Evidence-based Cardiology – part 4 pot

California between 1985 and 1990 compared CHD and CBVD death rates in six ethnic groups. Once again, African American men and women in all age groups were found to have the highest CVD death rates. Hispanics, Chinese, and Japanese had much lower CVD rates, although the CBVD deaths were proportionally a more important cause of death among the Chinese and Japanese. Furthermore, a study that compared the rates of hospitalization for CHD among Asian Americans compared to Americans in Northern California revealed that the risk of hospitalization for CHD was the lowest among the Chinese Americans (0·6), and the highest among the South Asians (3·7, P Ͻ 0·001). 126 Recent data from the United Kingdom (UK) reveals that although the CHD mortality rates were approximately 43% higher among South Asian men and women compared to the general UK population (ASMR men 282/100000, women 89/100000), among South Asians a decline of 26% in men and 18% in women in the CHD rates occurred. 127 This is in keeping with a decline in CHD mortality in the UK as a whole over the past decade. In Canada, an analysis of the Canadian national mortality database of South Asians, Chinese and Canadians of European origin (EU), demonstrated that the ASMR per 100000 for CHD in South Asians (M 320, F 144) was similar compared to those of EU origin (M 320, F 110), yet was much higher than Chinese (M 107, F 40). Furthermore, a significant decline in CHD death rates between 1979–83 and 1989–93 was observed in all groups, with the greatest declines being apparent among South Asian men and women compared to EU and Chinese respectively (M 22%, 13%, and 5·4%, F 6%, 4%, and 2%) 49 (Table 21.7). Furthermore, in Canada the inverse relation- ship between mortality and socioeconomic status is observed in European Canadians, but not in South Asians and Chinese. This raises the issue of whether this relation- ship is acquired within societies and therefore is potentially preventable/modifiable. Conclusions CVD accounts for the largest percentage of deaths world- wide. To date, recognition and modification of the major CVD risk factors have led to declines in CVD rates in most Western countries, although these declines have lagged behind in most non-white populations. Socioeconomic development, urbanization, and increasing life expectancy have led to a progressive rise in the CVD rates in developing countries such as India and China. It is clear that elevated serum cholesterol, elevated blood pressure, cigarette smoking, and glucose intolerance are the major risk factors for CHD and CBVD in most populations. However, the prevalence of these factors and the strength of association of these factors to CVD vary between ethnic groups. Furthermore, other risk or protective factors (levels of endogenous fibrinolysis, dietary factors such as flavonoids and antioxidants) probably exist. Identification of these factors is important so that new approaches to prevention of CVD in these populations may be developed. Research into ethnic populations who suffer adverse glucose and lipid changes upon urbanization (that is, Hispanics, Aboriginal, and South Asians) should be a priority, as a greater propor- tion of these groups are adopting urban lifestyles which are associated with observed increases in CVD rates. Furthermore, in developed countries, research into reasons for social disparity and its impact on the distribution of CVD risk factors among ethnic groups must be continued so that specific interventions may be developed to reduce the adop- tion of unhealthy lifestyle behaviors, and barriers to health- care services may be reduced. Ultimately all of this information will lead to special strategies for prevention which may be tailored to ethnic populations, and generate important areas for future study. References 1.Lenfant C. Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases (news). Circulation 1994;90:2609–17. 2.Anand SS. 