HOPE-3: No Effect of CVD Drugs on Erectile Function

Marlene Busko

February 15, 2018

A prespecified analysis of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial provides reassurance that long-term primary prevention therapy with a statin and/or the combination of candesartan and low-dose thiazide does not increase the risk for erectile dysfunction (ED) in middle-aged men at intermediate cardiovascular risk, researchers say.

On the other hand, while treatment lowered cholesterol and blood pressure, it did not reduce the likelihood of new or worsening ED, as had been hinted at in smaller, shorter trials.

In the HOPE-3 trial, more than 2000 men were randomly assigned to receive rosuvastatin (10 mg per day) or combined angiotensin receptor blocker candesartan plus hydrochlorothiazide (16 mg/12.5 mg per day) or placebo, in a 2 × 2 factorial design. They also replied to a validated questionnaire about ED at baseline and after close to 6 years.   

It was important to test whether optimizing risk factors, in this case blood pressure and cholesterol, could affect the progression of ED, and the results were neutral, Philip Joseph, MD, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, told theheart.org | Medscape Cardiology.

Moreover, "a lot of men attribute erectile dysfunction to medication, but they also have risk factors that cause erectile dysfunction," Joseph said. This research suggests that the tested medications in these doses "don't seem to adversely affect erectile dysfunction."

The new analysis was published in the January issue of the Canadian Journal of Cardiology.

GB John Mancini, MD, University of British Columbia, Vancouver, British Columbia, Canada, wrote an accompanying editorial. "What's new and important is the very high prevalence of erectile dysfunction [57%] in this middle-aged male group, and the good news is that the medications that they need for cardiovascular risk reduction don't worsen that in any way," Mancini said in an interview.

"If the primary prevention is warranted, it should proceed with a statin, and if appropriate, the antihypertensive, without fear of worsening erectile dysfunction and unfortunately without benefit [for this] ascribed to either of these classes."

Coinciding Effects

Men often develop ED and start receiving treatment for cardiovascular risk factors, such as hypertension or elevated cholesterol, around the same time, and they may attribute the ED to a medication side effect, Joseph and colleagues write. 

The researchers investigated changes in erectile function among men in HOPE-3 based on results of the International Index of Erectile Function (IIEF-EF) questionnaire.

Primary results of HOPE-3 were published in 2016 in the New England Journal of Medicine and were reported by theheart.org | Medscape Cardiology at that time. Of 6831 men in HOPE-3, who were all aged 55 years or older and had an INTERHEART risk score indicating an intermediate risk for a first cardiovascular event, 4314 men had complete IIEF-EF questionnaires at baseline and study end.

Of these, 2261 men (51%) had reported "no sexual activity" or "no intercourse" in the 4 preceding weeks at baseline and were excluded from the analysis.

The remaining 2153 men were included in this analysis. They had a mean age of 61 years, and 57% had ED, defined as an IIEF-EF score less than 26. They also had a mean systolic blood pressure of 138 mm Hg, a mean LDL cholesterol level of 127 mg/dL, and a mean waist-to-hip ratio of 0.96. One third were current smokers, but only 6% had diabetes. 

After a mean follow-up of 5.8 years, the mean IIEF-EF score in the overall group declined from 23 to 22 (P < .001). However, the mean change in IIEF-EF score did not differ significantly in the groups that received cholesterol-lowering therapy, blood pressure–lowering therapy, or both compared with the groups that received placebo, after adjustment for covariates.

Moreover, in men without ED at baseline, these therapies did not affect development of problems with erectile function.  

"We achieved significant reductions in LDL as well as blood pressure," with use of rosuvastatin and combined candesartan/hydrochlorothiazide, respectively, the researchers report, but neither affected erectile function.

"These findings suggest that modifying these risk factors [has] little impact on erectile function in this population."

The researchers acknowledge that study limitations include inability to separate the effect of candesartan from that of the hydrochlorothiazide  —  previous studies have suggested that high-dose thiazides are associated with increased risk for ED.

Few men had diabetes, a strong risk factor for ED, "so I think it is hard to generalize the data to the diabetic population," Joseph said. "We weren't modifying that risk factor; we were focusing on cholesterol and blood pressure."

Ask About ED

ED is "not necessarily top of mind among most practicing cardiologists [and], it would only be asked most typically if the patient brings it up," Mancini noted.

Given the "very typical" cardiovascular risk profile of these men — late middle age and risk factors for cardiovascular disease, such as diabetes, hypertension, and overweight — "then obviously a lot [of ED] is going undetected and unsaid in most cardiovascular assessments."

Mancini concludes: "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," as shown in this study.

"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," he said. "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."

HOPE-3 was funded by a grant from the Canadian Institutes of Health Research and an unrestricted grant from Astra Zeneca. Joseph and Mancini have no relevant financial disclosures. The disclosures of the other authors are listed with the article.

Can J Cardiol. 2018;34:38-44, 4-5. Abstract, Editorial

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