The success reported earlier this week from the ATLAS study, that adding a small dose of the anti-coagulant rivaroxaban to standard medical therapy of acute coronary syndrome patients led to a strikingly good drop in mortality, contrasted sharply with the fortune of another anti-thrombitc drug, vorapaxar. This drug failed to show any benefit in the same type of patients in a study with a very similar design to ATLAS. Results from each of the two studies were reported last Sunday at the annual Scientific Sessions of the American Heart Association.
The key factor tipping the balance toward rivaroxaban’s success and vorapaxar’s failue was what Dr. Keith Fox said at the meeting involved finding the “sweet spot” between safety and efficacy when dosing these drugs that aim to cut the risk from blood-clot formation while at the same time not producing untoward levels of bleeding. The researchers who ran the ATLAS trial with rivaroxaban found that sweet spot with a 2.5 mg b.i.d. regimen, one of two dosages tested in ATLAS. Those who ran the TRACER trial chose less well (at least in retrospect) with a 2.5 mg once daily dosage of vorapaxar.
Courtesy lb.Wikipedia/Oennenzopp/Creative Commons License
Why was the vorapaxar dose wrong, and the rivaroxaban dose right?
“You make an educated guess based on the phase 2 data,” said Dr. Robert Harrington, one of the lead investigators on the TRACER vorapaxar study. “It’s a limited sample size, and there’s limited length of follow-up. You also look at the pharmacokinetic and pharmacodynamic data, but you never know until you do the phase 3 trial if you’ll hit the right dose or if you don’t.”
Choosing the right dose to test in expensive phase 3 trials becomes even harder when, as in the case of these new treatments for acute coronary syndrome, several agents jockey to be first to a FDA-approved indication.
“There is a race, and sponsors know the quicker they get through phase 2 and into phase 3 the quicker the drugs can get to market” if they’re successful, noted Dr. Elliott Antman, a veteran of several big phase 3 studies. As a senior investigator of the TIMI study team, he was someone who saw the planning steps for ATLAS though he didn’t participate in the trial himself. “Sometimes there is wishful thinking and over-interpretation of small sample sizes in phase 2 that may lead to a dose selection that’s not optimal.”
Dr. Antman highlighted the two different rivaroxaban dosages that ATLAS compared with placebo in the 15,000+ patient trial. The 5 mg b.i.d. dosage it also tested produced efficacy results that were far less clearly beneficial than the smaller dosage, and the higher dosage also produced substantially more bleeding.
“There was a signal from the phase 2 study that the 2.5 mg b.i.d. dose was more effective and less harmful, but with the small sample size they decided to take them both forward.” A fortuitous move. “Two dosages meant more patients, more expense, and a longer trial,” he added. Sometimes you’re a little lucky and you get the dosing right, and sometimes you don’t. Imagine if ATLAS had only used the 5 mg dose. Then we’d be having a totally different conversation.”
“We were wise and lucky to hit the dose right, and it may have been more that we were lucky,” said Dr. Deepak Bhatt, an ATLAS co-investigator. “Two doses of a drug in phase 3 should happen more often, but because of the cost it usually doesn’t. You need to read the tea leaves from phase 2 and hope you’ve picked right, and you’re never certain. It’s just a gut feeling.”
And perhaps in the case of rivaroxaban and ATLAS there was wisdom, and experience, too. “The academic executive committee of ATLAS felt that two doses should be tested. Dr. Braunwald in particular felt strongly about it,” Dr. Bhatt recalled.
What he didn’t need to add is that Dr. Eugene Braunwald, now 82 years old, is the Hersey Distinguished Professor of the Theory and Practice of Physic at Harvard Medical School, founding chairman of the TIMI study group, founding editor of the 31-year-old Braunwald’s Heart Disease--a revered cardiology textbook, and overall reigning dean and wise man of cardiology. A good person to have around when confronting the sticky issue of which dosage to run with in a big clinical trial.
---Mitchel Zoler (on Twitter @mitchelzoler)