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This model, however, has had limited success. Obesity, cigarette smok- ing, and psychosocial stress have been implicated, and evidence on dietary fat has accumulated to the point where a public health policy of reduced intake is prudent, if not proven. The effects of modifying adult lifestyle, when formally tested in randomized trials have, however, been disappointingly small. 1 The model has proved incapable of answering important questions. For example, in Western countries the steep increase in the disease has been associ- ated with rising prosperity, so why do the poorest people, and those living in the poorest parts of these countries, have the highest rates? 2 One explanation for our failure to understand and pre- vent rising epidemics of CHD is that people are hetero- geneous in their responses to environmental influences. Smoking, for example, is harmful to some people but not others. Some statisticians argue that we therefore need much larger studies to overcome this, while geneticists argue that the heterogeneity results from genes as yet unknown. There is, however, another way forward which is to examine the biologic basis of the differences between individuals. The recent discovery that people who develop CHD grew differently to other people during fetal life, infancy, and childhood encourages this view, 3 and has led to a new “developmental” model for the disease. 4,5 Growth and CHD Figure 22.1 shows the growth of 357 boys who in later life were either admitted to hospital with CHD or died from it. 3 They belong to a cohort of 4630 men who were born in Helsinki, and their growth is expressed as Z-scores. The Z-score for the cohort is set at zero, and a boy maintaining a steady position as large or small in relation to other boys would follow a horizontal path on the figure. Boys who later developed CHD, however, were small at birth, remained small in infancy but had accelerated gain in weight and body mass index (BMI) thereafter. In contrast, their heights remained below average. Table 22.1 shows hazard ratios for CHD according to size at birth. The hazard ratios fall with increasing birthweight and, more strongly, with increasing ponderal index (birthweight/length 3 ), a measure of thin- ness at birth. These trends were found in babies born at term or prematurely and therefore reflect slow intrauterine growth. Table 22.2 shows that the hazard ratios also fell with increasing weight, height, and BMI at age 1 year. Small size at this age predicts CHD independently of size at birth. In a simultaneous analysis with birthweight the hazard ratio associated with each unit decrease in Z-score for weight between birth and 1 year is 1·21 (95% CI 1·08–1·36, P ϭ 0·001). The association between CHD and small size at birth has been shown in studies in Europe, North America, and India. 6–10 The association with poor weight gain in infancy was first shown in Hertfordshire, 6 and confirmed in Helsinki: 3 the strength of the association being similar in the two studies. The association with rapid childhood weight gain was first shown in a study of an older cohort of men 279 22 The fetal origins of coronary heart disease David JP Barker 0·05 Cohort BMI Weight Height –0·05 Standard deviation ( Z )-score –0·1 –0·15 –0·2 –0·25 0123456 Age (years) 789101112 0 Figure 22.1 Growth of 357 boys who later developed CHD in a cohort of 4630 boys born in Helsinki. 3 BMI, body mass index; CHD, coronary heart disease. born in Helsinki, 11 while the association with low rates of height growth is consistent with the known association between the disease and short adult stature in men. 12 Figure 22.2, based on the same data used in Figure 22.1, shows the combined effects of ponderal index at birth and BMI in childhood in the Helsinki cohort. 