Tim ; Schneider

Daniela Marschall-Kehrel

Jens Ulrich Hanisch

Martin C Michel
email: m.c.michel@amc.nl

Ulrich

Prof C Martin

Michel

Do gender, age or life style factors affect responses to anti-muscarinic treatment in overactive bladder patients?

Keywords: overactive bladder, urinary incontinence, gender, age, obesity, smoking, alcohol, caffeine, darifenacin

HAL is

INTRODUCTION

The overactive bladder symptom complex (OAB) is defined by the presence of urgency, with or without incontinence, frequently accompanied by urinary frequency and nocturia [START_REF] Abrams | The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society[END_REF]. It is a very common condition in the general adult population [START_REF] Milsom | How widespread are the symptoms of an overactive bladder and how are they managed? A populationbased prevalence study[END_REF][START_REF] Stewart | Prevalence and burden of overactive bladder in the United States[END_REF][START_REF] Irwin | Populationbased survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study[END_REF] with major adverse effects on quality of life of the afflicted patients and considerable costs to society. While the causes of OAB and specifically urgency remain largely unclear [START_REF] Michel | Basic mechanisms of urgency: basic and clinical evidence[END_REF], a number of risk factors have been demonstrated or proposed. A major risk factor is ageing, as the prevalence of OAB consistently increases with age [START_REF] Milsom | How widespread are the symptoms of an overactive bladder and how are they managed? A populationbased prevalence study[END_REF][START_REF] Stewart | Prevalence and burden of overactive bladder in the United States[END_REF][START_REF] Irwin | Populationbased survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study[END_REF][START_REF] Goepel | Prevalence and physician awareness of symptoms of urinary bladder dysfunction[END_REF]. While gender does not appear to be a risk factor for the presence of OAB in population-based studies [START_REF] Milsom | How widespread are the symptoms of an overactive bladder and how are they managed? A populationbased prevalence study[END_REF][START_REF] Stewart | Prevalence and burden of overactive bladder in the United States[END_REF][START_REF] Irwin | Populationbased survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study[END_REF], the vast majority of patients receiving OAB treatment are women [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]8).

Additionally, a number of life-style factors have been proposed to be risk factors for OAB.

Earlier studies have reported obesity, typically assessed as a high body mass index (BMI), [START_REF] Brown | Urinary incontinence in older women: who is at risk?[END_REF][START_REF] Espino | Prevalence and severity of urinary incontinence in elderly Mexican-American women[END_REF][START_REF] Hannestad | Are smoking and other lifestyle factors associated with female urinary incontinence? The Norwegian EPINCONT study[END_REF][START_REF] Melville | Urinary incontinence in US women. A population-based study[END_REF] or smoking [START_REF] Espino | Prevalence and severity of urinary incontinence in elderly Mexican-American women[END_REF][START_REF] Hannestad | Are smoking and other lifestyle factors associated with female urinary incontinence? The Norwegian EPINCONT study[END_REF] to be risk factors for incontinence in general but did not differentiate between stress and urgency incontinence. While obesity and smoking (via the associated frequent coughing) are pathophysiologically plausible risk factors for stress incontinence, their link to OAB or urgency incontinence is less clear. Nevertheless, both obesity and, to a lesser extent, smoking have also been linked as risk factors to urgency incontinence [START_REF] Dallosso | The association of diet and other lifestyle factors with overactive bladder and stress incontinence: a longitudinal study in women[END_REF], detrusor instability [START_REF] Arya | Dietary caffeine intake and the risk for detrusor instability: a case-control study[END_REF] and the classical albeit non-specific OAB symptom nocturia [START_REF] Shiri | The effects of lifestyle factors on the incidence of nocturia[END_REF] although such associations have not been confirmed for both factors in all studies [START_REF] Shiri | The effects of lifestyle factors on the incidence of nocturia[END_REF]16). An increased intake of alcohol and/or caffeine may affect voiding patterns based upon the diuretic effects of these agents. While increased intake of alcohol and/or caffeine have been proposed as risk factors for OAB or detrusor instability, the existing data are equivocal [START_REF] Arya | Dietary caffeine intake and the risk for detrusor instability: a case-control study[END_REF][START_REF] Shiri | The effects of lifestyle factors on the incidence of nocturia[END_REF](16)[START_REF] Dallosso | The association of diet and other lifestyle factors with the onset of overactive bladder: a longitudinal study in men[END_REF]. The life style-associated factors are of particular interest as they are modifiable, i.e. theoretically offer [START_REF] Wyman | Practical aspects of lifestyle modifications and behavioural interventions in the treatment of overactive bladder and urgency urinary incontinence[END_REF]. For example, a recent randomized trial has demonstrated that alterations of fluid intake can affect symptoms in OAB patients [START_REF] Hashim | How should patients with an overactive bladder manipulate their fluid intake?[END_REF] whereas weight loss may improve incontinence in obese patients [START_REF] Natarajan | Effects of obesity and weight loss in patients with nononcological urological disease[END_REF]. Muscarinic receptor antagonists are the main treatment option for OAB patients [START_REF] Chapple | The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis[END_REF][START_REF] Novara | A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder[END_REF].

While they have consistently been shown to be superior to placebo, it remains unclear how potential risk factors for OAB may affect the treatment response to these drugs. For example, age may alter the expression of muscarinic receptors in the bladder and its responsiveness to muscarinic receptor ligands [START_REF] Michel | Physiological and pathological regulation of the autonomic control of urinary bladder contractility[END_REF], but some clinical data indicate that age may have limited effect on treatment responses [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]24). Whether modifiable factors such as obesity, smoking or alcohol and caffeine ingestion may affect the therapeutic response to muscarinic antagonists has not been investigated to our knowledge.

Darifenacin is a muscarinic receptor antagonist with efficacy in the treatment of OAB symptoms in several randomized, double-blind, placebo-controlled studies [START_REF] Chapple | A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder[END_REF][START_REF] Foote | Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M 3 selective receptor antagonist[END_REF][START_REF] Michel | Novel muscarinic antagonists to treat incontinence and/or overactive bladder[END_REF]. Against the above background, we have used the database from a recent large observational study of the safety and efficacy of darifenacin to explore possible roles of gender, age and life-style factors in the clinical response to a muscarinic receptor antagonist.

MATERIAL AND METHODS

This manuscript describes a post-hoc analysis of a large, open-label, observational study into the safety and efficacy of darifenacin which had been performed as part of its post-marketing surveillance in Germany. Thus, no specific inclusion and exclusion criteria were applied other than a minimum age of 18 years and the recommendations from the Summary of Product The study included a total of 5821 patients, of which 3766 patients completed a 3-day micturition diary both pre-treatment and at least once after initiation of treatment, apparently reflecting clinical practice in Germany. Our analysis is based upon the latter group only to ascertain validity of the reported voiding data, but the demographic characteristics including the presence of potential risk factors were very similar in the total population and those with documented micturition diaries (data not shown). Our analysis is based upon the office visit prior to and at the end of the observational period; in cases of premature study discontinuation, the data from the last available visit were used in a last-observation-carried-forward manner.

