Using two lower dose rivaroxaban regimens with either a single P2Y12 inhibitor or standard dual antiplatelet therapy (DAPT) instead of a combination of warfarin and DAPT reduced clinically significant bleeding rates in patients with atrial fibrillation (AF) undergoing PCI, new findings from PIONEER AF-PCI reveal.
The findings could signal an end to warfarin-based triple oral therapy in this group of patients who must trade off a greater bleeding risk for protection against stent thrombosis and thromboembolism when they are on treatment regimens that combine oral anticoagulation with DAPT.
Dr Michael Gibson from the Beth Israel Deaconess Medical Center in Boston in the US who presented the late breaking trial data at the 2016 American Heart Association Scientific Sessions this week said treating just 11-12 patients with one of the rivaroxaban-based regimens instead of using warfarin-based triple therapy would prevent one bleeding event and treating 10-14 people would prevent one recurrent hospitalisation.
Experts commenting on the study at a press conference said the findings are a ‘critical advance’ to the field and likely to change practice.
Dr Gibson estimates that between five and 10% of all patients who come into the cath lab and require stenting have AF.
“This is a substantial number of patients who present with this treatment dilemma,” he told the conference.
To find out if bleeding rates could be reduced in these patients, Dr Gibson and colleagues looked at replacing traditional warfarin-based regimens with a NOAC.
The study, of just over 2000 stented patients with AF randomised patients to one of 3 groups: reduced dose rivaroxaban 15 mg daily plus a P2Y12 inhibitor of the treating doctor’s choice for 12 months; rivaroxaban 2.5 mg taken twice a day with stratification to a pre-specified duration of DAPT of 1, 6, or 12 months; or to the control arm of dose-adjusted VKA daily with a similar DAPT stratification.
The lower 2.5 mg twice a day dose in the current study has been studied previously in ATLAS AC2 TIMI 51. In that trial, very low dose anticoagulation reduced stent thrombosis by 31% and was associated with a statistically significant reduction in mortality, Dr Gibson noted.
The composite primary endpoint of all cause-mortality or recurrent hospitalisation was significantly lower in both experimental arms than in the control arm (34.9%, 31.9%, and 41.9% respectively) due to reductions in hospitalisations for cardiovascular causes and bleeding, which was measured by TIMI major bleeding, TIMI minor bleeding, or bleeding requiring medical attention.
According to Dr Gibson, the lower bleeding rate was consistent across all subgroups in the experimental arms.
“It didn’t matter about kidney function, CHADS score, age or gender – the results all favoured the rivaroxaban strategies,” he said.
When it came to efficacy outcomes the results were homogenous, he said.
The secondary endpoints, cardiovascular death, MI, or stroke occurred in 6.0% of warfarin-treated patients, 6.5% of those receiving rivaroxaban-based double therapy, and 5.6% of those receiving rivaroxaban-based triple therapy.
“There was no subgroup that had a different result to the rest of the cohorts.”
Mortality rates were similar across the three arms and there were no significant effects on other types of hospitalisations.
PIONEER AF PCI likely to be compared to WOEST
Dr Gibson said he expected PIONEER AF PCI would be compared to WOEST – which looked at what would happen if aspirin were removed from therapy and patients were treated only with an anticoagulant and a P2Y12 inhibitor.
That approach showed that warfarin plus clopidogrel reduced bleeding and improved efficacy versus triple therapy but Dr Gibson took the opportunity to stress some significant differences between the two studies.
According to Dr Gibson, only 69% of the patients studied in WOEST had AF whereas all the patients in PIONEER AF PCI had the condition.
About two thirds of patients in WOEST continued their triple therapy for one year. But in PIONEER AF only 22% of patients remained on triple therapy through the year which meant that there was much less anticoagulation with warfarin in PIONEER.
While there wasn’t a treatment arm in PIONEER that looked at dual therapy with warfarin Dr Gibson pointed out that about 60% of people in the warfarin arm of the study had come off triple therapy and had switched to a WOEST-like dual therapy.
What’s more, WOEST also reported a reduction in all cause mortality with the double therapy group rather than the triple therapy, he said.
Lower doses not approved by the FDA
“The overlap of AF and PCI is an important issue … we need information on the optimal strategy – the choice of agent, the dose of each agent and the duration of treatment for each agent [because] there’s a myriad of ways to combine these drugs,” said Dr Philippe Gabriel Steg from Hôpital Bichat in Paris, France who was a discussant on the trial.
He said while the overall findings from PIONEER were ‘robust’ it was critical to remember that the lower doses used in the trial had neither been formally tested or approved by the US FDA.
He also added that while the recurrent hospitalisation data was ‘intriguing’ and ‘potentially important’ it should be remembered that they come from a post hoc analysis and should be viewed as hypothesis generating.
For now he said that doctors would have to make a judgement call rather than an evidence-based decision on whether to ditch warfarin-based triple therapy in this group of patients.
“I don’t think we have the full evidence we would like to have … to really justify a complete change in practice [but], having said that, we recognise its going to be very hard to gather that evidence and I think the NOACs have tremendous advantages over warfarin for treating patients with AF who also need stents because they are much more convenient and they’re safer.
“Having some evidence that reassures us that you bleed less when you use a NOAC and that you have a low rate of stroke or MACCE I think is very interesting and I’m sure it’s going to impact practice.”
Clopidogrel was the P2Y12 inhibitor used in 95% of patients in PIONEER AF PCI, with ticagrelor and prasugrel used in the rest. The time in therapeutic range for warfarin-treated patients was 65%.