3 The figure uses BMI at age 11 years, but BMI at ages around this gives sim- ilar results. The lines on the figure join points with the same hazard ratios. For example, the line for the highest ratio, 1·75, is associated with low ponderal index at birth but above average BMI in childhood. Boys who had a low pon- deral index at birth increased their risk of CHD if they attained even average BMI in childhood. In contrast, among boys with a high ponderal index, no increased risk was asso- ciated with a high childhood BMI. The interaction between ponderal index at birth and BMI in childhood is strongly statistically significant (P Ͻ 0·001). Findings among girls are similar, and again the risk of CHD is determined more by the tempo of weight gain than the body size attained. 13 Table 22.3 is taken from the total Helsinki cohort which comprises 15846 men and women of whom 13517 had their BMI recorded at 11 years of age. 3,11,13 It is based on 1235 patients who were admitted to hospital or died from CHD, and 480 patients who died from the disease. It shows hazard ratios according to birthweight and quarters of BMI at age 11 years. The risk of disease falls with increasing birthweight and rises with increasing BMI. The pattern is similar in the two sexes. The hazard ratios for admissions and deaths are 0·80 (95% CI 0·72–0·90) for each kilogram Evidence-based Cardiology 280 Table 22.2 Hazard ratios for CHD according to body size at one year 3 Hazard ratio Cases (n)/ (95% CI) Men (n) Weight (kg) up to 9 1·82 (1·25–2·64) 96/781 up to 10 1·17 (0·80–1·71) 85/1126 up to 11 1·12 (0·77–1·64) 89/1243 up to 12 0·94 (0·62–1·44) 49/852 Ͼ12 1·00 38/619 P for trend Ͻ0·0001 Height (cm) up to 73 1·55 (1·11–2·18) 79/636 up to 75 0·90 (0·63–1·27) 68/962 up to 77 0·94 (0·68–1·31) 87/1210 up to 79 0·83 (0·58–1·18) 64/1011 Ͼ79 1·00 59/802 P for trend 0·007 Body mass index (kg/m 2 ) Յ16 1·83 (1·28–2·60) 72/654 up to 17 1·61 (1·15–2·25) 89/936 up to 18 1·29 (0·91–1·81) 83/1136 up to 19 1·12 (0·77–1·62) 59/941 Ͼ19 1·00 54/954 P for trend 0·0004 Abbreviation: CHD, coronary heart disease Table 22.1 Hazard ratios for CHD according to body size at birth 3 Hazard ratio Cases (n)/ (95% CI) Men (n) Birthweight (kg) Յ2500 3·63 (2·02–6·51) 24/160 up to 3000 1·83 (1·09–3·07) 45/599 up to 3500 1·99 (1·26–3·15) 144/1775 up to 4000 2·08 (1·31–3·31) 123/1558 Ͼ4000 1·00 21/538 P for trend 0.006 Ponderal index (kg/m 3 ) Յ25 1·66 (1·11–2·48) 104/1093 up to 27 1·44 (0·97–2·13) 135/1643 up to 29 1·18 (0·78–1·78) 84/1260 Ͼ29 1·00 31/578 P for trend 0·0006 Abbreviation: CHD, coronary heart disease 22 22 24 26 Ponderal index at birth (kg/m 3 ) 28 30 32 20 BMI at age 11 years (kg/m 2 ) 18 16 14 12 1·75 1·5 1·25 1 0·75 0·75 0·5 Figure 22.2 Hazard ratios for CHD (coronary heart disease) according to ponderal index at birth and BMI (body mass index) at 11 years. Arrows indicate average values: lines join points with the same hazard ratios. 3 increase in birthweight and 1·06 (95% CI 1·03–1·10) for each kg/m 2 increase in BMI at age 11 years. The hazard ratios for deaths alone are 0·83 (95% CI 0·69–0·99) and 1·10 (95% CI 1·04–1·16). Growth and hypertension and type 2 diabetes There is now a substantial body of evidence showing that people who were small at birth remain biologically different to people who were larger. The differences include an increased susceptibility to hypertension and type 2 diabetes, two disorders closely linked to CHD. 14–17 Table 22.4 is based on 698 patients being treated for type 2 diabetes and 2997 patients being treated for hypertension. It again shows odds ratios according to birthweight and quarters of BMI at age 11 years. The two disorders are associated with the same general pattern of growth as CHD. The risks for each disease fall with increasing birthweight and rise with increas- ing BMI. The odds ratio for type 2 diabetes is 0·67 (95% CI 0·58–0·79) for each kilogram increase in birthweight and The fetal origins of coronary heart disease 281 Table 22.3 Hazard ratios (95% CI) for CHD according to birthweight and BMI at 11 years: 13 517 men and women born 1924 to 1944 Birthweight (kg) BMI at 11 years (kg/m 2 ) up to 15·7 up to 16·6 up to 17·6 Ͼ17·6 Hospital admissions and deaths (1235 cases) up to 3·0 1·4 (0·8–2·4) 1·6 (0·9–2·8) 1·8 (1·0–3·2) 2·1 (1·1–3·8) up to 3·5 