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ACC2020: Brilinta reduserte bldning hos pasienter med alvorlig hjertesykdom

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I on behalf of the twilight investigators it is my pleasure to present to you the analysis on that diabetic patients enrolled in the twilight study as already mentioned before the twilight trial was a funded with an investigator initiated grant from astra zeneca to mount sinai which was also the coordinating center of the trial these are my disclosures my disclosures

Mostly relate to makers of antiplatelet therapy which include astra zeneca so i was away a background we know that dual antiplatelet therapy would aspen and a p12 inhibitor is the standard of care for the prevention of thrombotic complications and patients undergoing pci however this does occur at the expense of increased bleeding which increases with a prolonged

Exposure to a dual antiplatelet therapy and overall these observations on the score the need to identify identify badhak regimens that can reduce the risk of bleeding while maintaining efficacy and amongst these the use of a p12 inhibitor mono therapy strategy after a brief period of that has emerged as a very promising one and this was also shown in the twilight

Trial showing clearly that among a high risk pci patients after three months of death like hagler monotherapy reduced bleeding without increasing harm so after these are very exciting results from the twilight trial it obviously becomes of interest understanding if this anti thrombotic strategy remains effective in a patient courts are particularly high risk such

As patients with diabetes now we know that patients with diabetes are high risk for both ischemic and bleeding complications and this is due to a number of reasons which characterized this high risk patient population and the topic becomes of clinical relevance giving the increase in the prevalence of diabetes or world-wide so the objective of this analysis was a it

Was a pre-specified analysis specifically evaluate the safety and efficacy of attica hormone therapy strategy versus standard dual antiplatelet therapy in patients with diabetes enrolled in a twilight trial as already mentioned this was a randomized double-blind placebo-controlled study and here you see the outline all patients after their run in phase of three

Months of dual antiplatelet therapy where they had to be a bent free and a compliant to treatment they were randomized and from this point on randomized to twelve months of treatment of takara plus aspen versus tai chi or plus a placebo we already heard that patients to be enrolled in the trial needs to have at least one clinical and one angiographic high-risk

Criteria and amongst the clinical criteria diabetes actually represented one of them in this actually allowed for our population to be enriched with patients with diabetic status and again they had to also have one high risk and your graphic criteria as a reminder the key exclusion criteria were presence of stemi salvage pci need for chronic oral anticoagulation

Prior stroke and planned coronary revascularization the the target population were the patients with diabetes enrolled in the trial in line with the primary a trial the primary endpoint was marked two three or five bleeding between zero to twelve months after randomization and the key secondary endpoint was all caused that non fatal mi or stroke between 0 and 12

Months after randomization our analytical approach includes the survival analysis for both the primary and secondary endpoints using a kaplan-meier method what hazard ratios and 95% confidence intervals using generated using a cox regression the analysis of leading was using the intention-to-treat cohort while ischemic outcomes the per protocol cohort and treatment

Effects were estimated according to the presence of diabetes with formal interaction testing to assess for modification and we also conducted a of exploratory analysis according to clinical presentation type of glucose lowering treatment and we also did an analysis of net adverse clinical events here you see the outline of the trial over 9,000 patients enrolled in

A study with 7,000 patients ultimately randomized key criteria for not being randomized was non-adherence with around 37% of the patients being diabetic there were obviously clear difference between patients with and without diabetes with most patients with diabetes coming from north america a non white race and clearly with having many more cardiovascular risk

Factors prioritization and multi vessel disease compared to non diabetics in the cohort of patients with diabetes which were equally distributed between the attacker plus plus ebo and at a calpers aspirin arm in the 2,620 patients we had a little bit more than 1/4 patients who were insulin treated diabetics i would also like to highlight that adherence rates to

Tech haggle or and adherence rates to the blinded study drug were a similar were overall very similar here you see the baseline characteristics of the study we had that mean age was close to 65 with a high prevalence of chronic kidney disease anemia which 61% of patients who had an acs presentation and 30% of patients with a prior mi this was overall very high-risk

