Viagra And Heart Disease

In the 1990s, the Pfizer cardiovascular (CV) research group in the UK was looking for new drugs to treat cardiovascular disease….CONTINUE READING

This group had already scored some major successes in this area most notably with Norvasc (amlodipine) which became the premier calcium channel blocker for the treatment of hypertension. In the course of their work, the UK scientists explored blockadeof a specific enzyme, phosphodiesterase-5 (PDE-5). Their early work demonstrated that blocking PDE-5 in animals enhanced blood flow to a variety of organs and that an inhibitor of PDE-5 could be of value in treating CV conditions such as angina and heart failure.

The team was able to find a novel, potent PDE-5 inhibitor, UK-92,480, and they rapidly advanced this compound to the clinic. The initial trials in volunteers were disappointing. UK-92,480 had a minimal acute impact on important CV parameters such as blood pressure, heart rate, cardiac output and blood flow. The program was almost discontinued – not a rare occurrence. A promising hypothesis can initially be exciting but then fails when actually tested with a compound in humans. However, in this case an important observation was made in male volunteers who were dosed with 50mg of UK-92,480 daily over a week. They were getting more erections – a finding that wasn’t far-fetched. UK-92,480 was designed as a drug to enhance blood flow. However, the enhanced blood flow was occurring in a different organ than had been anticipated – the ***. Suddenly, the prospects for UK-92,480 changed dramatically. It had the potential to be the first oral drug to treat erectile dysfunction (ED).

The rest of the story is well known. Pfizer began a major development program for sildenafil, the generic name given to UK-92,480. In many ways, this was uncharted territory. No one had developed an oral drug to treat ED. Pfizer consulted with the FDA to put together a plan to demonstrate the safety and efficacy of sildenafil. For example, working with the FDA, Pfizer developed the “International Index of Erectile Function”, a tool that has become the gold standard for evaluating ED drugs. Pfizer went on to conduct clinical trials involving thousands of patients and the drug was, in fact, safe and effective. On March 27, 1998, sildenafil was approved by the FDA for the treatment of ED. This drug was trademarked by Pfizer as Viagra and was sold as the now famous diamond-shaped blue pill.

While the focus of Viagra (sildenafil) was on ED, it turns out that this drug was also found to be useful in treating a lung disease – pulmonary arterial hypertension (PAH). In PAH, the arteries of the lung are constricted and the heart has to work harder to pump blood through the lungs. This increased work can eventually lead to heart failure. Since PDE-5 is found throughout the pulmonary vasculature and, given that sildenafil blocks this enzyme, it was thought that it could also be used to treat PAH. Sure enough, clinical trials showed that this PDE-5 inhibitor improved exercise capacity, functional capacity and hemodynamics in PAH patients, leading to a second FDA approval for sildenafil for this condition. For PAH, sildenafil is sold under the trademark Revatio.

Over the years scientists have speculated that PDE-5 inhibitors (PDE-5is) like sildenafil could have long-term benefits in treating CV disease – the original motivation for the Pfizer scientists to begin this research. Now, a new study

from the University of Southern California (USC) provides evidence that this could indeed be the case. The USC investigators sought to determine whether PDE-5is reduce the incidence of major adverse cardiovascular events (MACE) defined as CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure and unstable angina. They carried out a retrospective observational cohort study in a large US claims database in men with one or more diagnoses of ED without prior MACE within one year from January 1, 2006 to October 31, 2020. The analysis compared 23,816 men who had been exposed to PDE-5is vs. 48,682 men with no exposure to PDE-5is. Their average age was 52.

The results proved extremely interesting. The general population of men who had taken ED drugs had a 13% lower rate of MACE, 25% lower rate of mortality and 39% lower rate of CV mortality when compared to men who had not been exposed to ED drugs. (The results were adjusted for factors like race, height and weight.) Furthermore, those who had the highest exposure to PDE-5is were associated with the greatest reduction in MACE and death. As originally envisioned by the Pfizer scientists, PDE-5is do seem to have a beneficial impact over the long-term on blood flow parameters that lead to better CV outcomes.

So, does this mean that we will see the generic form of Viagra routinely prescribed for men at risk for cardiovascular disease? That’s unlikely. This was a retrospective study looking for evidence of a potential benefit. For the FDA to approve a PDE-5i for preventing heart attacks and strokes, it would require an actual study to prove this. Such a study would involve looking at perhaps 20,000 heart patients – half on their standard therapy and the other half on their standard therapy plus sildenafil – and then following these patients for three to five years to measure MACE outcomes. Such a study would cost between $1 – $2 billion. Further complicating things is that PDE-5is are now generic and pretty cheap. Essentially, this would be a losing proposition for any company in that, even if such an outcomes study were successful, it would be difficult to recoup the costs of running such a clinical program, much less turn a profit, given that these drugs are now cheap generics.

Theoretically, the NIH could run this type of study. However, the NIH has neither the financial resources nor the capacity to carry out such a program.

So, we are left with the fact that Viagra and other PDE-5is are important drugs to treat ED and PAH. We can also take comfortthat they not only are safe but they might even afford long-term CV protection – as the Pfizer UK scientists had hoped thirty years ago. But, we won’t see formal regulatory approval for such an indication.

(John L. LaMattina is the former president of Pfizer Global R&D and the author ofPharma & Profits: Balancing Innovation, Medicines, and Drug Prices.)….CONTINUE READING