1·3 (0·7–2·2) 1·5 (0·9–2·7) 1·5 (0·8–2·6) 1·6 (0·9–2·9) up to 4·0 1·3 (0·7–2·3) 1·4 (0·8–2·4) 1·3 (0·8–2·4) 1·4 (0·8–2·6) Ͼ4·0 1·0 1·2 (0·6–2·3) 1·1 (0·6–2·1) 1·0 (0·5–1·8) Deaths (480 cases) up to 3·0 1·4 (0·5–4·0) 1·8 (0·6–5·1) 2·1 (0·7–6·2) 3·0 (1·0–8·6) up to 3·5 1·4 (0·5–3·9) 1·9 (0·7–5·2) 2·2 (0·8–6·1) 2·7 (1·0–7·6) up to 4·0 1·9 (0·7–5·3) 1·8 (0·7–5·2) 1·7 (0·6–4·8) 1·6 (0·6–4·5) Ͼ4·0 1·0 1·4 (0·4–4·6) 1·6 (0·5–4·7) 1·3 (0·4–4·0) Abbreviations: BMI, body mass index; CHD, coronary heart disease Table 22.4 Odds ratios (95% CI) for hypertension and type 2 diabetes according to birthweight and BMI at 11 years: 13 517 men and women born 1924 to 1944 3,11,13 Birthweight (kg) BMI at 11 years (kg/m 2 ) up to 15·7 up to 16·6 up to 17·6 Ͼ17·6 Men and women (n) up to 3·0 991 719 581 560 up to 3·5 1394 1422 1264 1246 up to 4·0 827 984 1122 1110 Ͼ4·0 167 254 413 463 Type 2 diabetes (698 cases) up to 3·0 1·3 (0·6–2·8) 1·3 (0·6–2·8) 1·5 (0·7–3·4) 2·5 (1·2–5·5) up to 3·5 1·0 (0·5–2·1) 1·0 (0·5–2·1) 1·5 (0·7–3·2) 1·7 (0·8–3·5) up to 4·0 1·0 (0·5–2·2) 0·9 (0·4–1·9) 0·9 (0·4–2·0) 1·7 (0·8–3·6) Ͼ4·0 1·0 1·1 (0·4–2·7) 0·7 (0·3–1·7) 1·2 (0·5–2·7) Hypertension (2997 cases) up to 3·0 2·0 (1·3–3·2) 1·9 (1·2–3·1) 1·9 (1·2–3·0) 2·3 (1·5–3·8) up to 3·5 1·7 (1·1–2·6) 1·9 (1·2–2·9) 1·9 (1·2–3·0) 2·2 (1·4–3·4) up to 4·0 1·7 (1·0–2·6) 1·7 (1·1–2·6) 1·5 (1·0–2·4) 1·9 (1·2–2·9) Ͼ4·0 1·0 1·9 (1·1–3·1) 1·0 (0·6–1·7) 1.7 (1.1–2.8) Abbreviation: BMI, body mass index 1·18 (95% CI 1·13–1·23) for each kg/m 2 increase in BMI at age 11 years. The corresponding figures for hypertension are 0·77 (95% CI 0·71–0·84) and 1·07 (95% CI 1·04–1·09). Similarly to CHD the risk of disease is determined not only by the absolute value of BMI in childhood but also by the combination of body size at birth and during childhood. 15,17 It is the tempo of growth as well as the attained body size that determine risk. Associations between low birthweight and hypertension and type 2 diabetes have been found in other studies. 14–17 There is also a substantial literature showing that birthweight is associated with differences in blood pressure and insulin secretion within the normal range. 14,18,19 These differences are found in children and adults but they tend to be small. For example, a 1kg difference in birthweight is associated with around 1–2mmHg difference in systolic pressure. 19 This contrasts with the large effects on hypertension. A pos- sible explanation for this is that, following an intrauterine lesion, regulatory mechanisms may maintain homeostasis for many years until further damage, owing to age, obesity, or other influences, initiates a self-perpetuating cycle of progres- sive functional loss. 20 Brenner has proposed such a model for the development of hypertension following reduced nephron numbers at birth, a known correlate of low birth weight. 20 Biologic mechanisms The association between altered growth and CHD has led to the suggestion that the disease may originate in two phenomena associated with development – “developmen- tal, or phenotypic plasticity” and “compensatory growth”. Phenotypic plasticity is the phenomenon whereby one genotype gives rise to a range of different physiologic or morphologic states in response to different environmental conditions during development. 21,22 Such gene–environment interactions are ubiquitous in development. Their existence is demonstrated by the numerous experiments showing that minor alterations to the diets of pregnant animals, which may not even change their offspring’s body size at birth, can produce lasting changes in their physiology and metabolism – including altered blood pressure and glucose/insulin and lipid metabolism. 23,24 The evolutionary benefit of phenotypic plasticity is that, in a changing envi- ronment, it enables the production of phenotypes that are better matched to their environment than would be possible if one genotype produced the same phenotype in all envi- ronments. 