CardioSource WorldNews Editor-in-Chief Chris Cannon, MD, speaking in the Late Breaking Clinical Trials session at ACC.04, talks about lipid-lowering therapy with statins in patients who had recently experienced acute coronary syndromes. The results he discussed were from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, a study for which he served as principal investigator.
And gentlemen mr. chairman it’s a privilege to follow first lady mrs. bush in talking about an important way of improving the health of women and men by treating cholesterol now we know from multiple trials over the past decade that lipid-lowering therapy with statins is highly effective at versus placebo in the long term management of a wide variety of patients with
Coronary heart disease but two questions have remained first our statins effective in reducing cardiac events when started early after an acute coronary syndrome and second among people receiving active statin therapy does intensive lowering of ldl cholesterol to a level of about 65 confer added reduction in benefit and clinical risk when compared with the current
Standard of getting ldl below a hundred and so we addressed this in the previous emmy 22 trial where we randomized 4162 patients who had been hospitalized for an acute coronary syndrome within the last ten days all patients received aspirin and standard medical and interventional therapy for their acute coronary syndrome and in a double-blind fashion were randomized
To two different levels of lipid lowering the standard therapy matching the guidelines we used pravastatin 40 milligrams and the intensive therapy we used a 12 a statin 80 milligrams to get the lowest possible level in ldl cholesterol in a 2×2 factorial design we also studied an antibiotic as compared with placebo the results of which are not yet complete and i
Will not cover today the duration of treatment and follow-up on average was two years and was such in the trial that we collected at least 925 events before performing the follow-up visits in all patients and we ended up with 1001 events in this trial the primary endpoint was a five-part composite including all cause mortality myocardial infarction unstable angina
With documented evidence of ischemia that required rehospitalization revascularisation performed at least 30 days after the initial index event and stroke the details of the patient population illustrated here patients had to be hospitalized for an acute mi or unstable engine with other high-risk features within the last 10 days they had to have a total cholesterol
Of less than 240 or if they were receiving lipid-lowering therapy a total cholesterol of less than 200 measured within the first 24 hours of their hospital admission they also were involved after being stabilized that is they were without ischemia heart failure and we’re following a percutaneous coronary intervention if performed major exclusion criteria included
Other major comorbidity therapy with high dose statin at baseline deed or anticipated need for fibrates or niacin and thus this trial looked at patients only being treated with statins if patients were going to be managed with coronary artery bypass surgery for the treatment of their initial index event they were excluded liver disease and unexplained creatine
Kinase elevations for an exclusion and patients who were taking strong inhibitors of the cytochrome p450 enzyme 3a4 were excluded because that is the way that a torva statin is metabolized the 4162 patients were enrolled at 349 centers worldwide in the eight countries that are illustrated here and the national investigators for each of the countries is listed as
Shown the top ten enrolling centers of the more than 800 investigators and research coordinators illustrated here and this is the the results of this trial are the result of their hard work over the last three and a half years the study was conducted under the chairmanship of my mentor dr. eugene brown wald and under the direction of carolyn mccabe and the timmy
Study group data coordination was carried out by the nottingham clinical research center under the direction of dr. alan skiing the sponsors of this trial were both bristol-myers squibb and sankyo and the clinical events committee was chaired by dr. mark pfeffer the baseline characteristics of the patients are illustrated here the mean age was 58 and we had about a
Quarter of the patients were women about 20% had diabetes and of the type of acute coronary syndrome it was evenly divided with one third of the patients having st segment elevation mi 1/3 with non-st elevation y and 1/3 with unstable angina and a quarter of the patients were receiving statin therapy at the time of their index event that then was switched to study
Therapy these patients also were managed with an early invasive strategies such that 69% of the population had undergone percutaneous coronary intervention prior to randomization in response to their initial acute coronary syndrome and then during the treatment of the trial the patients received one or sometimes two antithrombotic agents with aspirin warfarin and/or
Clopidogrel during the follow-up period 85% of patients retreated with beta-blockers and 83% of patients were treated with ace inhibitors or angiotensin receptor blockers and thus these patients received optimal medical and interventional therapy in the two randomized arms we sought out to see two different levels of cholesterol lowering and illustrated here are
The changes in the ldl cholesterol from baseline and so beginning here measured within the first 24 hours is the ldl cholesterol of 116 that then fell as has been seen in all patients with acute coronary syndromes to 106 at baseline at the time of randomization with standard therapy this was reduced by 21% and achieved a median ldl of 95 thus matching the goal of
Being less than 100 according to our current national guidelines in the intensive lipid-lowering therapy this was reduced by 49% and achieved a median ldl of 62 with the interquartile range ranging from 50 to 80 and so the question has been in patients getting active therapy that meechum meets our current guidelines is it important to lower the cholesterol even
Further so the answer is yes we saw that compared with gold standard treatment with a validated level of lipid lowering that more intensive lipid lowering with a tour of statin 80 milligrams was associated with a 16% reduction in the risk of all-cause mortality or major cardiovascular events this was a highly significant difference with a p-value of zero point
Zero zero five now the benefit that was observed with more intensive lowering of the lipids was seen very early so that at just 30 days the risk reduction the hazard during follow-up to that point was already 17% lower and this was consistently seen over the entire follow-up period that there was an early and ongoing benefit of more intensive lipid-lowering therapy
Now another harder endpoint of a three-part endpoint of death my or the need for urgent revascularisation is illustrated here this too was significantly reduced by 25% with the more intensive therapy a p-value of 0.0004 other individual components of the endpoint er illustrated here all cause mortality was reduced over the treatment period during follow-up by 28%
