Stenting stenosis in the internal pudendal artery (IPA) as a treatment for erectile dysfunction (ED) appears to be safe and improve erectile function. But researchers aren’t advocating stents as an ED treatment just yet. Instead, they recommend stepping back to understand disease prevalence and the vasculature of the pelvis to better identify who among the 322 million men worldwide projected to have ED by 2025 are likely to benefit from treatment (BJU Int 1999;84:50-56). More immediate, they agree, is leveraging ED to reduce risk factors for cardiovascular disease.
ZEN and now
Simply put, ED often is a vascular disease that involves blood flow to the penis. But nothing is simple about ED.
Causes range from inadequate blood flow in, leaking of blood flow out, psychological factors or a combination of any of the three. The first-line treatment, phosphodiesterase type 5 (PDE-5) inhibitors such as Viagra, Cialis and Levitra, work in about two-thirds of men prescribed the drugs, but one-third remain non-responders (BMJ 2006;332:589-592).
Enter the ZEN trial, sponsored by Medtronic and led by Jason H. Rogers, MD, director of interventional cardiology at the University of California, Davis, Medical Center in Sacramento, Calif., and colleagues. ZEN was designed to test the use of drug-eluting stents (DES) to improve blood flow by treating atherosclerotic lesions in the IPA of the pelvis. The trial enrolled 30 men from 16 sites with suboptimal response to PDE-5 inhibitors with stenosis of the IPA that were treated unilaterally or bilaterally with DES.
Rogers reported the 30-day and three-month results at the Vascular InterVentional Advances (VIVA) conference in October 2011, which showed no adverse events associated with stenting. At three months, more than one-third of patients reported improvement in intercourse success; almost two-thirds responded in a validated International Index of Erectile Function (IIEF) questionnaire that they experienced improvement in erectile function; and duplex ultrasound showed blood flow to the penis increased by 16 cm per second.
“We learned that these patients have atherosclerotic narrowing in their pudendal arteries, and if they are focal, they can be treated successfully with this DES,” Rogers says.
ZEN also revealed many challenges, including that the vascular anatomy in the pelvis varies; the degree and distribution of atherosclerotic plaque also vary; and the select group of patients with favorable lesions in ZEN may be the exception rather than the rule, with some men’s blood inflow limitations related to vessels other than the IPA that are too small to stent.
“We screened far more patients and performed far more diagnostic angiograms in people who ultimately did not qualify for treatment,” says David E. Kandzari, MD, director of interventional cardiology at Piedmont Heart Institute in Atlanta, who is among the ZEN co-investigators and partners.
“One of the lessons that emerged from ZEN is a need to better understand the disease prevalence, its relationship to erectile dysfunction and its association with other vascular disease territories,” adds Kandzari.
Taking time out
Several observational trials are now underway in an attempt to fill the knowledge gaps, including IMPASSE and INDEED.
ZEN co-investigator Krishna Rocha-Singh, MD, director of the Prairie Vascular Institute in Springfield, Ill., serves as principal investigator of IMPASSE, launched last year to chart the angiographic anatomy of erectile-related arteries and correlate angiographic findings with ED to determine which patients may benefit from stenting.
IMPASSE, also sponsored by Medtronic, is enrolling up to 350 men from 15 sites who are 35 to 70 years old and undergoing coronary or peripheral angiography or intervention for known or suspected coronary artery disease (CAD) or peripheral arterial disease (PAD). Through IMPASSE, investigators hope to determine the proportion of men with CAD and PAD who have stenoses greater or equal to 50 percent in an erectile-related artery.
“Ultimately, that is the big question: What percentage of patients with ED may actually be candidates for this therapy?” Rogers says.
Howard C. Herrmann, MD, director of interventional cardiology and cardiac catheterization at the Penn Heart and Vascular Center, and Zachary Gertz, MD, a cardiology fellow at the University of Pennsylvania, both in Philadelphia, designed INDEED to better understand the significance of IPA disease in patients with ED. INDEED will enroll 200 patients who are scheduled for cardiac or peripheral artery catheterization with at least one risk factor for ED.
They will use angiography and fractional flow reserve to examine stenoses to determine the degree of IPA disease, and the IIEF questionnaire to determine the degree of ED. INDEED is supported by unrestricted grants from St. Jude Medical and Abbott.
“As in the coronary circulation, we need to understand both the anatomy and function of what we see,” Herrmann says. “We are trying to measure that in this study by looking at cohorts of patients with ED; cohorts without ED; and, in those patients with pudendal artery disease, a functional assessment of lesions.”
Coronary connection
Herrmann describes ZEN as premature, and Rogers and Kandzari acknowledge IMPASSE is a necessary step back to establish angiographic protocols and ensure stenting targets the appropriate patient population. But ZEN offers a number of additional benefits, including a multidisciplinary approach for caring for patients with ED, and recognition within the cardiovascular community that physicians may use ED as both a marker for cardiovascular disease and a motivator for eliminating modifiable high-risk behaviors.
Collaboration with urologists, such as Irwin Goldstein, MD, a ZEN co-investigator and director of San Diego Sexual Medicine at Alvarado Hospital in San Diego, Calif., will be key to ED therapy that involves stenting, Rogers says. While cardiologists excel at revascularization therapy, they likely are not qualified to assess the many causes of ED.
“The last thing we want to do is to start putting stents in a patient without thoroughly evaluating him or her and making sure that the stent is going to help this patient,” Rogers says.
For Goldstein, stenting offers a potentially promising therapy that requires neither drugs nor prostheses. “This is dealing with the root cause and theoretically could restore functionality in a normal way,” he says. “It is similar to a patient with angina and can’t exercise, who is able to run a marathon post-stenting.”
ED also has been shown to be a marker for cardiovascular disease (JACC 2010;55[4];350-356). Kandzari argues that mechanistically it makes sense. While a small amount of plaque may not be clinically relevant in larger vessels, in smaller vessels of the pelvis it may contribute to the early onset of ED and presage later cardiovascular disease and stroke. ED offers cardiologists who are willing to inquire about sexual issues an opportunity to identify patients potentially at risk and intervene before cardiovascular disease progresses.
“There was a large secondary opportunity to treat patients in the trial for risk factors, such as smoking, diabetes, untreated high cholesterol and high blood pressure,” Kandzari says.
Rogers adds that for male patients, the specter of ED may provide a powerful motivator for making lifestyle changes such as losing weight. “It may be a wakeup call for the patient that if he does everything possible to improve his vascular health, then maybe his erectile function will improve as well,” he suggests.
Bottom line, the more light that ZEN, IMPASSE, INDEED and other studies shed on links between ED and cardiovascular disease, the more awareness is likely to grow among physicians who then can counsel patients, cardiologists say. “Ultimately patients aren’t dying from erectile dysfunction,” Rogers points out. “They are dying from heart disease.”