Bypassing Big Pharma

There have been many resounding victories in the war against coronary artery disease. Among those are antiarrhythmic drugs, pacemakers, coronary bypass surgery, coronary angioplasty, reperfusion therapy, and statins. But the one goal that has continuously eluded us has been the clinical availability of an effective cardioprotective agent. Although reperfusion therapy has partially achieved the goal of limiting infarct size in the setting of acute myocardial infarction, the logistics usually prevent restoration of perfusion until after a significant amount of myocardium has been lost to infarction. In 1974, when Braunwald1 proposed that priority should be given to the identification of interventions that would make the myocardium resistant to infarction, nobody knew what an arduous task that would be. In the beginning, “big pharma” was a strong partner in this quest, and many drugs were evaluated. The first wave of drugs like β-blockers and calcium antagonists were examined because it was believed that they would reduce oxygen consumption and that an improvement in the supply-demand relationship in the heart would suppress infarction. Unfortunately, the determinants of oxygen consumption in the ischemic heart are very different from those in the well-perfused heart, and not surprisingly, these drugs were ineffective. Then, the focus shifted to antioxidants and antiinflammatory agents. Their preclinical performance was inconsistent, and the clinical trials that they spawned were all decidedly negative. Most recently, a great deal of money was spent on the development of the sodium–hydrogen exchange blocker cariporide, which again failed in clinical trials. Adenosine and insulin suffered similar fates. With each negative trial, the industry has become increasingly leery of cardioprotective interventions, and most companies are now very reluctant to include primary cardioprotectants in their development pipelines. Nobody knows …