At the initial visit, a medical history including questions about the possible risk factors of smoking, alcohol and caffeine use was recorded in a standardized manner. BMI was calculated from the height and weight of the patient. The physician applied qualitative scoring to record smoking status (never smoked, past smoker and present smoker), alcohol consumption (abstinent, light, moderate, strong) and caffeine intake (none, moderate, strong) based upon information provided by the patient. This information was used to stratify the population for all further analyses, but no instructions were given on how to rate these factors in order not to minimize interference with the observational character of the study. Moreover, at each visit the intensity of OAB symptoms (based upon diaries), a problem assessment ("The overactive bladder presently causes no/mild/moderate/severe problems"), possible adverse events and prescribed darifenacin dose were recorded. At the final visit, global physician assessments of efficacy and tolerability and patient-reported satisfaction with treatment and alteration in the ability to hold urine were also documented.

Data handling was performed by a contract research organization (Dr. Schauerte, Oberhaching, Germany). Baseline data are presented as means ± SD of absolute values of n patients. In line with previous similar analyses [START_REF] Michel | Relationships among symptoms, bother, and treatment satisfaction in overactive bladder patients[END_REF], treatment data are presented as % changes for OAB symptoms. Adverse events were coded according to MedDRA Version 8.1.

Descriptive statistical analysis was performed with the SAS for Windows program package (version 9.1). For interval-scaled variables, multiple ordinary least squares regression was applied, and logistic regression models for dichotomous dependent variables. As independent variables, BMI (kg/m 2 ), age (years), and factors of gender, alcohol consumption, smoking and caffeine intake were entered into the models to explore the statistical contribution of these factors to treatment responses. A p < 0.05 was considered significant.

RESULTS

The study population had an average age of 62.6 ± 12. 8 years, body weight of 75.8 ± 12.0 kg, height of 168.5 ± 7.2 cm and BMI of 26.7 ± 4.0 kg/m 2 . Among them 77.1% were female, 75.3% non-smokers, 16.8% present smokers and 7.9% past smokers. Abstinence, light, moderate and strong alcohol consumption was reported by 28.7%, 58.3%, 12.6% and 0.5% of participants, respectively (the latter two being pooled for all further analysis). No, moderate or strong caffeine consumption was reported by 11.8%, 80.6% and 7.6%, respectively. The patients reported OAB symptoms for <1, 1-5, 6-10 and > 10 years in 26.0%, 54.7%, 14.2% and 5.2%, respectively. 56.4% of patients had received some type of OAB treatment in the past. At enrolment 31.7% used pads, 27.9% toilet training, 34.4% pelvic floor exercises and 4.2% electrostimulation (multiple nominations possible), whereas no adjunct treatments for voiding dysfunction were reported by 32.3%. The prevalence of concomitant urological medication (WHO Drug Directory class G04) was <5%. A darifenacin starting dose of 7.5 and 15 mg q.d. was used in 97.2% and 2.8%, respectively. The episode frequency of urgency, incontinence, micturitions and nocturia as well as problem assessment before and after treatment are shown in figure 1. Ability to hold urine after treatment as compared to the start of treatment was rated as significantly longer, longer, same or shorter by 46.9%, 40.2%, 12.2% and 0.6% of patients, respectively. The global efficacy of treatment was rated as very good, good, moderate or insufficient by 42.7%, 36.1%, 10.3% and 10.9%, respectively. At the end of the observation period 84.7% and 15.3% of patients received the 7.5 and 15 mg dose of darifenacin, respectively. Gender and smoking status had little association with dose selection, whereas greater age (15 mg used by 14.4% aged <50 years vs. 17.1% >75 years), BMI (13.9% for <25 kg/m 2 vs. 21.7% for >30 kg/m 2 ) or alcohol consumption (15.7% for abstinent patients vs. 18.3% for those reporting moderate-strong consumption) were associated with a higher probability of receiving the 15 mg dose; in contrast, coffee consumption of any degree was associated with a smaller probability for receiving the higher dose (14.6% vs. 20.5%).

Based upon the data from the overall population, multiple regression models were applied to explore the roles of various factors in treatment-associated improvements of urgency, incontinence, micturition and nocturia episodes (Table 1). The baseline episode frequency of a symptom was the strongest predictor of its treatment-associated improvement (Table 1 Increasing age was significantly correlated to decreased improvements in urgency, incontinence, daytime micturition and nocturia episodes, but the magnitude of the age effect was very small relative to the overall treatment effect. For example, darifenacin treatment was associated with a reduction in the number of urgency episodes/24 h from 9.1 ± 5.8 to 5.0 ± 4.1, whereas each additional year of age was statistically associated with a decreased improvement of 0.01 episodes. Female gender did not significantly affect treatment-associated improvements of incontinence episodes but was associated with a statistically greater improvement of urgency, micturition and nocturia episodes (Table 1). However, the correlation of gender with the overall improvement was relatively weak. Except for a small but significant effect of increasing BMI on the improvement of urgency episodes, none of the life style factors significantly affected improvements of any of the four OAB symptoms (Table 1).

In line with the results from the above linear models regarding OAB symptoms, increasing age was also associated with a significantly smaller likelihood for a positive problem assessment and global efficacy or tolerability rating, whereas female gender was associated with a significantly greater likelihood for a positive problem assessment or global efficacy rating, but here as well effect sizes were small (Table 2). None of the life style factors significantly affected problem assessment or global efficacy (Table 2).

In line with post-marketing studies on other muscarinic receptor antagonists [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]8,[START_REF] Michel | Comparison of symptom severity and treatment response in patients with incontinent and continent overactive bladder[END_REF], adverse events were noted in only 2.7% of patients and consisted largely of dry mouth and constipation. Accordingly, the global tolerability was rated as very good, good, moderate and poor by 50.1%, 43.6%, 4.6% and 1.8% of patients, respectively, and the overall patient satisfaction was reported as very satisfied, satisfied or not satisfied by 42.4%, 44.9% and 2).

DISCUSSION

Age as well as several life style factors have been reported to be potential risk factors for OAB (see introduction). While female gender has not been established as a risk factor for OAB, the majority of patients receiving OAB treatment are female [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]8). Limited clinical data have explored the effects of age and gender on treatment responses in OAB patients [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]24), but the potential effects of life-style factors have not been reported to our knowledge.

