Back in 1983, scientists in Pfizer’s R&D labs in Sandwich, England were looking for a new way to treat angina – a painful cardiac condition that is caused by insufficient blood flow to the heart. Investigating a series of enzymes known as phosphodiesterases, they began to focus on a specific one, PDE-5, because it was present in very high concentrations in vascular smooth muscle. This suggested that an inhibitor of PDE-5 could enhance blood flow thereby alleviating the pain caused by angina. By 1988, the team discovered a selective PDE-5 inhibitor with the code name UK-92,480. Animal studies showed that it was sufficiently safe and effective to justify clinical studies.
Unfortunately, the first studies were disappointing. UK-92,480 had minimal effects on important cardiovascular parameters as blood pressure, heart rate, cardiac output, and blood flow. In fact, the compound would have been dropped from development had it not been for an interesting observation. In one study that was done in 1992 in Wales, male volunteers who were taking 50mg of UK-92,480 every 8 hours for 10 days reported more erections. This wasn’t a far-fetched result. The same biological mechanisms that were hypothesized to treat angina could instead come into play in the penis. PDE-5 inhibition was indeed enhancing blood flow – but to a different organ than was initially envisioned.
The rest is now the stuff of drug R&D lore. Pfizer ran formal studies with UK-92,480, now with the generic name sildenafil, in patients with erectile dysfunction and the compound proved safe and wonderfully effective. It is important to note that there were no guidelines at the time for developing such a drug and so Pfizer had to work with regulatory authorities and key physician opinion leaders to come up with the trial design, efficacy measures, patient selection, etc. The New Drug Application was filed in 1997 and the drug, now with the trademark name of Viagra, was approved by the FDA on March 27, 1998. Ironically, there were worries that, if men with heart disease took Viagra, they might experience heart attacks once they were able to again have sex. However, this fear dissipated as the drug gained more and more use. (It should be noted that PDE-5 inhibitors are contraindicated for use with nitro compounds due to the potential for acute drops in blood pressure.)
PDE-5 inhibitors have since been found to have other uses, including the treatment of a debilitating lung condition known as pulmonary hypertension and relieving the symptoms of benign prostatic hyperplasia. However, a recent publication now suggests that Viagra and other PDE-5 inhibitors like Cialis (Lilly) may have cardioprotective effects as well. Researchers from Sapienza University in Rome have done a meta-analysis of a number of randomized controlled trials (RCTs) trying to determine if chronic inhibition of PDE-5 would provide cardioprotection. What they found was that continuous use of Viagra improves cardiac performance in patients, cardiac hypertrophy, and heart failure, conditions where the cardiac pump function is compromised.
This is a pretty interesting result. Here’s what the authors said about it.
“With respect to the initial purpose of the study, we showed that in selected cohorts long-term continuous PDE-5 inhibition can produce clinically meaningful improvements in cardiac remodeling and performance with an excellent cardiovascular safety and tolerability profile even in older patients and under prolonged use.”
As stated, this study was a meta-analysis of data pooled from a number of previously run clinical trials. As such, this study can point to important signals emerging from a number of different clinical studies. However, before Viagra could be approved for use in heart failure patients, RCTs would be needed to prospectively seek benefits of Viagra in heart failure patients. The authors acknowledge this point.
“Our analyses reveal that the ideal target population to benefit from PDE-5 is patients with HF and LVH. Given the paucity of published data, on the basis of these encouraging findings large clinical trials are urgently needed on the long-term effects of continuous PDE5 inhibition administration, focusing on cardiovascular outcomes and sex-specific response in these patients.”
That is exactly what is needed. However, who will conduct such studies? Such a clinical program would require a large number of patients who will need to be monitored for many years as you are looking for long-term benefits in heart failure patients. Such an outcome study could cost hundreds of millions of dollars. Would Pfizer be willing to invest in such a study? Perhaps. But Viagra will soon be off-patent and generic sildenafil will be readily – and cheaply - available. It is possible that a separate patent could be issued for using Viagra for heart failure patients, but it is unlikely that, even if the clinical trials are successful, a newly branded version of sildenafil for use in heart failure would be a success. That’s because payers would urge patients to take generic sildenafil off-label for heart failure, thereby avoiding the premium price of a newly branded and expensive version. Thus, it would be hard for any of the companies with marketed PDE-5 inhibitors to profit from a version of these drugs for heart failure.
Despite the interesting results, it remains to be seen whether a study of sufficient size and robustness necessary for the regulatory approval of a PDE-5 inhibitor for use in heart failure patients will ever be done. It is possible that an entity like the NIH would take this on. However, the cost and complexity of such a study, particularly at a time of tight budgets, may make it prohibitive. In this time of reining in healthcare costs, the potential of PDE-5 inhibitors as drugs for treating heart failure may never be realized.