Patient population we’re multi vessel disease was present in almost 70 percent of patients and overall complex anatomy with total ijen lag close to 40 millimeters i will now present the data on the primary endpoint the park bark two three or five bleeding you can see that in the tactile approach aspirin arm this was 6.7% and in tokaido placebo arm this was a poor 0.5%

‘Ok waiting to a 2.2 percent absolute reduction and i has a ratio of 0.65 and a p-value of a point oh one i will highlight in this slide the comparative data bleeding with and without diabetes as you can see here the data on the primary endpoint where the interaction p-value was was a 0.23 supporting consistency in the findings between the diabetic and non-diabetic

Cohorts when it comes to other bleeding definitions of note also bark three or five bleeding also significantly reduced and there was consistency in the finding with all other definitions of bleeding yes there was a positive interaction 4zu of 0.03 which should be considered as nominal for gustl moderate severe giving the this was a secondary endpoint and with

Very low memories i will now show the ischemic events of death mi or stroke which was 5.9 percent in the takagi was aspirin arm and this was a 4.6 percent in the chicago plus placebo arm and with a hazard ratio of 0.77 i will now show the data compare of the ada patients with and without diabetes and you can see there was overall higher vent rates as expected in

Patients with diabetes but overall very consistent findings there was an interaction p-value which was nominal at 0.05 but this needs to be considered in the context of a secondary endpoint but what i would also like to highlight where jake is particularly important with regards to the safety of a multi-camera therapy strategy that the vast majority of ischemic

Events as you can see here were clearly lower than with the tokaido monotherapy strategy compared to takigawa plus aspirin without any significant interaction we also conducted an exploratory analysis this was not pre specified of net adverse clinical events in which we considered a barque 3 or 5 bleeding therefore the most severe bleeding’s that a meyer stroke

This was 6.7% in the die calipers aspirin arm and sixty five point four percent and the tokaido placebo arm equating a number needed to treat of a 34 not in that adverse clinical events we also looked at outcomes according to clinical presentation of acs versus stable as you can see consistent findings for the bleeding and ischemic events and this was also very

Similar when looking at management of diabetes according to the use or not of insulin therapy consistent effects there are some limitations to this analysis all those was pre-specified randomization was not stratified according to diabetic status and we did not account for multiplicity therefore increasing the chance for a type 1 error diabetic status was based upon

Physician diagnosis we did not do any type of biomarker our findings cannot be generalized to patients treated with other oral p2i 12 inhibitors in particular for pitter girl this could be a topic of discussion we did not include stemi so we cannot extrapolate our results to this cohort and there was a lack of power to that differences in the risk of important yet

Rare clinical bands such as stent thrombosis and stroke therefore in conclusions compared with the catalyst aspirin the effect of takayama therapy and reducing the risk of clinically relevant bleeding without any christian ischemic events was consistent among patients with without by b’s undergoing pci and overall these findings support such a bleeding avoiding

Strategy which can be implemented without any signals for harm even in high-risk patients such as those with diabetes i would like to thank all the country leaders investigators coordinators and study participants who really made the twilite trial possible and the data is now available online in the journal of american college of cardiology thank you very much for

Your attention creating congratulations on dr. tam as holland would you like to lead off with some comments or questions i’ll congratulations dominic that’s just really outstanding presentation and again really contributing to the literature on this issue i think that uh with the findings being so dramatic i guess the question i have for you is well i understand

That this is a subgroup analysis so the interaction p-value is just somewhat nominal how could you explain or give some insight into why if anything there was perhaps more of a benefit in the diabetic patients from the ischemic endpoint yes it’s it’s a great point and i think this ultimately derives from the potential harm that derives from from bleeding what we

Did notice in in in the trial there was although there was consistency in the findings when we look at particularly at the at the badly it’s the mark three or five bleeding’s there there was a a clear difference and i think this all relates to the safety profile of of aspirin or interrogators aspirin in patients with with diabetes there is literature suggesting