Critique of methods

Our analysis is based upon an observational, large-scale, open-label study on the efficacy and tolerability of darifenacin in routine clinical use. In the absence of a placebo group, observational data do not allow for absolute conclusions about the safety and efficacy of darifenacin. However, multiple placebo-controlled studies have already demonstrated the absolute efficacy and tolerability of darifenacin [START_REF] Chapple | A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M 3 selective receptor antagonist, in the treatment of overactive bladder[END_REF][START_REF] Foote | Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M 3 selective receptor antagonist[END_REF][START_REF] Michel | Novel muscarinic antagonists to treat incontinence and/or overactive bladder[END_REF]. On the other hand, observational studies have proven useful for comparisons of relative efficacy and tolerability between patient groups of OAB patients [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]8,24). An observational study from routine clinical use may be particularly advantageous to explore the roles of potential OAB risk factors in treatment responses, because the strict inclusion and exclusion criteria of randomized controlled studies may limit variability of these factors in the study population, particularly for life style factors. Moreover, the expected inter-relatedness of several risk factors, e.g. of smoking and alcohol use, requires large patient numbers to yield the necessary statistical On the other hand, for reason of practicality, assessments in post-marketing surveillance studies are somewhat cruder than in controlled clinical or dedicated epidemiological studies.

For example, the quantitative assessment of life style factors is everything but straightforward, particularly when it comes to factors such as alcohol consumption where many patients may provide somewhat "beautified" responses. Given the practical limitations of a large and noninterventional study we had chosen for an assessment graded by the physician into 3-4 categories. While this may be suboptimal for a dedicated study into e.g. alcohol consumption, it reflects a necessary compromise between the scientifically desirable and the practically feasible. Finally, we have also used physician ratings of global efficacy and tolerability, as particularly the latter has proven to yield a statistically sensitive means to pick up differences in tolerability despite a typically reported incidence of adverse events in observational studies in OAB [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]8). These specific advantages and limitations should be kept in mind in the interpretation of our data.

Treatment results

Age not only is a well-established risk factor for OAB [START_REF] Milsom | How widespread are the symptoms of an overactive bladder and how are they managed? A populationbased prevalence study[END_REF][START_REF] Stewart | Prevalence and burden of overactive bladder in the United States[END_REF][START_REF] Irwin | Populationbased survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study[END_REF] but is also known to affect the expression of muscarinic receptors in the bladder and other tissues including salivary glands and heart [START_REF] Michel | Physiological and pathological regulation of the autonomic control of urinary bladder contractility[END_REF][START_REF] Brodde | Adrenergic and muscarinic receptors in the human heart[END_REF]. Until now only limited data on the effects of age on treatment results in OAB patients had been reported: One large observational study with tolterodine demonstrated a statistically significant but probably clinically irrelevant adverse effect of age on treatmentassociated symptom improvement and global efficacy [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]. On the other hand, this small negative effect was compensated by increasing severity of baseline symptoms with age and the strong statistical effect of baseline symptoms on the overall improvement. The present data for darifenacin also report a statistically significant but very small negative effect of age on treatment-associated improvements of OAB symptoms and global efficacy. This may even be somewhat under-estimated due to a trend for a higher dose with increasing age. While age did not significantly affect the global tolerability of tolterodine [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF], it was shown to have a statistically significant but very small adverse effect on the tolerability of solifenacin (8).

Very similar findings were obtained in the present study with darifenacin. Therefore, the overall data show that muscarinic receptor antagonists have similar efficacy across all age groups. The overall tolerability may decline with increasing age, but this may reflect the overall health status of the elderly rather than specific treatment-related adverse effects.

Although women receive muscarinic antagonist treatment of OAB symptoms more frequently than men, the prevalence of OAB does not exhibit major gender differences (2-4) and muscarinic receptor expression in the bladder is similar in both genders across multiple species [START_REF] Michel | Physiological and pathological regulation of the autonomic control of urinary bladder contractility[END_REF]. An observational study with tolterodine has reported that gender may have statistically significant effects on therapeutic efficacy, which are very small and not seen for all OAB symptoms; moreover, gender did not significantly affect the tolerability of tolterodine [START_REF] Michel | Do gender or age affect the efficacy and safety of tolterodine?[END_REF]. Gender did not affect the efficacy or tolerability of solifenacin in a similar study (24). In line with these observations, the present study found very similar effects in both genders upon treatment with darifenacin. Therefore, it appears that muscarinic antagonists as a class are similarly effective and tolerated in male and female OAB patients.

The major novel aspect of the present analysis was the exploration of potential effects of life style factors on the efficacy and tolerability of a muscarinic antagonist in the treatment of our data demonstrate that it does not affect the efficacy or tolerability of darifenacin in a clinically relevant manner. This is interesting as obesity and treatment response could not only interfere pathophysiologically but also a greater body weight would be associated with a smaller drug exposure per kg body weight. Accordingly, a greater BMI was associated with a greater likelihood for a higher darifenacin dose in the present study. While the role of alcohol, smoking and caffeine intake as risk factors for OAB remains under debate (see introduction), neither affected the efficacy or tolerability of darifenacin in the present study, although a trend for a higher darifenacin dose with greater alcohol (but not smoking or coffee) consumption may have masked an effect of alcohol on treatment.

CONCLUSION

In conclusion, the available data show that age, gender and several life style factors have no clinically relevant impact on the efficacy or tolerability of the muscarinic receptor antagonist darifenacin. Thus, muscarinic receptor antagonists can be expected to be similarly effective and tolerated regardless of the presence of such factors. While only limited data are available with regard to the modification of life style factors to improve OAB symptoms [START_REF] Hashim | How should patients with an overactive bladder manipulate their fluid intake?[END_REF][START_REF] Natarajan | Effects of obesity and weight loss in patients with nononcological urological disease[END_REF], we propose that an optimal therapeutic approach to OAB will involve both medical treatment and life style advice.

  improve the condition

  darifenacin. The participating 1155 physicians (including 81.0% boardcertified and office-based urologists, 13.8% general practitioners) were asked to systematically record their observation of patients receiving darifenacin based upon their medical judgment. Based upon the package insert, recommended darifenacin doses were 7.5 and 15 mg q.d. The planned observation time was 12 weeks. At the time the study was performed, ethical committee approval, registration in clinical trials databases or written patient consent were neither required nor recommended for purely observational studies, such as this one, in Germany.

  , respectively. In multiple linear models none of the life style factors was associated with an altered global tolerability rating (Table

  of minor effects. Such large patient numbers are easier to collect from observational studies.

  a high BMI has been demonstrated as a risk factor for OAB (see introduction),

Figure 1 :

 1 Figure 1: OAB symptoms and problem assessment at baseline and after treatment with

  Figure 1 120x267mm (600 x 600 DPI)

  ).

