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Rapid Responses: Rapid Responses published:
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Erectile dysfunction as a screening tool for cardiovascular disease
- Anne L. Appleton (12 October 2008)
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Erectile Dysfunction is the best predictor of Cardiovascular risk in men - why do we ignore it?
- Geoffrey I Hackett (13 October 2008)
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Optimal targeting of statins for primary prevention: global cardiovascular risk or LDL-cholesterol and CRP?
- Aroon D Hingorani, Tina Shah, Juan Pablo Casas, Liam Smeeth (12 November 2008)
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Anne L. Appleton, Clinical Research Physician Lilly UK, Lilly House, Basingstoke, RG24 9NL
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I read the debate ‘Will screening individuals at high risk of cardiovascular events deliver large benefits?’ (1) with interest. However, I am surprised that neither of the protagonists mentioned the use of a simple and cheap screening tool for identifying significant number of patients with potential cardiovascular disease (CVD): that of asking adult males about erectile dysfunction (ED). ED is a vascular disorder which shares with latent CVD a common aetiopathology: that of endothelial dysfunction (2). The clinical manifestation of such endothelial dysfunction occurs earlier in the penis than elsewhere, due to the narrower bore of the penile vessels in comparison to those of, say, the lower limb or even the coronary arteries. Hence, ED is known to pre-empt overt CVD by 2-4 years (3). And we are not just talking about a disease of older men: many men in this cohort are socio-economically active men in their 50s and even 40s, with financially-dependent spouses and children. Thus, it is time to change societal attitudes towards ED, from that of a ‘lifestyle’ or ‘choice’ issue, to that of a serious public health concern (4). Yes, it can be embarrassing to raise the subject of sexuality and sex with our patients, but as a profession we need to lead by example (5). The medical profession largely still enjoys the trust and respect of society. Simply asking patients about their erectile function as part of a normal consultation helps to empower men to talk about this aspect of their health and ‘normalises’ this as part of the medical consultation. A simple explanation of the value of a blood pressure check in this context may defuse any potential embarrassment. A recent document from the public health intervention programme of NICE to identify and support people most at risk of dying prematurely, PH15, does not even mention ED (6). It is sobering that the content of this BMJ debate concerning screening for CVD, whilst interesting and thought-provoking, also suggests that the trivialisation of ED, as merely about sex and not about health, also extends to attitudes within our own profession. 1) Jackson R, Wells S, Rodgers A, Capewell S. BMJ 4 Oct 2008; 337: 784-785. 2) Solomon H, Man JW, Jackson GW. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003; 89: 251-253. 3) Montorsi F, Briganti A, Salonia A et al. Erectile dysfunction prevalence, time of and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003; 44 (3): 360-4. 4) Billups KL, Bank AJ, Padma-Nathan H et al. Erectile dysfunction as a harbinger for increased cardiometabolic risk. Int J Impot Res 2008; 20 (3): 236-242. 5) Hackett G, Kell P, Ralph D et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction. J Sex Med 2008; 5(8): 1841-1865. 6) http://www.nice.org.uk/Guidance/PH15/Guidance/pdf/English Competing interests: The author works for a pharmaceutical manufacturer of an erectile dysfunction medication |
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Geoffrey I Hackett, Consultant in Urology (Sexual Medicine) Good Hope Hospital, Sutton Coldfield