This p-value was zero point zero seven and thus of borderline statistical significance the rates of mortality at two years were 3.2 percent as compared with 2.2 percent in the standard treatment arm coronary heart disease death myocardial infarction the combination of death or mi the need for revascularization and rehospitalization for unstable angina were all
Reduced in a similar fashion between 15 and 30 percent for the endpoint of stroke we did not see a difference between standard statin therapy as compared with more intensive statin therapy but there were fortunately very few events and patients who had stroke unless the confidence intervals are wide here is the primary endpoint illustrated in major subgroups
And i want to highlight here with the importance of treating heart disease in women the 22% of this group who had who were women they had a significant reduction with more intensive lowering of lipid luring with event rates of two years going from 27 percent down to just over 20 percent so a seven women out of every hundred treated with more intensive therapy
After going home from the hospital for an acute coronary syndrome had fewer events similarly patients with diabetes or no diabetes elderly or younger patients and those with different levels of high-density lipoprotein cholesterol all had a similar reduction that was not different in the subgroups analyzed the one subgroup of the 19 that we examined that did
Show a greater benefit was a patients with an ldl cholesterol of over 125 where it was a 34% risk reduction in the hazard over the period of time and a lesser benefit in those with a lower cholesterol on the safety profile of these two strategies we did observe that there were more patients who had elevations of liver enzymes with the more intensive therapy 3.3%
As compared with 1.1 percent for patients treated with pravastatin 40 milligrams a significant difference on the other hand elevations in creatine kinase or discontinuation of study medication for myalgias or elevations in creatine kinase were similar between the two treatment groups and so to summarize we studied patients who had recently been hospitalized for an
Acute coronary syndrome and we saw that intensive lipid lowering with ido statins to a median ld of 62 significantly reduced the risk of all-cause mortality or major cardiac events by 16 percent as compared with the current standard dos lipid-lowering therapy that did achieve a median ldl below our current guideline recommendations a highly significant difference
These benefits emerged within 30 days after the acute coronary syndrome and continued over the two and a half year period with a constant 16% relative benefit favoring more intensive therapy and these were consistent across all of the cardiovascular endpoints with the exception of stroke and in most of the clinical subgroups and highlighting today as well in women
And so as published now this morning in the new england journal of medicine we conclude that our findings indicate that patients recently hospitalized for an acute coronary syndrome benefit from early and continued lowering of ldl cholesterol two levels substantially below current target levels and i think more broadly for all patients with cardiovascular disease
The results of timmy 22 emphasize the central role of lowering ldl cholesterol for the treatment and prevention of mortality and morbidity from heart disease thank you very much for your attention thank you dr. cannon you didn’t disclose any conflict of interest shall we assume that we have no consequent rest in presenting these data and please put up my first slide
I did risk all of my conflicts of interest on the first slide as usually requested thank you we have time for one question from the floor is there is no question i’ve got one for you you showed very clearly that in the patient in patients raised initial ldl cholesterol below a hundred and twenty-five there is apparently no significant difference in the outcome as
Compared to patient with more than 150 a 25 ldl cholesterol is a bit and discrepancy with also previous reports in different settings like ahps city for example where there is a consistent with a risk prediction for the long term outcome whatever the initial blood cholesterol and ldl cholesterol could you comment in this case this is a very good observation i think
We have seen in the heart protection study that in patients at risk for heart disease treatment will the standard dose of a statin lowers the risk substantially we use that as the baseline therapy and we sought to ask the question if you go even further down in the ldl cholesterol is that of benefit and so in the lowest group of patients with the low cholesterol the
Achieved cholesterol was actually 87 in patients receiving standard therapy and when that was taken down to 50 there didn’t appear to be a big difference in that subgroup of patients however taken together the studies again reaffirmed the importance of from other trials establishing that statin therapy reduces the risk of all cardiac endpoints relative to placebo
And we see today across a wide variety of subgroups of patients that further lowering the ldl cholesterol can lead to added benefit thank you very much for attention we have got one question there for just one question please since their chairman permits a question professor cleveland kingston hall uk over here i was astonished to see a two-year mortality down
At two to three percent for these high-risk unstable angina post mi which leads to the question of how representative this patient population is to patients having mi it was a relatively young population it seems a very low-risk population to begin with well this is a very good point i should emphasize that we enrolled patients at the time of hospital discharge
So during hospitalization the mortality tends to be about four or five percent in the patients with acute coronary syndromes and other cardiac events also as well we enrolled patients and thus the start of the event rates is at the time of hospital discharge now these patients were also very intensively treated both with interventional or therapy and every single
Secondary preventive medication at very high levels and thus we feel that this offers an insight into the optimally managed patient we see the added benefit of the further lowering of ldl cholesterol in these high-risk patients but again this begins following hospital discharge and is exactly what we had estimated from all of our prior trials in terms of the event
Rates and so it’s different from other trials that enroll at the time of admission this is begun therapy at the time of hospital discharge so i think this tells us as cardiologists that when we have patients going home after an acute coronary syndrome that we need to use early and intensive lipid therapy to try and prevent even further the rate of mortality and
Cardiac events as compared with standard therapy with statins thank you dr. cranum thank you very much
Transcribed from video
Flashback: Chris Cannon, MD, Presents PROVE IT-TIMI 22 at ACC.04 By CSWNews