	F o r
	P
	e
	e r
	R
	e
	v i e
	w
	O n l
	y
	10

Table 1 :

 1 Multiple regression models exploring the effects of potential risk factors for darifenacin treatment-associated improvement of OAB symptoms. A positive number for the parameter indicates a numerically worse result, and a negative number a numerically better result. Data are means ± SD. P-values are based on a Wald Chi-square test.

	Parameter estimate	p-value
	Urgency episode improvement
	Age, per year	0.0127 ± 0.0045	0.0049
	Gender, relative to male	-0.4416 ± 0.1379	0.0014
	BMI, per kg/m 2	0.0298 ± 0.0146	0.0421
	Previous smoking, relative to none	-0.0128 ± 0.2124	0.9521
	Current smoking, relative to none	0.2335 ± 0.1575	0.1382
	Mild alcohol, relative to none	-0.1812 ± 0.1325	0.1715
	Moderate to severe alcohol, relative to none	-0.1920 ± 0.2008	0.3391
	Moderate caffeine, relative to none	-0.1372 ± 0.1747	0.4325
	Severe caffeine, relative to none	0.4276 ± 0.2647	0.1063
	Baseline urgency, per episode	0.5047 ± 0.0097	<0.0001
	Incontinence episode improvement
	Age, per year	0.0047 ± 0.0020	0.0210
	Gender, relative to male	-0.0011 ± 0.0659	0.9863
	BMI, per kg/m 2	0.0116 ± 0.0065	0.0727
	Previous smoking, relative to none	-0.1764 ± 0.1016	0.0827
	Current smoking, relative to none	0.0994 ± 0.0708	0.1607

Page 22 of 25 International Journal of Clinical Practice International Journal of Clinical Practice F o r P e e r R e v i e w O n l y 23Table 2 :

 2 Logistic regression models exploring the effects of potential risk factors for darifenacin treatment-associated improvement of problem assessment and the global efficacy and tolerability of darifenacin. Data are shown as odds ratios for a beneficial effect (greater improvement of problem assessment, very good or good global efficacy and tolerability) with 95% confidence intervals in parentheses (intervals excluding unity indicate statistical significance). In this regard an odds ratio > 1 indicates a numerically better result, and an odds ratio < 1 a numerically worse result.

		Problem assessment	Efficacy	Tolerability
		(improvement vs. no	(very good/good vs.	(very good/good vs.
		improvement)	moderate/poor)	moderate/poor)
	Age, per year	0.981 (0.975; 0.988)	0.978 (0.970; 0.985)	0.982 (0.971; 0.993)
	Gender, relative to male	1

.313 (1.087; 1.587) 1.396 (1.135; 1.716)

				1.047 (0.746; 1.471)
	BMI, per kg/m 2	1.010 (0.990; 1.032)	0.979 (0.957; 1.001)	0.998 (0.963; 1.034)
	Previous smoking, relative to none	1.114 (0.823; 1.508)	0.950 (0.690; 1.309)	1.074 (0.615; 1.877)
	Current smoking, relative to none	0.870 (0.695; 1.089)	0.923 (0.719; 1.186)	0.739 (0.501; 1.090)
	Mild alcohol, relative to none	1.037 (0.858; 1.253)	1.036 (0.840; 1.277)	1.371 (0.998; 1.883)
	Moderate to severe alcohol, relative to none	0.951 (0.717; 1.263)	0.952 (0.698; 1.298)	1.429 (0.863; 2.364)

Page 23 of 25 International Journal of Clinical Practice International Journal of Clinical Practice

	Moderate caffeine, relative to none	1.261 (0.989; 1.608)	1.125 (0.858; 1.474)	1.224 (0.818; 1.830)
	Severe caffeine, relative to none	1.073 (0.738; 1.561)	0.840 (0.559; 1.262)	1.052 (0.556; 1.992)
	F o r P e e r R e v i e w	O n l y
					24

Page 24 of 25 International Journal of Clinical Practice International Journal of Clinical Practice

	F o
	r
	P
	e e r
	R e v i e w
	O n
	l y

Michel MC, Wetterauer U, Vogel M, de la Rosette JJMCH. Cardiovascular safety and overall tolerability of solifenacin in routine clinical use. Drug Safety 2008; 31: 505-

Brown JS, Grady D, Ouslander JG, Herzog AR, Varner E, Posner SF. Prevalence of urinary incontinence and associated risk factors in postmenopausal women. Obstet

Witte LPW, Peschers U, Vogel M, de la Rosette JJMCH, Michel MC. Does the number of previous vaginal deliveries affect overactive bladder symptoms or their

Acknowledgements: Bayer Vital had funded the underlying study as well as the present analyses.

Bayer Vital had funded the underlying study as well as the present analyses. Tim Schneider has received consultancy and/or speaker honoraria from Astellas, Bayer and Pfizer, Daniela Marschall-Kehrel has received consultancy honoraria from Allergan, Apogepha, Astellas, Bayer, Ferring, Lilly, and Pfizer. Jens U. Hanisch is an employee and stock owner of Bayer. Martin C. Michel has received research funds, speaker and/or consultancy honoraria from Allergan, Astellas, Bayer, Lilly and Pfizer.


Michael Aboud

Ali Elgalib

Laura Pomeroy

George Panayiotakopoulos

Elias Skopelitis

Alastair Duncan

Ranjababu Kulasegaram

Consultant Sexual Health/HIV Caroline Dimian

Fiona C Lampe

Anthony S Wierzbicki

& St

Thomas ' Hospitals

Alastair Duncan Senior

Dietician Guys'

St Thomas'

Thomas St

Barry S Hospitals

Peters Reader

Hiv Stds

Dr Barry Peters
email: barry.peters@kcl.ac.uk

Cardiovascular Risk Evaluation and Anti-retroviral Therapy Effects in an HIV cohort: implications for clinical management: The CREATE 1 study

scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Anti-retroviral therapy (HAART) has reduced traditional HIV-associated disease and death [START_REF] Bozzette | Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection[END_REF]. Cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality in HIV following initial reports of dyslipidaemia [2 3 4], probably as a result of the combination of the pro-inflammatory effects of HIV infection, an increased prevalence of traditional risk factors (RFs), and the effects of HAART[5 6 7 8].