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As a physician of 30 years experience, it disturbs me once again to see an article on cardiovascular risk totally ignore the massive evidence base linking erectile dysfunction (ED) with cardiovascular risk and can tolerate this no longer. For years, I have seen patients referred with ED after a CHD event to hear that they developed ED 2-3 years beforehand, went to their GP but were dismissed. The facts are as follows : Men live 7-8 years less than women. ED is the manifestation of vascular disease in smaller arteries and gives a 2-3 year early warning of myocardial infarction. ED carries a 50% additional risk of CHD events,a level comparable to moderate smoking or positive first degree relative family history. ED in type 2 diabetes is a better predictor of CHD risk than HbA1c, hypertension, microalbuminuria or hyperlipidaemia. Over 50% of T2Ds are hypogonadal which carries a 60% additional risk of early cardiovascular death. Despite this evidence we don't even screen for ED or low testosterone in type 2 diabetes or CHD patients. We prescribe drugs for CHD which make ED worse even though there are medications as effective, which improve ED and then make the patients pay privately because we treat ED as a recreational or "lifestyle" issue. Continuing to ignore these issues on the basis that cardiologists feel uncomfortable mentioning the word "erection" to their patients is no longer acceptable amd probably clinically negligent. In case the authors have missed the papers, the references are below: Kirby M, Jackson G, Simonsen U Endothelial dysfunction links erectile dysfunction to heart disease. Int J Clin Pract 2005. 59 (2) 225- 229. Kloner RA Erectile Dysfunction and Cardiovascular Risk Factors. Urol Clin North Am 2005: 32 (4): 397-402. Kloner RA Erectile Dysfunction. The new harbinger for major adverse cardiac events in the diabetic patient. J Am Coll Cardiol 2008: 51 (21), 2051-2052. Laughlin GA, Barrett-Connor E, Bergstrom J Low serum testosterone and mortality in older men J Clin Endocrinol Metab 2008: 93 (1) 68-75. Ma RCW, So WY, Yang XL et al. Erectile dysfunction predicts coronary heart disease in type 2 diabetes J Am Coll Cardiol 2008: 51 (21) 2045- 2050. Montorsi F, Briganti A, Salonia A et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003: 44 (3): 360-4; discussion 364-5. Phillips GB, Pinkernell BH, Jing TY The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb 1994:14 (5): 701-6. Shabsigh R, Arver S, Channer KS et al. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. Int J Clin Pract 2008: 62 (5) 791- 798. Sun P, Cameron A, Seftel A, Shabsigh R et al Erectile dysfunction - An observable marker of diabetes mellitus? A large national epidemiological study. J Urol 2006: 176 (3) 1081- 1085. Thompson IM, Tangen CM, Goodman PJ et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005: 294 (23): 2996-3002. HSC/115. 1999. HSC/148, 1999. HSC/177, 1999. Araujo AB, Esche GR, Kupelian V et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 2007: 92 (11) 4241- 4247. Billups KL Erectile dysfunction as an early sign of cardiovascular disease. Int J Impot Res 2005: 17 (Suppl. 1) S19- S24. Dusing R Sexual dysfunction in male patients with hypertension - Influence of antihypertensive drugs Blood Pressure 2005: 65 (6) 773- 786. Feldman HA, Goldstein I, Hatzichristou DG et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994: 151 (1): 54-61. Ma R So W, Yang et al. Erectile dysfunction predicts coronary heart disease in type 2 diabetes. J Am Coll Cardiology 2008:51: 2045-50 Gazzaruso, Solerte S B, Pujia et al. Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease. A protective role for statins and PDE5 inhibitors. J Am Coll Cardio 2008:51:2040-2044 Kloner R. Erectile Dysfunction. The new harbinger of major cardiovascular events in the diabetic patient. J Am Coll Cardiol 2008;51:2051-2 Laughlin GA, Barrett-Connor E, Bergstrom J Low serum testosterone and mortality in older men J Clin Endocrinol Metab 2008: 93 (1) 68-75. Competing interests: None declared |
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Aroon D Hingorani, Professor Centre for Clinical Pharmacology, Rayne Building, 5 University Street, London, WC1E 6JJ, Tina Shah, Juan Pablo Casas, Liam Smeeth
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Optimal targeting of statins for primary prevention: global cardiovascular risk or LDL-cholesterol and CRP?
