August 26th, 2012
Prasugrel vs. Clopidogrel in ACS: The TRILOGY Take
John Ryan, MD
The results of TRILOGY-ACS were released today simultaneously at the ESC and in the New England Journal of Medicine. In this study, 7243 under the age of 75 with unstable angina or NSTEMI were randomized to 30 months of aspirin plus clopidogrel or aspirin plus prasugrel.
The primary endpoint studied was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The authors found no significant difference in between each group, with the primary endpoint occurring in 13.9% of patients on prasugrel and 16% of the patients on clopidogrel. There was no significant difference in major bleeding events. Click here to see our news story and here to read Harlan Krumolz’s summary and comment in Journal Watch Cardiology.
At CardioExchange, we are fortunate to be joined by lead author Matthew Roe MD MHS to discuss aspects of this study.
RYAN: The primary endpoint in TRILOGY-ACS was reduced by an absolute risk reduction (ARR) of 2.1%. This is a similar ARR as to what was observed in TRITON-TIMI 38, but that study showed a significant improvement in their primary endpoint (same as in TRILOGY-ACS). Can you describe the differences in TRILOGY-ACS such that the results failed to show a difference in between the strategies- even as the absolute difference was 2.1%. Is this due to the difference in power between the two studies?
ROE: Thank you for this question. You are correct. We estimated a higher event rate in TRILOGY ACS compared with what was observed in the TRITON trial given the higher-risk features of the TRILOGY population and the longer duration of follow-up in our study. Importantly, among patients <75 years of age (the primary analysis cohort), we accumulated far more events for the primary endpoint than we had calculated would be necessary for the trial to be adequately powered (761 vs. 688 events). Thus, TRILOGY was not an under-powered study. Additionally, the sample size for the primary cohort in TRILOGY (7,243 patients) is roughly half the size of the overall TRITON population. So, even though we observed the same ARR for the primary endpoint in TRILOGY compared with TRITON, we did not show a significant reduction in the primary endpoint due to the smaller sample size in TRILOGY.
RYAN: How should we interpret this study overall? And should it change practice? You note that there prasugrel starts to have a more pronounced benefit later in the study (beyond 30 months). What do you think this means and do you think that prasugrel should be studied for longer in order to realize it’s full therapeutic benefit?
ROE: The implications of this study for clinical practice will require further deliberation and consideration. TRILOGY ACS is a unique study that evaluated a previously under-studied population, studied the longest duration of dual anti-platelet therapy post-ACS, and is the first study to test individualized dosing of anti-platelet therapy. We believe that patients with ACS who are medically managed without revascularization are fundamentally different than patients who undergo in-hospital revascularization and we showed that they respond differently to intensified anti-platelet therapy compared with the TRITON results. Since patients in TRILOGY were unlikely to undergo post-randomization revascularization procedures, they typically remained medically managed for the duration of the study. As a result, these patients may have delayed benefit from intensified anti-platelet therapy that is not related to the reduction of revascularization-related events, although it is important to recognize that we did not design the study to evaluate this specific question. However, the favorably long-term safety profile of prasugrel compare with clopidogrel suggests that there are no safety concerns in terms of evaluating longer-term treatment in the post-ACS setting.
RYAN: Given the cost difference, are there any groups of patients in whom prasugrel is definitely preferable? In looking at the hazard ratio (Figure 2), there are many pre-specified comparisons, but it appears that prasugrel therapy is very beneficial in smokers with UA/NSTEMI. Based on TRILOGY-ACS, should we be considering prasugrel for this population and what is your opinion for this observation?
ROE: Given that we did not demonstrate a significant reduction in the primary endpoint with prasugrel vs. clopidogrel, sub-group analyses should only be considered to be hypothesis-generating and not definitive. Nonetheless, we plan further analyses of many of the presented sub-groups, including current/recent smokers, and we will be presenting results of an embedded platelet function sub-study from TRILOGY-ACS at the AHA 2012 Sessions in November, 2012 and these data will be helpful for evaluating the impact of prasugrel within certain sub-groups.
August 26th, 2012
First Detailed Look At Why Aliskiren Failed To Gain ALTITUDE
Larry Husten, PHD
Last December the once-promising direct renin inhibitor aliskiren (Rasilez, Tekturna) suffered a fatal setback with the early termination of the ALTITUDE trial. The trial was stopped when the Data Monitoring Committee (DMC) found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after 18-24 months.