Cardiovascular disease risk screening is an increasing priority in national health care strategies [9]. Risk is calculated using tools derived from epidemiological studies including the USA Framingham study [START_REF] Anderson | Cardiovascular disease risk profiles[END_REF], UK primary care databases (QRISK) [START_REF] Hippisley-Cox | Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2[END_REF] and European prospective cohort studies (SCORE) [START_REF] Conroy | Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project[END_REF]. In all these calculators, CVD or CHD risk is calculated using age, gender, smoking, systolic blood pressure (SBP), and total cholesterol: high-density lipoprotein cholesterol (TC: HDL-C) ratio [START_REF] Wierzbicki | Vascular risk screening: possible or too much, too soon?[END_REF]. Ad hoc adjustments can be made to CVD risk factor profiles to add the effects of family history of premature CHD, ethnicity and obesity [START_REF] Wierzbicki | Vascular risk screening: possible or too much, too soon?[END_REF]. HIV cohorts in the UK, and most of the developed world, are an "aging population", and hence there is an increasing need to focus on CVD. Traditional CVD RFs are increased in HIV populations [14 15], and seem to predict risk in a similar fashion to uninfected populations [START_REF] Law | The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study[END_REF].

This study was designed to describe the CVD RF burden in a large HIV cohort and to apply these findings to recommendations for clinical practice.

Methods

Setting CREATE (cardiovascular risk evaluation and antiretroviral therapy) is a cross-sectional study looking at estimated 10-year CVD and CHD risk, and the metabolic syndrome in HIV, and this study, CREATE 1, concentrates on the former aspects. Recruitment was from a large inner London teaching hospital with a large HIV cohort (exceeding 2500), and a mediumsized local district hospital with a more affluent demographic.

Study population

Patients at both hospitals are from a diverse ethnic and socioeconomic group. The Ethnicity was self reported and categorised as: Afro-Caribbean, black African, white (Caucasian), Asian, and other. Details of HAART were recorded, including the date of commencement, protease inhibitor use, and the current regimen.

Anthropometric, physiological and biochemical parameters required to define cardiovascular risk and the metabolic syndrome were collected. The use of anti-atheroma therapies, including anti-thrombotic, antihypertensive, lipid-lowering and hypoglycaemic drugs, was collected, and the use of recreational drugs recorded. Weight, height, waist circumference and blood pressure, were measured by trained experienced research nurses or doctors using standard criteria. Blood pressure was measured in the sitting position after 5 minutes rest with an Omron 320 automated system calibrated to British Hypertension Society standards. Blood lipids were measured fasting when possible, and assayed on a Roche Hitachi platform by standard techniques of CHOD-PAP for cholesterol and a non-ionic precipitation method for HDL-cholesterol. Data were entered directly onto the proforma during clinic attendance. Missing information on the database was checked with the source data, clinical notes, on scheduled review. The database was regularly cross-checked with the source data.

The estimated risk of CVD and CHD was calculated using the Framingham (1991) [START_REF] Anderson | Cardiovascular disease risk profiles[END_REF] To assess CVD risk in a control population, data was compared with the QRESEARCH database [START_REF]QResearch database. QResearch Group[END_REF], which is derived from a UK general practice population, a selfreferred CVD risk programme in the UK (HEART-UK/Unilever CVD risk assessment study) [START_REF] Neil | Estimated 10-year cardiovascular risk in a British population: results of a national screening project[END_REF] and with the combined DAD cohort studies of cardiovascular risk in HIV[ 15 21]

Statistical Analysis

Statistical analysis was performed with SPSS. This analysis included only patients free of pre-existing CHD diagnoses. Estimated 10-y CHD/CVD risk was summarised using medians and the proportion with values >10% and >20% per decade. Subgroups were compared using Chi-squared or Fishers exact test for categorical variables and Mann-Whitney tests for continuous variables. Logistic regression was used to assess the association of HAART use with 10-y CHD risk >10% and to investigate the extent to which this association was independent of traditional CHD risk factors. The association of duration of HAART use with 10-y CHD risk was examined in a subgroup of patients on first line HAART.

Results

Patient Characteristics

1021 patients were recruited, of which 990 were free of pre-existing CVD (table 1).

For the purposes of data presentation and analysis (

Cardiovascular and coronary Heart Disease Risk

The median CVD risk was 4 (0-56)%/decade in men and 1.4 (0-37) %/decade in women while CHD risks were 3.5 (0-36) %/decade and 0.6(0-16)%/decade respectively.

CVD risk was >20% in 6% of men and 1% of women and >10% in 12% of men and 4% of women while CHD risk exceeded 10% in 13% of men and 2% of women and was >20% in 2% of men but no women. CVD risk was lower in all decade cohorts than the HEART-UK/Unilever study, although our patients were significantly younger and had a higher prevalence of smoking (table 1a & 1b). There was suggestion of increased CHD risk among males in our cohort compared to general population seen by general practitioners [START_REF]QResearch database. QResearch Group[END_REF] In this study for men aged 45-55years, CHD risk >15% was present in 14.7% compared with 7.76% in the control group.. There was insufficient data to make meaningful comparisons for females.

Analyses were performed to investigate the associations of gender, ethnicity A similar analysis was performed for 245 patients on first-time HAART according to duration of HAART (<1 year, 1-3 years, ≥3 years) (figure 1). The unadjusted odds ratio for high CHD risk were 1.24 for 1-3 years and 5.13 for ≥ 3years groups, compared to the <1 year group (Figure 3). Again the greatest contribution to the excess risk in both the 1-3 years and ≥ 3 years groups was total cholesterol, as indicated by the comparatively large fall in odds ratio after adjustment for total cholesterol.

Discussion

The increased frequency of observed CHD in HIV-infected versus uninfected patients has focused attention on appropriate strategies to prevent cardiovascular disease in this population. Observational cohort studies have shown an increase in observed CVD events with the use of HAART, particularly with protease inhibitors [ 15 21]. Some of the protease inhibitor effect can be attributed to drug-associated dyslipidaemia [START_REF] Friis-Moller | Combination antiretroviral therapy and the risk of myocardial infarction[END_REF]. high compared to similar age groups in the general population, with a higher prevalence of smoking and hypercholesterolaemia. The average CVD and CHD risks in our cohort were 6.0% and 4.15% respectively. The CHD risk was much lower than the 7-7.4% CHD risk seen in the Italian SIMONE cohort of HIV infected patients [22 23], where the prevalence of elevated CVD risk >10% was 17% and CHD risk>10% was 10%. CVD risk >20% was present in 4.9% and CHD risk >20% in 1.6%. Other cohort studies of HIV-infected patients have shown higher prevalence of CHD risk >10% of 23% and >20% in 8% [START_REF] Knobel | Global cardiovascular risk in patients with HIV infection: concordance and differences in estimates according to three risk equations (Framingham, SCORE, and PROCAM)[END_REF] or 11% [START_REF] Bergersen | Elevated Framingham risk score in HIVpositive patients on highly active antiretroviral therapy: results from a Norwegian study of 721 subjects[END_REF].