22 When undernutrition during development is followed by improved nutrition many animals stage acceler- ated or “compensatory” growth in weight or length. This restores the animal’s body size but may have long-term costs which include reduced life span. 25 There are several possible mechanisms by which reduced fetal and infant growth followed by accelerated weight gain in childhood may lead to CHD. Babies who are thin at birth lack muscle, a deficiency that will persist as the critical period for muscle growth is around 30 weeks in utero, and there is little cell replication after birth. 26 If they develop a high BMI in childhood, they may have a disproportionately high fat mass. This may be associated with the development of insulin resist- ance, as children and adults who had low birthweight but are currently heavy are insulin resistant. 18,27,28 Small babies have reduced numbers of nephrons. 20,29 It has been suggested that this leads to hyperperfusion of each nephron and resulting glomerular sclerosis, further nephron death, and a cycle of increasing blood pressure and nephron death. This may be exacerbated if accelerated growth increases the degree of hyperperfusion. This framework fits with the hypothesis that essential hypertension is a dis- order of growth with two separate mechanisms, a growth- promoting process in childhood and a self-perpetuating mechanism in adult life. 30 People who were small at birth also have different vascu- lar structure. One aspect of this is that they have reduced elastin in their larger arteries as a consequence, it is thought, of the hemodynamic changes that accompany growth retar- dation in utero. 31 Elastin is laid down in utero and during infancy and thereafter turns over slowly. Reduced elastin leads to less compliant, “stiffer” arteries and to a raised pulse pressure. The gradual loss of elastin, and its replacement with collagen that accompanies aging, tends to amplify the increase in pulse pressure. 31 The existence of such self-perpetuating cycles, initiated in utero, but triggered by aging, obesity, or other influences in later life, would explain the small effects of birth size on blood pressure in the normal population, but its large effects on blood pressure in people with hypertension. Studies in South Carolina showed that hypertensive patients with low birthweight more often require second-line therapy, with calcium-channel blocking agents or ACE inhibitors, as opposed to first-line therapy with diuretics or ␤ blocking agents. 32 The suggestion that among hypertensive patients those with the lowest birthweights have the highest blood pressures has been confirmed in the Helsinki cohort (unpublished). Findings in Hertfordshire suggest that one of the mecha- nisms linking poor weight gain in infancy with CHD is altered liver function, reflected in raised serum concentra- tions of total and low density lipoprotein cholesterol, and raised plasma fibrinogen concentrations. 33,34 Unlike organs such as the kidney, the liver remains “plastic” during its development until the age of around 5 years. Its function may be permanently changed by influences that affect its early growth. 35–37 Support for an important role for liver development in the early pathogenesis of CHD comes from findings in Sheffield. 38 Among men and women, reduced abdominal circumference at birth a measure that reflects reduced liver size, gave stronger predictions of later serum Evidence-based Cardiology 282 [...]... income 1000 marks (pounds sterling) per year Ponderal index Յ26.0 (n ϭ 147 5) Ponderal index Ͼ26.0 (n ϭ 21 54) Ͼ 140 (15 700) 11 1–1 40 (15 700) 9 6–1 10 (12 40 0) 7 6–9 5 (10 700) Յ75 ( 840 0) 1·00 1· 54 (0·8 3–2 ·87) 1·07 (0·5 1–2 ·22) 2·07 (1·1 3–3 ·79) 2·58 (1 4 5 4 ·60) 1·19 (0·6 5–2 ·19) 1 42 (0·7 8–2 ·57) 1·66 (0·9 0–3 ·07) 1 44 (0·7 9–2 ·62) 1·37 (0·7 5–2 ·51) P for trend Ͻ0·001 0·75 P for interaction between the effects of... et al BMJ 2001;322:123 3–6 43 .Phillips DIW, Walker BR, Reynolds RM et al Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations Hypertension 2000;35:130 1–6 44 .Zimmet P, Alberti KGMM, Shaw