Capewell and Jackson debated the optimal approach for primary prevention of cardiovascular disease (CVD) and for targeting statin treatment. Against this background, Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), randomised 17, 802 people (62% men; 16% smokers, mean age 66.3 years) with no prior evidence of cardiovascular disease, with a high baseline C-reactive protein (CRP; ≥2; median 4.3 [2.8–7.1] mg/L) and a low-LDL cholesterol (3.36; median 2.8 [2.4-3.1] mg/L) to 20 mg/day rosuvastatin or placebo. The aim of the trial was to: “assess the effect of rosuvastatin on first ever cardiovascular events in apparently healthy men and women who do not qualify for statin therapy due to low levels of LDL cholesterol, but who are at increased cardiovascular risk due to elevated levels of hs-CRP” . Ninety thousand participants were screened to identify the 17, 802 who met the LDL/CRP profile necessary for inclusion. We modelled a similar hypothetical trial based on the known relationships between established risk factors and CVD risk , and the risk reductions from statin treatment , without consideration of the CRP value. We first estimated the weighted average annual risk of CVD and CHD in the JUPITER participants using published aggregate level information on average levels of CV risk factors at baseline1 and an online Framingham risk calculator (http://www.mycvrisk.co.uk/). We set this as the baseline risk for the simulated trial. The annual CHD risk was 1.21% (10-year risk 12.1%) and the annual CVD risk 1.95% (10-year risk 19.5%). The National Institute for Health and Clinical Excellence (NICE) currently recommends statin treatment for primary prevention if the 10-year CVD risk is 20% or more. Assuming risk is distributed normally, about half the participants of the hypothetical trial would now be eligible for statin therapy according to English guidelines. A meta-analysis of short term trials of cholesterol-lowering drugs estimated rosuvastatin 20mg daily reduces LDL-cholesterol by 2.32 mmol/L . However, because LDL cholesterol reductions may be attenuated in longer term trials, we estimated that LDL would be reduced by 1.6 mmol/L with this dose of rosuvastatin, though even this may be an overestimate in subjects who start with a low LDL. In the Cholesterol Treatment Triallists (CTT) meta-analysis, the proportional reduction in major vascular events was related linearly to the LDL reduction and we estimated that a 1.6 mmol/L reduction in LDL would yield a relative risk reduction in major vascular events of 16, 35, 42, and 45% in years 1, 2 , 3 and 4 respectively3. In the JUPITER trial, 8901 individuals were randomised to rosuvastatin and 8901 to placebo. We used the estimated annualised CVD and CHD risk, and the risk reduction from rosuvastatin treatment, to simulate the number of cardiovascular events expected in each year in the two arms of a similarly sized hypothetical trial. We initially made the simplifying assumptions of equal follow up of all participants, and no drop outs or fatal events so that all participants were at risk throughout. The results of the simulated trial are tabulated. Year of trial Cumulative events (placebo) Cumulative events (rosuvastatin 20mg) P 0 to1 174 146 0.12 1 to 2 348 226 <0.0001 2 to 3 522 305 <0.0001 3 to 4 696 384 <0.0001 Note: We used Pocock’s “simplest statistical test” to check for a difference between treatment arms . For this test, for a trial with balanced 1:1 randomisation, the difference between the number of events in the control and treatment arms is divided by the square root of their sum to give a z-value. Under the null hypothesis that the treatment has no effect, the z-value exhibits an approximately a standardised normal distribution with mean zero and a variance of 1. An online calculator (at http://www.fourmilab.ch/rpkp/experiments/analysis/zCalc.html) was used to translate z into a 2-sided P value. In this simulation, which likely overestimates the treatment effect, the difference between groups is significant within the first year, becoming increasingly so as the trial progresses. By years two and three the difference in CVD events is very highly significant and, in the real world, a trial such as this might be halted early because of the treatment effect. In sensitivity analyses, where the lower bound of the confidence limit for the estimated relative risk reduction inferred from the LDL-lowering effect of 20mg rosuvastatin was used rather than the point estimate, or when individuals suffering events in the previous year were removed from subsequent analysis, thus reducing the number at risk year on year, statistical significance was still achieved by the second or third year of the simulated trial. The full details of the JUPITER trial are not yet known. However, we already know that the manufacturer made the decision to stop the trial ahead of the expected date of termination based on a recommendation from an Independent Data Monitoring Board and the JUPITER Steering Committee, which met on March 29, 2008. This was because of “unequivocal evidence of a reduction in cardiovascular morbidity and mortality amongst patients who received CRESTOR (rosuvastatin) when compared to placebo”. (http://clinicaltrials.gov/ct2/show/NCT00239681?term=jupiter&rank=1) In our simulated trial, the expected effect size is based on the known effect of statins on LDL alone, without knowledge of the participants CRP values. LDL is an important modifiable risk factor for CVD, but even people with low LDL values may be at substantial risk of CVD by virtue of age, or other risk factors and this can be estimated by a validated risk equation incorporating established risk factors. In previous trials of statins the relative reduction in risk of cardiovascular events was similar at high and low levels of the other risk factors, over a range of absolute risk and LDL values3. It will be of interest to recalculate the expected treatment effect in the simulation, based on the achieved LDL reduction in the JUPITER trial, when available, to assess whether patients with a risk profile similar to that of patients in JUPITER trial could be identified and targeted by routine assessment of CVD risk, without measuring CRP. Competing interests: None declared |
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