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Canadian Journal of Cardiology

Cardiovascular Risk Reduction and Male Sexual Health: No Free Ride

      The issue of erectile dysfunction (ED) and cardiovascular drugs has been a longstanding subject of interest as well as concern. Conclusions from recent reports about the role of statins have ranged from cautious claims of a beneficial effect of statins on ED, to beneficial effects with some but not other statins, to neutral effects on ED but with beneficial effects on quality of life.
      • Chou C.Y.
      • Yang Y.F.
      • Chou Y.J.
      • Hu H.Y.
      • Huang N.
      Statin use and incident erectile dysfunction - a nationwide propensity-matched cohort study in Taiwan.
      • Davis R.
      • Reveles K.R.
      • Ali S.K.
      • et al.
      Statins and male sexual health: a retrospective cohort analysis.
      • Cai X.
      • Tian Y.
      • Wu T.
      • et al.
      The role of statins in erectile dysfunction: a systematic review and meta-analysis.
      • Kostis J.B.
      • Dobrzynski J.M.
      The effect of statins on erectile dysfunction: a meta-analysis of randomized trials.
      • Nurkalem Z.
      • Yildirimturk O.
      • Ozcan K.S.
      • et al.
      The effect of rosuvastatin and atorvastatin on erectile dysfunction in hypercholesterolaemic patients.
      • Trivedi D.
      • Wellsted D.M.
      • Collard J.B.
      • Kirby M.
      Simvastatin improves the sexual health-related quality of life in men aged 40 years and over with erectile dysfunction: additional data from the erectile dysfunction and statin trial.
      • Trivedi D.
      • Kirby M.
      • Wellsted D.M.
      • et al.
      Can simvastatin improve erectile function and health-related quality of life in men aged 40 years with erectile dysfunction? Results of the Erectile Dysfunction and Statins Trial ISRCTN66772971.
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Statins and erectile dysfunction: a critical summary of current evidence.
      Similarly, although ED is commonly ascribed to β-blockers, centrally acting sympatholytic drugs, thiazide-class diuretics, and aldosterone receptor blockers, recent reports suggest that the β-blocker nebivolol with vasodilating properties might either help or not impair ED
      • Sharp R.P.
      • Gales B.J.
      Nebivolol versus other beta blockers in patients with hypertension and erectile dysfunction.
      ; and others suggest that when ED is of concern, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers should be used preferentially
      • Chrysant S.G.
      Antihypertensive therapy causes erectile dysfunction.
      ; and still others suggest a rank order of preference of an angiotensin receptor blocker followed by consideration of either angiotensin converting enzyme inhibitors or calcium channel blockers.
      • Patel J.P.
      • Lee E.H.
      • Mena-Hurtado C.I.
      • Walker C.N.
      Evaluation and management of erectile dysfunction in the hypertensive patient.
      Almost all of these reports and recommendations are plagued by the perniciousness of placebo as well as nocebo effects facilitated through ready access to sources of lay information provided in a fashion devoid of critical clinical appraisal or credible clinical expertise. The latter effects are pervasive in clinical practice when dealing with individuals but they are also pervasive in many of the observational reports that cannot exclude these effects among participants.
      In this issue of the Canadian Journal of Cardiology, Joseph and coworkers report an a priori, secondary analysis of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial, a prospective, randomized and placebo-controlled clinical trial regarding male sexual health on the basis of participants who completed the International Index of Erectile Dysfunction (IIED) questionnaire.
      • Joseph P.
      • Lonn E.
      • Bosch J.
      • et al.
      Long-term effects of statins, blood pressure-lowering, and both on erectile function in persons at intermediate risk for cardiovascular disease: a substudy of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) randomized controlled trial.
      This is a validated tool comprising 5 domains or components of ED (ie, erectile function itself, intercourse satisfaction, orgasmic function, sexual desire, and overall sexual satisfaction). The main focus was on the IIED domain of erectile function (IIED-EF), quantitated at baseline and after a mean follow-up of 5.8 years using the self-reported answers to 6 of a total of 15 questions.
      Of 6831 men in the trial, 4414 had complete IIED-EF scores at baseline as well as at follow-up. However, 51% of these men aged 55 years and older with at least 1 cardiovascular risk factor and at intermediate risk of cardiovascular disease reported no sexual activity or intercourse and were therefore excluded from the analyses. In the remaining large number of participants (2153) there were minor imbalances in the demographic characteristics compared with those not included but these factors were duly considered in the final results. In patients who were sexually active, scores compatible with ED were already present in 57.6% at baseline.