J Global and societal implications of the diabetes epidemic Nature 2001 ;41 4: 78 2–7 45 .Robinson R The fetal origins of adult disease BMJ 2001;322: 37 5–6 46 .Ravelli ACJ, van der... maps to chromosome 14q23-q 24 Hum Mol Genet 19 94; 3:95 9–6 2 71.Rampazzo A, Nava A, Erne P et al A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43 Hum Mol Genet 1995 ;4: 215 1 4 72.Severini GM, Krajinovic M, Pnamonti B et al A new locus for arrhythmogenic right ventricular dysplasia on the long arm of chromosome 14 Genomics 1996;31:19 3–2 00 73.Rampazzo A, Nava... as $ 54 000 per QALY (male aged 3 5 4 9 years with all three additional risk factors) or as high as $42 0 000 Most of the subgroups had Table 24. 1 5 Year clinical outcomes and costs of lipid lowering in major randomized trials Study Reductions per 1000 patients Cost per patient ($) Deaths MI Revasc Tx Offset Net 1Њ Prevention WOSCOPS AFCAPS 5 4 19 26 8 31 3700 46 54 100 5 24 3600 41 30 2Њ Prevention 4S CARE... myocardial infarction Circulation 1989;80:23 4 4 4 307 Evidence-based Cardiology 39.Oldridge N, Furlong W, Feeny D et al Economic evaluation of cardiac rehabilitation soon after acute myocardial infarction Am J Cardiol 1993;72:15 4 6 1 40 .Ades PA, Pashkow FJ, Nestor JR Cost-effectiveness of cardiac rehabilitation after myocardial infarction J Cardiopulm Rehab 1997;17:22 2–3 1 41 .Antiplatelet Trialist’s Collaboration... infarction JAMA 2000;2 84: 2 74 8–5 4 45.Tsevat J, Duke D, Goldman L et al Cost-effectiveness of captopril therapy after myocardial infarction J Am Coll Cardiol 1995;26:91 4 1 9 46 .Franzosi MG, Maggioni AP, Santoro E et al Cost-effectiveness analysis of early lisinopril use in patients with acute myocardial 308 infarction Results from GISSI-3 trial Pharmacoeconomics 1998;13:33 7 4 6 47 .Yusuf S, Sleight P, Pogue... Study Group Randomised trial of cholesterol lowering in 44 44 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet 19 94; 344 :138 3–9 16.Pedersen TR, Kjekshus J, Berg K et al Cholesterol lowering and the use of healthcare resources: results of the Scandinavian Simvastatin Survival Group Circulation 1996;93:179 6–8 02 17.Johannesson M, Jonsson B, Kjekshus J et al Cost... involved and heart failure is the predominant manifestation Several loci for ARVD have been mapped, including loci on 14q23-q 24 (ARVD1),70 1q42-q43 (ARVD2),71 14q12q22 (ARVD3),72 2q32-q32·3 (ARVD4),73 3p23 (ARVD5) 74 and 10p 14- p12 (ARVD6).75 The causal gene for the ARVD2 locus on chromosome 1q42-q43 has been identified as the cardiac ryanodine receptor gene (RYR2).76 Mutations in RYR2 have been identified in... 1998; 76:20 8–1 4 44. Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A A structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene Biochem Biophys Res Commun 1999;262 :41 1–1 7 45 .Mogensen J, Klausen IC, Pedersen AK et al ␣-Cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy J Clin Invest 1999;103:R39–R42 46 .Olson TM,... Development 2000; 127: 41 9 5–2 02 24. Desai M, Hales CN Role of fetal and infant growth in programming metabolism in later life Biol Rev Camb Philos Soc 1997;72:32 9 4 8 25.Metcalfe NB, Monaghan P Compensation for a bad start: grow now, pay later? Trends Ecol Evol 2001;16:25 4 6 0 26.Widdowson EM, Crabb DE, Milner RDG Cellular development of some human organs before birth Arch Dis Child 1972 ;47 :65 2–5 27.Barker DJP, . (1· 1–3 ·8) up to 3·5 1·3 (0· 7–2 ·2) 1·5 (0· 9–2 ·7) 1·5 (0· 8–2 ·6) 1·6 (0· 9–2 ·9) up to 4 0 1·3 (0· 7–2 ·3) 1 4 (0· 8–2 4) 1·3 (0· 8–2 4) 1 4 (0· 8–2 ·6) 4 0 1·0 1·2 (0· 6–2 ·3) 1·1 (0· 6–2 ·1) 1·0 (0· 5–1 ·8) Deaths. (48 0 cases) up to 3·0 1 4 (0· 5 4 ·0) 1·8 (0· 6–5 ·1) 2·1 (0· 7–6 ·2) 3·0 (1· 0–8 ·6) up to 3·5 1 4 (0· 5–3 ·9) 1·9 (0· 7–5 ·2) 2·2 (0· 8–6 ·1) 2·7 (1· 0–7 ·6) up to 4 0 1·9 (0· 7–5 ·3) 1·8 (0· 7–5 ·2) 1·7 (0· 6 4 ·8). (1· 5–3 ·8) up to 3·5 1·7 (1· 1–2 ·6) 1·9 (1· 2–2 ·9) 1·9 (1· 2–3 ·0) 2·2 (1· 4 3 4) up to 4 0 1·7 (1· 0–2 ·6) 1·7 (1· 1–2 ·6) 1·5 (1· 0–2 4) 1·9 (1· 2–2 ·9) 4 0 1·0 1·9 (1· 1–3 ·1) 1·0 (0· 6–1 ·7) 1.7 (1. 1–2 .8) Abbreviation: