median values shown, *comparison of day 7 selenium levels P!0.001, **PZ0.014 compared to trial patients, #P!0.001 compared to trial patients.

in the CS group (PZ0.904). Plasma vitamin A levels were unchanged after 7 days of AO therapy but did increase significantly in the CS group (P!0.001). Selenium levels increased significantly in both groups after 7 days treatment. However, day 7 levels were significantly higher in the AO group where levels approached those of the normal controls.

4. Discussion The original hypothesis that AO therapy would result in a survival advantage compared to CS therapy at 30 days was not proven as the interim analysis showed a statistically significant survival advantage in favour of CS and the odds of dying by 30 days were 2.4 greater for patients on AO. The difference was even more striking in the patients who completed the intended course of treatment. On this basis the trial was terminated. At 1 year of follow-up the survival advantage of CS had been lost and this is in keeping with previous reports that also found that the benefit of CS was short-term and as such was useful only as a bridge to further therapy e.g. liver transplantation. The design of the current trial was intended to be both pragmatic and inclusive of cases of severe AAH as encountered in hospital practice. Although a double blind study is ideal, it was not considered possible to develop an intravenous placebo. Patients with features of severe disease were deliberately not excluded except for very recent sepsis and gastrointestinal bleeding. The severity of the disease is also manifest in the Maddrey disciminant function scores which are higher than in all other published trials in AAH except one trial [16]. The decision to defer histological verification of the diagnosis of AAH was intended to reflect clinical reality and permit early initiation of therapy. Ultimately, this approach was vindicated by the high diagnostic accuracy seen in the cohort that was biopsied and although not always assessed as severe, histological

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changes of AAH are known to resolve rapidly in patients treated with CS [40]. In addition, a subset analysis of this cohort with histological confirmation of AAH was similar to the findings in the overall study. The design of this study reflected the belief that a single agent, e.g. N-acetylcysteine was unlikely to be effective, particularly as so many antioxidants have been shown to be deficient in AAH. The combination selected was derived from several sources and previous work including a cocktail used in neonatal hemochromatosis [41]. Desferrioxamine is very effective in ameliorating free radical-induced hepatocyte damage in experimental animal models [42]. Allopurinol has been shown to be a potent antioxidant and prevents alcohol-induced liver injury in animal models [43]. Intralipid may be beneficial to the microcirculation by inducing post-capillary venodilatation [44]. It is feasible that some of the components of the AO therapy may have had deleterious effects. Desferrioxamine may increase susceptibility to infection [45], while vitamin A has been linked to hepatotoxicity [46]. However, low doses of vitamin A were used and plasma levels were not altered by the AO treatment. The alternative interpretation is that this study simply confirms the beneficial effects of CS in severe AAH as suggested by the earlier data. The reluctance to accept CS as standard of care because of possibly aggravating co-existing morbidity may be misplaced, either because the holistic effect of therapy is superior or the actual risk of perceived complications is lower than conventionally considered [47].

Acknowledgements We acknowledge the support of Robin Hughes, Peter Langley, Paul Cheeseman, Kishor Raja and Roy Sherwood, amongst others.

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