Guideline for the primary care management of male lower urinary tract symptoms

review Article GUIDELINES FOR LUTS M.J. SPEAKMAN et al. As my Comment in the first section of the journal suggested, the MTOPS results have offered the possibility to general practitioners of reducing the risk of side-effects of BPH, particularly urinary retention, by giving patients dual therapy with 5a-reductase inhibitor and alpha-adrenergic blocker. Authors from the UK present guidelines for the primary case management of male LUTS, which significantly fills this gap in the literature. Any help in the management of chronic nonbacterial prostatitis is welcome to clinicians; many treatments have been proposed after non-comparative trials, and so their value must be viewed cautiously. The authors from Canada and USA present the results of a randomized placebocontrolled study into the use of finasteride in such patients. The other papers in this section all deal with LUTS, e.g. frequency and nocturia, in a variety of situations. There is still great interest in the epidemiology of these symptoms, and in the various methods of grading their severity. Guideline for the primary care management of male lower urinary tract symptoms M.J. SPEAKMAN, R.S. KIRBY, A. JOYCE, P. ABRAMS and R. POCOCK The British Association of Urological Surgeons, London, UK Accepted for publication 20 January 2004 INTRODUCTION The Oxford Dictionary defines a guideline as a principle or criterion guiding or directing an action. The development and use of guidelines in medical practice is common, although many are not based on strong evidence but on the personal preferences and clinical experience of the clinicians developing them. Clinical practice guidelines have been defined as systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances [1]. Their purpose has been stated to be to make explicit recommendations with a definite intent to influence what clinicians do [2]. From the start of the development process for this guideline the development group had the advice of the AGREE collaboration available for scrutiny [3]. The guideline development group included five consultant urologists, two GPs, one nurse practitioner with specialist knowledge of prostate assessment clinics, one patient and one experienced medical facilitator. The group met on six occasions and communicated extensively by e-mail. The initial stage involved reviewing the existing major world guidelines [4 7], relevant literature on medical [2] and urological guidelines [8] in particular, and then reviewing the background literature for each section. The evidence base for the recommendations in each section is referenced. There was no formal systematic review of all LUTS/BPH publications because this had recently been completed by the AUA when updating its 1994 guideline [4]. The relatively few sections where the 1994 guideline had been changed because of the literature review were carefully documented [9]. However, each of the sections in this guideline involved a detailed review of the literature by the authors during its compilation. LUTS attributed to benign prostatic obstruction (BPO) is a very common problem affecting the ageing man. The prevalence of LUTS in Europe varies with age, ranging from 14% for men in their fourth decade to >40% in their sixth. Assuming an overall prevalence of LUTS of 30%, this would mean that ª4 million men aged >40 years have LUTS in the UK. A reliable assessment guideline to manage this workload is justified on the basis of these figures alone, but the addition of more possible treatment options and a very variable cost of some of these treatments make this highly suitable for a British guideline. There are many BPH guidelines around the world, some country-specific and others, e.g. the WHO International Consensus [5] and the European Urology Association guidelines [7], provide advice to doctors in many countries. This BAUS guideline presents an approach that is in line with world opinions, but is aimed specifically at GPs, nurse practitioners and patients (through the linked patientinformation leaflets) in the UK. The present guideline is intended to help with the diagnosis, treatment and monitoring of LUTS in men. The guideline is presented both as a 2004 BJU INTERNATIONAL 93, 985 990 doi:10.1111/j.1464-410x.2004.04765.x 985

M.J. SPEAKMAN ET AL. very simple one-page algorithm with short supplementary notes, and as an interactive electronic program via CD or website (http:// www.baus.org.uk) (Fig. 1). BACKGROUND The characteristic histological changes of BPH are extremely common and found in 80% of men aged >80 years. In about half of these men the prostate gland enlarges to produce benign prostatic enlargement and in about half of those with such enlargement, BPO develops. These distinctions are important because most treatments aim to alleviate symptoms by removing or reducing BOO. While prostatic enlargement secondary to BPH is a major cause of LUTS, by resulting in BOO, LUTS are a multifactorial problem possibly involving cardiac, renal or neurological abnormalities in addition to, or instead of, urological causes. Patients with LUTS suggestive of BPO present with two types of symptoms: of voiding (e.g. weak stream, hesitancy, intermittency, abdominal straining and incomplete bladder emptying); and of storage (e.g. frequency, nocturia, urgency and urge incontinence). While voiding symptoms are more