      The therapeutic protocol was a 2 × 2 factorial design with randomization to either rosuvastatin 10 mg per day or placebo, or candesartan/hydrochlorothiazide 16 mg/12.5 mg per day or placebo. Results indicate that IIED-EF scores worsened significantly during the long-term observation and neither intervention, alone or in combination, significantly altered this course. Additionally, in the subset without ED at baseline, neither intervention alone or in combination was associated with new-onset of ED after adjusting for all important covariates.
      Other subset analyses on the basis of low-density lipoprotein cholesterol, and blood pressure at baseline or changes during the trial were subtle and not of clinical importance and not statistically robust. Similar conclusions were reached when additional domains of ED were analyzed. The overall result was that long-term therapy with rosuvastatin or candesartan/hydrochlorothiazide or both had no important positive or adverse effect on male sexual health assessed using the validated IIED tool. Neither the development of new ED or progression of established ED was materially altered.
      This article has certain limitations including the large proportion of subjects who did not provide data or were not sexually active before enrollment in the study, the high proportion of patients with established ED at baseline but without any indication of its duration before study enrollment, the paucity of patients with baseline as well as follow-up cholesterol values (only 326 patients), the use of a combination blood pressure intervention that precluded assessment separately of specific effects of candesartan or hydrochlorothiazide on ED, the lack of earlier assessment of the IIED-EF to determine short-term benefits or harms, inclusion of patients who might not warrant primary prevention use of any antihypertensive drugs, and no analysis of interactions of the study agents with users of ED therapies, primarily phosphodiesterase 5 inhibitors.
      Despite these factors, the report is critically important and a unique contribution to this area of research. ED becomes more prevalent with aging and especially in the setting of smoking, obesity, metabolic syndrome, diabetes, hypertension, and dyslipidemia. These modifiable risk factors have well known, generalized vascular effects including a major effect on endothelial dysfunction of penile arteries. It is likely quite sobering to most cardiologists that even in the primary prevention population reported on, the prevalence of sexual dysfunction is so high. A general principle of prevention therapy is to minimize and avoid side effects and to prioritize quality of life, particularly when implementing lifelong therapy. However, the interplay between implementation of proven preventive therapies and perceived side effects or benefits goes well beyond the known mechanisms of action of these drugs on vascular health and well beyond plausible mediation of side effects. In the case of ED, this requires especially careful consideration of preexisting ED, noncardiovascular risk factors potentially contributing to ED either before or after initiation of therapy, and placebo as well as nocebo effects.
      • Chrysant S.G.
      Antihypertensive therapy causes erectile dysfunction.
      • Patel J.P.
      • Lee E.H.
      • Mena-Hurtado C.I.
      • Walker C.N.
      Evaluation and management of erectile dysfunction in the hypertensive patient.
      This analysis from a placebo-controlled randomized clinical trial provides a large degree of reassurance that indicated therapies are not altering the natural course of ED in any adverse fashion, even with a combination antihypertensive agent that includes a thiazide and even when statins are used. Although there is no “free ride” (ie, it is disappointing that new-onset ED or the rate of decline of ED were not altered as a result of the known benefits on vascular endothelial function), it is still important to emphasize the landmark significance and importance of effective primary prevention through modification of lipid- and blood pressure-related risk with safe medications.
      In conclusion, patients who might express concern about ED should be reassured about the lack of effect with statin use or the combination of angiotensin receptor blocker/thiazide. However, perhaps more importantly, they should be assessed more comprehensively and directed to and/or instructed in the safe use of phosphodiesterase 5 inhibitors when appropriate, and when nitrates are not being used.
      • Chrysant S.G.
      Antihypertensive therapy causes erectile dysfunction.
      • Patel J.P.
      • Lee E.H.
      • Mena-Hurtado C.I.
      • Walker C.N.
      Evaluation and management of erectile dysfunction in the hypertensive patient.
      The current report provides strong motivation for cardiologists to develop confidence and competence in the overlap between quality of life as reflected by male sexual health and reduction of cardiovascular risk.

      Disclosures

      The author has no conflicts of interest to disclose.

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