In the DAD study the same version of the Framingham risk scoring tool used in our study determined that the CHD risk was 2.4% [START_REF] Law | Modelling the 3-year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study[END_REF]. Thus the population recruited to CREATE 1 is at intermediate risk for CVD compared to other HIV cohort studies. The CHD risk in the CREATE 1 cohort was elevated compared to a similar cohort of the general population from the QRESEARCH database and the proportions with elevated CVD risk were similar to sexmatched age cohorts from the self-selected general population recruited for the HEART-UK/Unilever Study [START_REF] Neil | Estimated 10-year cardiovascular risk in a British population: results of a national screening project[END_REF].

We found in CREATE 1 that caucasians were much more likely to have a CVD or CHD risk ≥10% than non-Caucasians. Even amongst the non-Caucasians, the proportion with raised CVD or CHD risk increased with the duration of HAART (from 3.5% with <1 year use to 17.9% with >3 years use; n=245 first line users only). While many guidelines recommend adjustment of the Framingham risk for additional risk factors, this remains controversial. The Framingham risk calculator was derived from data on a mainly white working class population, and predicted the correct proportion at risk in patients with HIV in DAD cohort study [START_REF] Law | Modelling the 3-year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study[END_REF]. Aside from Caucasians, the largest ethnic sub-group in CREATE 1 was African and diverse with respect to country of origin. Secondary adjustment for ethnicity is possible and tends to reduce CVD and CHD risk in African-derived populations compared to Asian or Caucasian populations in the UK [START_REF] Brindle | Primary prevention of cardiovascular disease: a webbased risk score for seven British black and minority ethnic groups[END_REF] but is limited and is mostly based on West Africans.

The degree of adjustment required for other African populations has not been determined but CVD risk is elevated in urban or migrant populations[ 27 28]. In this study as CVD and CHD risks had already been adjusted for family history further adjustment was not performed [START_REF] Diabetes | JBS 2: the Joint British Societies' guidelines for prevention of cardiovascular disease in clinical practice[END_REF].

In Afro-Caribbean general population the age-adjusted prevalence of CVD is 0.61 but there is no data on patients with HIV with this ethnic background in the UK.

In our study, the increased predicted CVD and CHD risk among Caucasians is at variance with a large prospective HIV cohort study of observed acute myocardial infarctions from the USA [START_REF] Triant | Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease[END_REF], where African-American race was a significant predictor of acute myocardial infarction, with a relative risk 1.43 compared to non-African-Americans. This may well reflect differences in underlying risk factors between the 2 cohorts, such as proportions of smokers, differences in BMI and dysglycaemia and effects of social deprivation. Similar discrepancies were found between our cohort and the same US cohort in respect of gender as among our female patients there were very few with even a moderately high predicted CVD or CHD risk. There was a marked increase in the relative rate of females with observed acute myocardial infarctions in the same US HIV cohort, with a relative risk of 2.98, compared to the control population [START_REF] Triant | Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease[END_REF].

In this study smoking was less frequent than in the DAD cohort (37 vs. 52%) and showed pronounced ethnic and gender differences. Smoking was most associated with CVD risk in males and was commoner in Caucasians. In females the prevalence of smoking was slightly increased compared to the general population. A large proportion of the cohort was heterosexual black African, where smoking was less prevalent than among Causasians (23% vs. 51%). Therefore, the relative contribution of smoking to CVD risk in this population is likely to be lower than in other studies. The greatest population-attributable risk in the INTERHEART study was dyslipidaemia. Dyslipidaemia is frequent in HIV [START_REF] Law | Modelling the 3-year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study[END_REF]. Dyslipidaemia related to the duration of HAART therapy contributed most to an increased predicted CVD and CHD risk amongst our cohort. The duration of first line HAART use was associated with a CHD risk ≥10%, with a relative risk >5 for those on HAART for over 3 years compared to those who on HAART for under one year. This finding replicates those of the DAD study recruited from 1999-2003 [START_REF] Friis-Moller | Combination antiretroviral therapy and the risk of myocardial infarction[END_REF] and shows that despite the availability of newer protease inhibitors that do not significantly affect lipid concentrations , most patients were still receiving HAART regimens that induced dyslipidaemia and increased CHD risk.

These findings provide a rationale for specific policies for the management of cardiovascular risk in people with HIV, using adaptations of standard guidelines from the Joint British Societies [START_REF] Diabetes | JBS 2: the Joint British Societies' guidelines for prevention of cardiovascular disease in clinical practice[END_REF] or NICE [START_REF]Lipid modification[END_REF]. This study demonstrates that management of CVD risk in HIV patients should consider length of exposure to HAART as well as ethnicity and gender. Risk calculators give only broad estimates of risk [START_REF] Reynolds | Accuracy of cardiovascular risk estimation in patients without diabetes[END_REF] protease inhibitors, such as atazanavir [START_REF] Colafigli | Cardiovascular risk score change in HIV-1infected patients switched to an atazanavir-based combination antiretroviral regimen[END_REF], although this advantage is mitigated in part by the concomitant use of ritonavir as a pharmacological enhancer [START_REF] Bentue-Ferrer | Clinical pharmacology, efficacy and safety of atazanavir: a review[END_REF]. Other agents that have a favourable lipid profile include raltegravir, an integrase inhibitor [START_REF] Markowitz | Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatmentnaive patients with HIV-1 infection: results of a 48-week controlled study[END_REF], as well as some of the agents that have been available for many years, such as nevirapine [34 35].

  Cardiovascular Risk Evaluation and Anti-retroviral TherapyEffects in an HIV cohort: implications for clinical management: The CREATE 1 study

5 A

 5 study recruited from June 2005 to September 2006.The protocol was approved by the St Thomas' Hospital Ethics Committee. In order to minimise selection bias, all HIV-infected outpatients were eligible providing they were regular attendees for their general HIV care and were not pregnant. Patients were not recruited from specialist clinics, such as the lipodystrophy or hepatitis co-infection clinics, to avoid unfair weighting of patients with metabolic issues. These patients were still open to study entry from their general HIV clinic attendance. The research staff identified clinics for inclusion, and all such patients were offered entry. structured proforma was used to collect data on demographics, basic anthropometry, HIV and HAART history, current CD4 cell counts, HIV viral loads and details of coinfections.

  -based cohort in CREATE1, levels of CVD and CHD risk appeared

16 Figure 1 .

 161 Figure 1. Comparison of CHD risk with length of treatment with HAART before and after adjustment for CHD risk factors.

Table 1a

 1a

	-c. The DAD study (Data Collection on Adverse Events of Anti-HIV Drugs) is a
	collaboration of eleven prospective cohorts of HIV-infected individuals from across Europe,
	Australia, and the US, totalling over 30,000 participants.