common, storage symptoms are more bothersome and interfere more with daily activities. Thus they have a considerable effect on quality of life and are the main reason that patients seek medical advice. Besides improving urinary flow rate, treatment for LUTS should provide relief of both the common voiding LUTS and the more bothersome storage LUTS. The use of a symptom score, e.g. the IPSS, to measure symptoms and bother can aid in both the planning of initial treatment and in monitoring disease progression. The extent of symptom bother can vary amongst individual patients even with the same symptom score. Studies of LUTS in primary care and of the use of shared-care facilities in particular have shown that about half of new patients with LUTS can be investigated and managed in primary care [10]. Patients for whom medical treatment has failed, or with severe symptoms or signs, and those with absolute indications for hospital investigation or treatment, should be referred to a urologist. THE GUIDELINE The BAUS guideline was designed to start with the first presentation of a man, typically FIG. 1. The single-page algorithm. Algorithm PSA elevated for age DRE abnormal/of concern Haematuria Elevated urea/creatinine Palpable bladder Recurrent UTI Abnormal cytology Severe symptoms Urological referral 50 years old, to their GP or to a nurse practitioner in a prostate assessment clinic. While this guideline will also inform urologists in secondary care, this was not the principal goal. The basic assessments therefore have to be evidence-based, but also practical and achievable. The medical history should be sufficiently detailed to cover all the patient s symptomatic concerns, including fear of prostate cancer, and then focus on quantifying the patient s urinary symptoms. While this can be done by broad open questions, there is proven value in quantifying the symptoms with a symptom score. The IPSS has the principal advantage that it is universal and has been validated; it can measure the severity of symptoms and can monitor disease progress or the effects of treatment, but it is not a diagnostic tool, as many conditions can produce similar symptoms. Other causes of LUTS, e.g. heart failure, diabetes, neurological disorders and various drug therapies, should be considered. The examination should include the abdomen to check for an enlarged bladder, and careful examination of the genitalia, particularly the urethral meatus. A DRE is an integral part of good clinical examination and is strongly recommended. The primary purpose of this examination is to assess prostate size, shape and consistency, and to check for other rectal pathologies. The size of the prostate can give LUTS Patient GP - History including symptoms assessment (IPSS) - Examination and DRE - Urinalysis / MSU - PSA Urinary tract infection? Investigate & Treat Unresponsive or recurrent UTI? cturnal Polyuria Investigate & Treat cturnal Polyuria? cturia? Overactive bladder? Prostatic Obstruction? Lifestyle advice alpha-blocker Review at 6-12 weeks high PSA (>1.4ng/ml) Bothersome LUTS? Risk factors for progression? Large prostate (>30cc) or Lifestyle advice, 5-alpha reductase inhibitor, alpha-blocker or combination useful information which helps in planning treatment for LUTS. THE ASSESSMENT AND IMPORTANCE OF PROSTATE SIZE Although most hospital-based studies have shown a poor correlation between prostate size and both symptoms and flow rate [11], more recent community-based studies report a useful correlation. The Olmsted study showed that the odds of having moderate to severe LUTS were 1.5 times higher for men with prostates of >30 ml and 3.5 times higher for men with prostates of >50 ml [12]. A focused neurological examination should be considered in appropriate patients. A urine sample should be analysed to check for the presence of blood, protein, glucose and any signs of infection. Measuring serum creatinine is important in patients in whom chronic retention is considered. Guidance on serum PSA testing is provided, together with age-related values above which a urological referral should be considered. The importance of information and counselling before PSA testing is stressed. PSA serves as a useful surrogate for prostate volume and is therefore also helpful in deciding to which treatment a given patient may respond. A useful suggestion is made within the latest Risk factors for progression? Large prostate (>30cc) or high PSA (>1.4ng/ml) Lifestyle advice, 5-alpha reductase inhibitor Review at 3-6 months Lifestyle advice 986 2004 BJU INTERNATIONAL

GUIDELINES FOR LUTS Test History and DRE Symptom score (e.g. IPSS) Frequency-volume chart Urine analysis Serum creatinine PSA test Postvoid residual urine measurement Flow rate Renal ultrasonography/ivu Cysto-urethroscopy Urodynamics TRUS *In special circumstances or research clinics only Indication PSA outside recommended age range dule in prostate Haematuria Acute retention Chronic retention Recurrent UTIs Dysuria with sterile pyuria AUA guideline, i.e. that serum PSA analysis should be offered to patients with at least a 10-year life expectancy and for whom knowledge of the presence of prostate cancer would change the management, or for those where the PSA measurement might change the management of their voiding symptoms [9] (Table 1). The suggestions for diagnostic tests for LUTS presumed secondary to BPO vary among the national guidelines, e.g. serum creatinine and PSA assessment are regarded as Recommended in the European guideline but in the AUA guideline. While cystoscopy is regarded as in both these guidelines, it is t recommended in the British guideline unless there are special circumstances, e.g. coexisting haematuria. Recommended implies that this test should be used in all symptomatic men while tests are used on the basis of individual patient judgement. t recommended tests are those where the evidence base for their routine use is so poor that they are not considered for this use. Once a GP has taken a history and completed an examination and basic investigations, the Status Recommended Recommended Recommended t recommended* t recommended* t recommended* Referral Under 2-week wait scheme Under 2-week wait scheme Under 2-week wait scheme Immediate treatment/referral Priority if creatinine is high To be seen soon To be seen urgently TABLE 1 BAUS recommendations for tests for the primary-care management of men with LUTS TABLE 2 Indications for direct urological referral; the National Institute for Clinical Excellence referral guidelines [13] first decision is whether the patient is appropriate for primary-care management or should be referred for secondary urological care. Complicated LUTS should be referred; the indications for hospital referral and the appropriate urgency are given in Table 2 [13]. The guideline includes electronic access to patient information leaflets (www.baus.org.uk.lutsguideline). Once the GP thinks that primary-care management is appropriate and before assuming that the prostate and BPO in particular are the causes of the problem, questions designed to identify men with a greater likelihood of either nocturnal polyuria or an overactive bladder are considered. Whether nocturia is numerically significant can be noted from the IPSS, and then the patient asked to complete a voiding frequency-volume diary, from which the presence of true nocturnal polyuria can be calculated. Ultimately the question Do the patient s symptoms suggest prostatic obstruction? must be considered. Although in an ideal world and in most of secondary care this question would be supplemented by data from flow-rate testing and postvoid bladder ultrasonography (US), these investigations are not universally available in primary care. However, evidence is provided to support the use of both flow-rate testing and postvoid US within the guideline, and these investigations are therefore encouraged but considered optional. The evidence for flow-rate testing before medical treatment is not sufficiently strong to make it Recommended in all cases. THE VALUE OF FLOW-RATE TESTING The main limitation of flow-rate measurement is its inability to discriminate between poor detrusor function and BOO. Flow rates will give a rough probability of obstruction but only pressure-flow studies can quantify the degree of obstruction. The greatest value of flow-rate testing in managing LUTS is as a diagnosis of exclusion. While it is inaccurate to claim that most patients with a poor flow are necessarily obstructed, it is true that most patients with a good flow will not be obstructed. There are exceptions to this; the so-called express voiders, who maintain a reasonable flow only because of a supranormal detrusor pressure (these patients usually have significant symptoms). In practice the principal problem is that any correlation between flow rate and symptoms or symptom bother is unreliable. As most patients are currently treated on the basis of their symptoms and their associated bother, the real value of flow-rate testing is not so much to identify who to treat but rather as one measure of the success or failure of medical or surgical treatment. Patients with mild symptoms and borderline flow rates may still respond well to medical therapy. However, a flow rate is recommended for all patients undergoing surgery. Many studies have shown a very poor outcome after surgery in unobstructed patients and in patients with low symptom scores. On the positive side, some studies have shown that a very low flow rate (<8 ml/s) can have a predictive value of 90% in indicating BOO. One study showed that the BOO index could be predicted from maximum urinary flow rate and prostate volume [14]. THE VALUE OF MEASURING THE POSTVOID RESIDUAL VOLUME (PVR) Transabdominal US measurements of PVR have become part of the assessment of men with LUTS, particularly in nurse-led clinics, 2004 BJU INTERNATIONAL 987

M.J. SPEAKMAN ET AL. and it was recommended by the Fourth International Consultation on BPH [15]. However, there is considerable variation in PVR in individual patients and there is a significant test-retest error. PVR measurement shares similar problems with flow-rate testing, i.e. an inability to distinguish those patients with BPO from those with an underactive bladder. PVRs do not correlate well with the urodynamic evidence of obstruction [16]. PVRs of >100 ml may predict an increased risk of retention [17]. There are also very few data on the significance of PVRs in conservatively treated patients, and many patients with PVRs of up to 300 ml do not develop UTI or renal insufficiency [18]. The level at which the potential clinical value of PVR becomes significant is unknown, but in a study assessing urodynamics in men with PVRs of >300 ml, two groups were identified [19]. One comprised patients with highpressure retention and therefore