That patients with diabetes may be more vulnerable to bleeding induced by enteric coated aspirin mostly attributed to integrity of the gastro intestinal mucosa derived by a vascular disease so these patients are bleeding more and having big bleeds we know that’s a clear a link with with ischemic events so that’s my interpretation to the study findings and that

Makes sense i guess that’s always been the question is you’re stopping when you’re getting the bleeding are you stopping all the antique leaflets and having a higher speed chris absolutely absolutely dr. bhatt so first of all i’d say to dr. angelou a great presentation very important study many of us were wondering whether the overall twilight results would hold

Up in this important so coop and it’s reassuring to see that within your study those with diabetes in fact did have higher ischemic event rates so that gives a lot of legitimacy to the analysis i guess my question for you would be you know how would you reconcile these results say with the thymus results were that suggested that longer term therapy in patients

With diabetes with aspirin plus tea kettle it would be warranted do you think one could extrapolate from your study and say maybe protracted ty cag or beyond this 12 to 15 month period might in fact be an order in patients with diabetes in particular those with acs or pci or both absolutely i think that there there’s a nice link between our analysis and and the

Temas a trial with with the understanding that in tennis there was the adjunctive use of aspirin but it does speak to some specific benefits of a casual or in patients with with diabetes we’ve seen very consistently not just in in tennis but also if you look at the diabetic analysis that you led a deepak from the from the pegasus trial where there’s actually there

Was a mortality benefit there’s something specific related to a cycle or in patients with diabetes one of these could be related to the twice-daily administration of the drug as we know patients with diabetes do have higher platelet turnover rates therefore having twice daily a drug which has been suggested also for for aspirin and there are pharmacodynamics

Ties to this extent but we don’t have clinical studies clinical studies which we do have with high cog or so i think there’s something very specific there obviously i would like to see in a famous trial which is the 60 milligram b id without aspirin but definitely these data together with them is leave open avenues for research on this specific topic of a psychic

Or sixty milligram vi d without aspirin yeah in fact you know one initial design of feminists had an arm without aspirin that the regulatory agencies insisted that there be concomitant aspirin well congratulations i just want to say i think it’s also tremendous that in this time of epidemic jack has managed to publish both twilight diabetes and twilight complex

Simultaneously and i’ll put a plug in for a very nice accompanying perspective by professor patrick steroid that puts both these trials in perspective into larger clinical context thank you deepak i’m gonna give mike i know we’re tight on time but perhaps if i could just ask one last quick question you know it seems by and large the people have become more and more

Accustomed to dropping a spring in the context of triple therapy that perhaps a little bit slower to do so for patients who are just on on dual antiplatelet therapy and for somebody like yourself who spent a lot of time thinking about clopidogrel response variability certainly alluded to this a little bit in your presentation but would you caution people against

Using clopidogrel as monotherapy if they are going to take a strategy of dropping aspirin absolutely and in particular in patients with diabetes or high-risk patients in general i know we do have some data from our from our asian colleagues that did the study in with patients on clopidogrel but let’s keep in mind that these were lower risk patients compared to

Those enrolled in twilight when we speak about specifically patients with diabetes there’s a clear association with compare response to capita grow in diabetic subjects which is mostly related to impaired metabolism of computer girl we know that the exposure of the active metabolite in patients with diabetes is approximately 30 to 40 percent lower in patients with

Diabetes so definitely if you’re going to go with a mono therapy a strategy aim particularly patients with with diabetes this should not imply the use of clopidogrel right well well thank you again and congratulations today for to all of our presenters and thank you to our panelists you know and certainly we’re thinking of all the healthcare workers right now who

Are the frontlines and i’m sending our thoughts and prayers so thank you again and this will conclude the session

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ACC2020: Brilinta reduserte blødning hos pasienter med alvorlig hjertesykdom By HealthTalk