  The majority, 74%, were male, 50.8% were white, 6.9% Afro-Caribbean, 33.3% African (various), 1.9% Asian, and 6.9 % from other ethnic groups. Men who have sex with men (MSM) comprised 43.9%, and 41% were heterosexual. Intravenous drug abuse was reported by 1.65%. The median HIV viral load was 50 copies/ml and CD4 count 406 cells/mm 3 , and 73.1% were on HAART. CVD was present in 3% of both men and women, and diabetes in 3% and 2% respectively. The mean (±SD) age was 41±9 years (48.6 % ≥40 years). Current or recent smoking (within 5 years) was reported by 37% and was commoner in whites (51% vs. 23%; p =0.02) than black Africans. The systolic blood pressure (SBP) was

	F o r F o r
	P P
	e e
	e r e r
	R R
	e e
	v i e v i e
	w w
	O n l O n l
	y y
	7

table 1 a & 1b)the total numbers in CREATE1 were 990 and exclude patients with established CVD. For purposes of comparison with the DAD study cohorts, which included CVD, data from the complete cohort of 1021 was used (table 1c).

120±14 mmHg and 11% had a SBP >140mmHg. The total cholesterol was 4.70±1.05 mmol/L and HDL-C was 1.32±0.48mmol/L. An elevated total cholesterol (>5 mmol/L) was present in 35.6%. HDL-C <1mmol/L in men or <1.2mmol/L in women was found in 33%. An elevated TC: HDL ratio > 5 was present in 18.7% and > 6 in 7.6%. Lipid-lowering drugs had been prescribed in 10.8%.

The male population in CREATE 1 was younger (41 vs. 52 yrs), contained more smokers (45 vs.13%), had lower SBP (121 vs. 140 mmHg), slightly lower total cholesterol (4.7 vs. 5.1 mmol/L) and less established CHD than those self-referring for CVD risk screening in the HEART-UK/Unilever study. Similarly women recruited to CREATE 1 were younger (39 vs. 52 yrs), had lower SBP (118 vs. 134mmHg) and cholesterol (4.7 vs. 5.2 mmol/L) and less CHD (3 vs. 9 %) but more smoked (16 vs.13%). HEART-UK/Unilever participants were markedly different in ethnic origin (92% were non-Caucasian) and were more centrally obese (64 vs. 40%). The population was similar to that recruited to the DAD study cohorts (table 1c) except for marginally lower total cholesterol (4.7 vs. 5.0 mmol/l), higher HDL-C (1.23 vs. 1.1 mmol/l) and BMI (24.7 vs. 23 kg/m 2 ) and a lower prevalence of current smoking (37 vs. 51%).

  The proportions with 10 year CVD and CHD risk > 20% for those on HAART <1yr were 4.3% and 0.8% and for ≥3yrs exposure 11% and 4.8% respectively (p=0.01). These differences were statistically significant for both Caucasians and non-Caucasians. A further analysis was performed to define variables within this group associated with increased CVD risk with duration of HAART. Age ≥40yrs, total cholesterol ≥5mmol/L, and SBP≥140mmHg were all more common in the group who had been on Table3b). Smoking was not a factor that contributed to a higher CHD risk for those on HAART for longer periods (as a group), as there were similar proportions of smokers in each group regardless of the duration on HAART.

	vs. 2.33; p<0.001), but also higher median CD4 count (432 vs. 381; p<0.001), more smoking (50% vs. 22%; p <0.001) and lower HDL-C (1.22 vs. 1.42 mmol/L; p<0.001). No significant differences in CVD or CHD risk were observed in MSM compared to male heterosexuals, despite significant differences in age (40 vs. 42 years; p <0.001), smoking (50% vs. 37%; on HAART (The contribution that each Framingham equation variable made to estimated
	p<0.001) and prevalence of drug-treated hypertension (5% vs. 11%; p=0.003) and higher viral CVD/CHD risk in patients on HAART was investigated. The unadjusted odds ratio for high
	loads (2.66 vs. 2.33; p<0.001) and CD4 counts (434 vs. 381; p<0.001). CVD risk was 1.36 (0.92, 2.00) for HAART users vs. non-users. Adjusting for age and sex,
	F o r HAART use F the odds ratio fell to 1.13(0.72, 1.80). Similarly the unadjusted odds ratio for high CHD risk o r was 1.59 (0.99, 2.57) for HAART users vs. non-users and after adjustment for age and sex,
	P e 705 patients out of 973 were on HAART; 245 were on their first line regimen, of whom 44.1% had used HAART for <1yr, and about a third and a quarter used HAART for 1-the odds ratio fell to 1.02 (0.57, 1.85). This excess risk was accounted for after adjustment for P e SBP, smoking and total cholesterol; the biggest fall in odds ratio was observed after
	e r r e correction for cholesterol alone (0.63 (0.34-1.20). 3yrs and >3yrs respectively.
	R R
	e e
	v i e v i e
	w w
	3.8% (p<0.001) and for CHD risk ≥10% 16.4% vs. 0.4% (p<0.001) respectively. Statistically significant differences in CHD risk were also seen for those in older age groups, and groups O n l O n l
	stratified by total cholesterol above or below 5mmol/L, SBP above or below 140mmHg and y y
	smokers vs. non-smokers. (data not shown)
	Compared to non-Caucasians, Caucasians had greater CVD and CHD risks, and
	approximately a 3-fold increase in the prevalence of CHD risk >10% or CVD risk >20%.
	10

(Caucasians vs. non-Caucasians), risk group (MSM vs. heterosexuals) and use of HAART with CVD and CHD risk. The median CVD and CHD risks was 4.4% and 2% for men and 1.4% and 1% for women (p<0.001). The proportions with CVD risk > 10% were 21.8% vs.

These differences could partly be attributed to more males among our Causasians (96% vs. 53%; p<0.001) hence more MSM individuals (73% vs. 13%; p<0.001), higher viral load

(2.63

Patients on HAART had significantly raised median CVD risk (3.57% vs. 2.34%; p=0.01) and CHD (0.64% vs. 0.38 %; p<0.001) risk, associated with increased age (42 vs. 37 years, p<0.001), higher total cholesterol (4.86 vs. 4.24 mmol/L; p<0.001) but also lower viral load (1.96 vs. 4.02; p<0.001), and higher HDL-C (1.39 vs. 1.12 mmol/L; p<0.001).

The duration of HAART was associated with CVD and CHD risk. For this analysis, only the 245 participants on first line therapy were included in order to avoid confounding from previous HAART use.