at risk of renal failure. This group also had a high incidence of recent onset enuresis. The second comprised patients with underactive detrusor muscles who were therefore unlikely to benefit from TURP. There is little good objective evidence that all patients being evaluated for LUTS should have their PVR measured, but a persistent PVR of >300 ml indicates a small risk of high-pressure retention, and therefore upper tract imaging is required. Second, a persistent high PVR may indicate an underactive detrusor and therefore be an indication for urodynamic studies. The PVR, even when associated with a slow flow, should not be used to select patients for surgery or to predict the outcome after TURP, without the added benefit of urodynamic studies. PRIMARY CARE TREATMENT Most patients present because of bothersome symptoms and a trial of treatment is therefore appropriate once the initial investigations have been completed and information on treatment options provided. Most, but not all, patients will elect to have medical treatment in the first instance. However, not all patients require treatment, and primary-care management should include reassurance, watchful waiting, advice on lifestyle and a review of their current medication. Treatment options, both pharmacological and surgical, for patients with LUTS presumed secondary to BPO, have increased considerably over the last decade. Data over the last 5 years have shown that prostate size, or PSA as a proxy for size, can influence both the decision to treat and the treatment choice. These data suggest that larger prostates are associated with more progressive disease, manifested as a greater likelihood of symptom progression [20], flow rate deterioration [21], increased prostate growth [22,23] and a greater risk of urinary retention and an increased probability of prostatic surgery [24]. Men with smaller prostates (estimated at <30 g or with a PSA of <1.4 ng/ml) are therefore at a lower risk of disease progression. If they have presented with bothersome symptoms they will benefit from treatment with an a-blocker. There is no strong evidence to suggest that any a-blocker is better for symptom or flow rate improvement than another [25], but there is a difference in side-effect profile and ease of use. The side-effects are caused by the effect of the drug on non-target tissues, e.g. the blood vessels and the nervous system, and the older preparations such as prazosin and indoramin have a higher risk profile as a result. Drugs that do not require dose titration are also preferred by both patients and doctors. The once-daily preparations of alfuzosin, doxazosin ( gastrointestinal system ) and tamsulosin present the best balance of beneficial effect and adverse events. Terazosin is also available as a oncedaily preparation but requires careful dose titration to avoid postural hypotension. These agents improve urinary flow rates and LUTS in most patients by ª40% compared with placebo, with less tiredness and dizziness and almost no orthostatic hypotension [26,27]. They also reduce blood pressure in men with hypertension, while having little effect on it in normotensive men [28,29]. The latest generation of a-blockers include tamsulosin, an a1 A and a1 D subtype-specific agent, and alfuzosin, a clinically uroselective compound [30,31]. Tamsulosin is effective at doses of 0.4 mg once daily and has similar efficacy to doxazosin (gastrointestinal system) and terazosin, but with less effect on blood pressure. The possibility that the a 1A/1D profile of tamsulosin may also have added benefits on the overactive storage symptoms from the bladder is continuing to be investigated. The case for alfuzosin and doxazosin in improving erectile dysfunction in men with LUTS has been made, although whether this is a general treatment effect of improving LUTS and thereby reducing the association between LUTS and ED, or a direct drug effect, is currently uncertain. In conclusion, there is now a large body of evidence to confirm the safety and efficacy of adrenoceptor-blocking agents in the treatment of LUTS associated with BPH. They work quickly and are effective irrespective of prostate size. They do not affect serum PSA values. Most agents can now be started with no need for dose titration. As single agents they improve LUTS and uroflow values. The a-blockers alone are less effective than the 5a-reductase inhibitors (5-ARIs) in terms of delaying BPH progression but combinations of both classes of drug appear to be the most effective therapy in this respect. Men with LUTS and larger prostates will usually benefit from treatment with 5ARIs; over 3 6 months most will have a significant improvement in both urinary flow and symptoms. Studies show that there is a greater risk of acute urinary retention (AUR) in men with larger prostates, and that the beneficial effect of 5ARIs in reducing that risk is greater in men with larger prostates [32,33]. In addition, a PSA of >1.4 ng/ml appears to be a useful proxy for a significant increase in prostate size and a greater probability of benefit from this class of drugs [34]. These drugs will also reduce the risk of AUR and the need for surgery by over half if the medication is continued. Finasteride significantly reduced the risk of AUR and of prostatectomy in the Proscar Long-term Efficacy and Safety Study (PLESS) [32]. The reduction of risk for either event compared with placebo was 57% and 55%, giving a numbers needed to treat of 15 over a 4-year period. These benefits were confirmed and surpassed in the recent Medical Therapy for Prostate Symptoms study (MTOPS), where there was a 64% reduction in the incidence of invasive therapy for BPH and a 67% reduction in the incidence of AUR at 5.5 years [20]. Similar data were presented for dutasteride, which reduces complications like AUR (risk reduction 57%) and BPH-related surgery (risk reduction 48%) to a level similar to that on finasteride [35]. It appears to be most effective in patients with prostates of >30 ml. However, the absolute risk of these complications varies widely from a risk of AUR 988 2004 BJU INTERNATIONAL

