Is there something special about the United States? We all know that the drug Ticagrelor has been awaiting approval for use as a novel anti-platelet agent with efficacy superior to Clopidogrel, as shown in the PLATO Trial. Interestingly, the buzz around why there has been a delay has centered on the subgroup analysis across countries which indicated that the drug was not efficacious (and perhaps even harmful) in the United States. Is this a play of chance or a real phenomenon? And, if real, what can it tell us about the relative merits of invasive and pharmaceutical treatment across countries?
It turns out this is not the first time that such discrepancies have been found. In general, it seems, whenever PCI is in the equation, the incremental benefits of even very powerful medications are meager in the US versus the rest of the world. But, let’s look at the PLATO trial first. While Ticagrelor in the overall population showed a benefit, this was driven primarily by the non-US sites (mainly in Eastern Europe, India and Brazil) where dramatic benefits were noted. In the US, meanwhile, the use of Ticagrelor actually conferred a worse prognosis, with all hard endpoints favoring Clopidogrel. Could it be that “strengthening” the peri-procedural medical regimen is less important in countries that have already perfected a “PCI for all” approach? Does such incremental increase in medication potency just lead to harm then?
Let’s look at a few other trials that suggest a similar pattern. In the COURAGE trial, the US population fared numerically better with routine PCI (15.8% vs. 21.8%), with all the hazard of a PCI strategy mainly in Canada and the VA system. In the VANQWISH trial of invasive versus conservative management of unstable angina, the hazard of early PCI in the VA sites was so high that it biased against the invasive arm, something we only learned later once a large meta-analysis and further studies ultimately proved the early invasive strategy preferable.
Trials strive for the “all things being equal” goal, so that we can compare one drug or strategy versus another drug or strategy; yet, all things are almost never equal in the real world, and even more so when you involve highly technical procedures like PCI across national boundaries. Different healthcare systems, background patient risk, operator experience and skill sets, technology and usage rates, and expectations (patient and physician) all have an impact on patient selection, the way they are treated and clinical outcomes, even though on paper they may all be considered “equal” as they go into a trial.
So, should the FDA approve Ticagrelor or not? Should it be available only outside the US? Is the drug less effective (or more harmful) in the US because we are already so aggressive here? In contrast, is the drug more useful outside the US, where invasive outcomes may need the additional help? At the end of the day, medications may be a great equalizer that improve outcomes in underserved populations up to a certain point regardless of race, ethnicity, gender, or country of origin, but perhaps do harm when outcomes are already quite good. In effect, I’m not so sure it’s coincidence that the more underserved countries drove the benefits of Ticagrelor.
The FDA either has to approve the drug (to avoid bringing this issue into the limelight) or not approve it. Regardless, we as a worldwide cardiovascular community need to take a serious look at how different health care delivery systems and associated clinical care affect treatment efficacy, be it medications or PCI. Perhaps, the US is different and that’s a good thing.
Dr. Srihari S. Naidu is Director of the Cardiac Catheterization Laboratory, Interventional Cardiology Fellowship Program and Hypertrophic Cardiomyopathy Treatment Center at Winthrop University Hospital, and Assistant Professor of Medicine at SUNY – Stony Brook School of Medicine.