HAART the longest. Conversely, there were fewer persons with low HDL-C in the ≥3 year compared with <1yr HAART groups and the TC/HDL ratio did not vary with length of time

Table 1a -

 1a c: Clinical characteristics of male and female patients attending a HIV service in the UK compared with a general cardiovascular risk screening group in the UK and the DAD cohort study. 1a -HIV positive males in CREATE 1 compared to a HEART UK population

			Cohort without CVD	HEART-UK
			(male; n=737)		(male; n= 27,776)
	Age		41.2± 9.2		51.5± 16.2*
	Caucasian(%)		65		Not available
	Smoking (%)		45*		13.4
	Systolic Blood Pressure	121± 14		140± 17*
	(mmHg)
	Hypertension (%)	12		13
	Total Cholesterol	4.70± 1.05		5.10± 1.00*
	(mmol/L)
	HDL-cholesterol (mmol/L) Diabetes (%) CHD (+) (%) BMI (kg/m 2 ) Waist > 102 cm (%) 1b -HIV positive females in CREATE 1 compared to a HEART UK population 1.25± 0.44 1.20± 0.40 2 4 NA 11 24.6± 3.8 -24 25 F o r
	Age Caucasian(%) Smoking (%) Systolic Blood Pressure (mmHg) Hypertension (%) Total Cholesterol	Cohort without CVD (female; n=253) 38.8± 8.8 P 9 16* e 118±14 9 4.74± 1.04 e r	HEART-UK (female; n=43,261) 52.1± 15.4* Not available 12.7 134± 19* 13 5.20±1.00*
	(mmol/L) HDL-cholesterol (mmol/L)	1.54± 0.54	R	1.50± 0.40
	Diabetes (%) IHD (+) (%) BMI (kg/m 2 ) Waist > 88 cm (%) 1c -Complete cohort in CREATE 1 compared to subjects in the DAD study	2 NA 27.8± 6.1 64* Complete CREATE 1 e 3 8.7* -40.1 cohort , including CVD (N=1022) DAD v i e (N=23,468) w
	Age Caucasian(%) Male (%) MSM Smoking (%) Systolic Blood Pressure (mmHg) Hypertension (%) Total Cholesterol	40 (35-46) 51 76 44 37* 120 (110-130) 12* 4.7 (3.9-5.3)		39 (34-47) -75 45 51 120 (110-130) O n l 8.5 5.0 (4.2-6.0) y
	(mmol/L)
	HDL-cholesterol	1.23 (1.00-1.53)		1.1 (0.9-1.4)
	(mmol/L)
	Diabetes (%)		3		2.5
	IHD (+) (%) CD4 count (mm	3 /L)	3 406( 289-562)		1.4 418( 255-612)
	Viral Load (log) BMI (kg/m 2 )		<1.70 (<1.70-3.54) 24.7 (22.3-27.7)	<2.7 (<2.7-6.9) 23( 21-25)
	Waist > 102 cm (%)	24		-
	Family history early	13		11.7
	CHD (%)

Table 2 . Association of factors with current HAART use

 2

	n/N (%)	Using	Not using	p value
		HAART	HAART
		N=705	N=258	(Chi-squared/Fishers Exact
				test)
	Male	509/705	204/258	p=0.031
		(72.2)	(79.1)
	Age >40 yrs	388/705	83/258 (32.2) p<0.001
		(55.0)
	Caucasian	330/690	149/253	p=0.003
		(47.8)	(58.9)
	MSM	279/705	144/258	p<0.001
		(39.6)	(55.8)
	Chol >5 mmol/l	296/705	47/258 (18.2) p<0.001
		(42.0)
	Lipid lowering drug	88/705 (12.5) 6/258 (2.3)	p<0.001
	use
	HDL <1 mmol/l	134/705	95/258 (36.8) p<0.001
		(19.0)
	TC/HDL ratio >4.5	192/705	88/258 (34.1) p=0.037
		(27.2)
	Sys BP >140 mmHg 77/705 (10.9) 29/258 (11.2) p=0.89
	Smoker	250/705	107/258	p=0.087
		(35.5)	(41.5)

Page 18 of 22 International Journal of Clinical Practice International Journal of Clinical Practice

	F o r
	P
	e
	e r
	R
	e
	v i e
	w
	O n l
	y

Table 3 a & b: Mean lipid values according to HAART use a) Mean Total cholesterol, HDL cholesterol and Total/HDL ratio by current HAART use

 3

	HAART now	Total		HDL-	TC: HDL
		Cholesterol	Cholesterol	ratio
	No	Mean	4.28	1.14	4.05
		N	258	258	258
		Std. Deviation	0.89	0.34	1.32
	Yes	Mean	4.88	1.40	3.84
		N	705	705	705
		Std. Deviation	1.06	0.51	1.34
	Total	Mean	4.72	1.33	3.90
		N	963	963	963
		Std. Deviation	1.05	0.49	1.34
	b)

Mean Total cholesterol, HDL cholesterol and Total/HDL ratio by years on first line

  BSP is senior author and conceived, designed and managed the clinical trial and wrote the manuscript. MA, ES, LP, GP, CD, RK, AD & A E helped with study design and recruitment and manuscript writing. FL and AW helped with study design, manuscript writing and statistical analysis. All authors have seen all the key drafts, including final submission.

		F o r F o r F o r
		P P P
		e e e
	Yrs 1	st Line	Total Cholesterol e r cholesterol HDL-e r e r	TC: HDL ratio
	<1	Mean		4.50		1.23	3.98
		N Std. Deviation		108 0.97 R R R	108 0.42	108 1.27
	1-3 >=3 Total	Mean N Std. Deviation Mean N Std. Deviation Mean N		4.81 76 0.96 5.31 61 0.86 4.80 245	1.41 76 e e e 0.50 1.49 61 0.49 v i e 3.75 76 1.33 3.91 61 v i e v i e 1.39 1.35 3.89 245 245 w w w
	Std. Deviation Contributions of authors:	0.99		0.48	1.32 O n l O n l O n l
						y y y

International Journal of Clinical PracticeInternational Journal of Clinical Practice

Contribution of CV risk factors to Odds Ratio (OR) for 10 year CHD risk>10% by length of time on HAART. N=243 first line HAART users only (Odds Ratio Y-axis). 1st adjustment for age/sex; then sequentially for sBP, Smoking and Total Chol. The degree of OR drop reflects the contribution of that factor to risk in the first place. Biggest OR drop seen when TC corrected for.

Acknowledgments

This study was supported by unrestricted educational grants of equal value from Abbott, Tibotec, Gilead and Roche Pharmaceuticals.

advisory boards for Abbott, GlaxoSmithKline, and Tibotec Pharmaceuticals. ASW has received grant support, lecture honoraria and travel grants from Abbott, AstraZeneca, Sharp & Dohme, Roche, Pfizer, Sanofi-Aventis and Takeda pharmaceuticals.

List of Abbreviations