GUIDELINES FOR LUTS of ª0.75% per year in community-dwelling men [24] to ª2% per year in men eligible for clinical trials [32]. If risk factors such as increased age, poor flow rate, large prostates (or increased PSA), large PVRs and high symptom scores are factored in, then suddenly the absolute risk in these men may be as high as 20% per year. In that case a reduction by half in the risk becomes both statistically and clinically significant. Data from the MTOPS study would indicate that a-blockers delay these events but do not finally prevent them. If patients symptoms are particularly bothersome and the patients are unhappy to wait for the delayed benefit of a 5-ARI drug because rapid symptom improvement is required, then an a-blocker could be substituted or added. If a-blocker monotherapy is the chosen treatment then this should be selected for men with no additional risk factors. The use of combined treatment is most appropriate in men with bothersome symptoms and significant risk factors for progression. These include large prostates or a PSA of >1.4 ng/ml, age >70 years, a poor flow rate (<12 ml/s), a high symptom score and a large PVR (>100 ml). The 5-ARIs lower serum PSA levels; after 6 months of treatment PSA levels will be reduced by half, and therefore doubling the PSA values for patients on long-term therapy allows their appropriate interpretation to avoid masking the early detection of localized prostate cancer [36]. MEN WITH LARGE PROSTATES AND NO BOTHERSOME SYMPTOMS Some men will present with symptoms that may not be particularly bothersome. Some of these patients may have had concerns about prostate cancer and once reassured may be less bothered about their condition. Traditionally, a man with no bothersome symptoms, even if his IPSS was moderate to severe, might simply have been reassured and allocated to watchful waiting. Although LUTS secondary to BPO tend to deteriorate in many patients over time, it has been known since the 1970s that in a significant minority of patients this does not happen and their symptoms remain stable or even improve [37]. However, more recent data from several epidemiological studies and the placebo arm of long-term trials like PLESS and MTOPS indicate which men are at greater risk of symptom progression and AUR [20,32]. These men should now be warned about the possibilities of progression and the option of long-term 5ARI treatment discussed. The risk factors include; men aged > 70 years, with LUTS. an IPSS of > 7, i.e. moderate or severe LUTS. a flow rate of < 12 ml/s. a prostate volume of >30 ml or a PSA level of >1.4 ng/ml, which is a proxy for prostate volume. Some studies have suggested that hesitancy and a PVR of >100 ml may also predict a greater risk of subsequent AUR. CONCLUSION Many men presenting with LUTS can be safely and effectively managed in primary care. Treatments should include reassurance, lifestyle advice, a review of their other medication and medical therapies. Symptom score and symptom bother appear to be the main factors to be considered when deciding whether a patient requires treatment. Prostate volume, and PSA as its proxy, now appear important in selecting which treatment to use. It would be ideal if at first presentation we could predict which patient would progress and which would not. Recent knowledge of the risk factors for progression has informed this decision process. In conclusion, the provision of a clinical practice guideline for LUTS provides an evidencebased framework for managing patients with LUTS. Information on which to base decisions is presented, although the evidence base, particularly for the investigational tests, is far from perfect. CONFLICT OF INTEREST ne declared. REFERENCES 1 Lohr KN, Field MJ. A provisional instrument for assessing clinical practice guidelines. In Field MJ, Lohr KN eds. 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Br J Urol 1981; 53: 613 6 For the DOH prostate cancer information sheet see: http://www.doh.gov.uk/cancer/prostate.htm For the DOH referral guidelines see; http://www.doh.gov.uk/pub/docs/doh/ guidelines.pdf Copies of the NHS/Cancer Research UK Prostate Cancer Risk Management Programme an information pack for primary care can be obtained by e-mail from: doh@prolog.uk.com or from the Department of Health Responseline 08701 555455 Correspondence: M.J. Speakman, BAUS, Royal College of Surgeons, Lincolns Inn Fields, London, UK. e-mail: mailto:mjspeakman@baus.org.uk Abbreviations: BPO, benign prostatic obstruction; US, ultrasonography; PVR, postvoid residual volume; 5-ARI, 5areductase inhibitor; AUR, acute urinary retention; PLESS, Proscar Long-term Efficacy and Safety Study; MTOPS, Medical Therapy for Prostate Symptoms. 990 2004 BJU INTERNATIONAL