At the ESC in Munich ALTITUDE investigator Hans-Henrik Parving presented the first detailed but preliminary results from the trial, which compared aliskiren to placebo in 8,561 type 2 diabetics at high risk for cardiovascular and renal complications already receiving single RAAS blockade.
After 32 months of followup, there was no significant difference between the two groups in the composite endpoint: CV death, resuscitated death, MI, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease, or doubling of baseline creatinine. However, Parving noted that the numbers went in the wrong direction for aliskiren, including a trend suggesting more strokes associated with the treatment drug:
- Composite endpoint: 17.9% for aliskiren vs. 16.8% for placebo (HR, 1.08; 95% CI, 0.98-1.20; P=0.142)
- Stroke: 3.4% for aliskiren vs. 2.8% for placebo (HR 1.25; 95% CI, 0.98-1.60; P=0.70)
Aliskiren-treated patients also had higher potassium levels and were more likely to develop hyperkalemia, hypotension, and diarrhea.
August 26th, 2012
TRILOGY at ESC: No Advantage for Prasugrel Over Clopidogrel in Medical ACS Patients
Larry Husten, PHD
The newer antiplatelet agent prasugrel was no better than the old standby clopidogrel for treating patients with acute coronary syndrome (ACS) who are not undergoing revascularization. The results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial were presented by Matt Roe at the European Society of Cardiology meeting in Munich and published simultaneously in the New England Journal of Medicine.
In the primary analysis of the trial, prasugrel (10 mg daily) was compared with clopidogrel (75 mg daily) in 7243 ACS patients younger than age 75. At 17 months, the rate of CV death, MI, or stroke did not differ significantly between the two groups:
- 13.9% in the prasugrel group versus 16.0% in the clopidogrel group (hazard ratio [HR] for prasugrel, 0.91; 95% CI, 0.79-1.05, P=0.21)
The results were similar in a secondary analysis, which also included 2083 patients who were age 75 or older and who received either low-dose prasugrel (5 mg daily) or the standard clopidogrel dose.
In a separate prespecified analysis, prausgrel patients under age 75 had a decreased risk for multiple recurrent ischemic events (HR, o.85; 95% CI, 0.72-1.00, P=0.04). According to the TRILOGY investigators, this finding is consistent with results from the earlier TRITON trial. TRITON compared prasugrel with clopidogrel in ACS patients undergoing revascularization; recurrent ischemic events in the prasugrel group were reduced by 30%, with most of the reduction occurring later in the trial. “Although this observation is exploratory,” the TRILOGY investigators wrote, ” it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional” in previous studies.
The prasugrel and clopidogrel groups did not differ significantly in the rate of severe and intracranial bleeding. However, within the younger subgroup (taking the higher prasugrel dose), prasugrel recipients had more major and minor bleeding complications than clopidogrel recipients did — a reflection, the authors wrote, of “the more intense platelet inhibition with prasugrel.”
The prasugrel and clopidogrel groups did not differ significantly in the rate of severe and intracranial bleeding. However, within the younger subgroup (taking the higher prasugrel dose), prasugrel recipients had more major and minor bleeding complications than clopidogrel recipients did — a reflection, the authors wrote, of “the more intense platelet inhibition with prasugrel.”
An exploratory analysis found that in the main group of patients under the age of 75, the Kaplan-Meier curves for the primary endpoint and for the individual components of the endpoint were not different for the first year but diverged afterward in favor of prasugrel. “The reasons for this finding remain uncertain,” the investigators wrote.
A subgroup analysis suggested the possibility that prasugrel might be more effective than clopidogrel in current or recent smokers, in patients who underwent angiography prior to randomization, and in patients taking a proton-pump inhibitor.
[ADDITIONAL COVERAGE: See Harlan Krumholz’s take on TRILOGY in Journal Watch Cardiology]
August 25th, 2012
New Universal Definition of MI Unveiled at ESC 2012
Larry Husten, PHD
A new universal definition of myocardial infarction (MI) was unveiled today at the European Society of Cardiology meeting in Munich. The document was developed jointly by the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the World Heart Federation (WHF). It will be published in five journals: the European Heart Journal, the Journal of the American College of Cardiology, Circulation, Global Heart, and Nature Reviews Cardiology. (The document was scheduled to go online on Sunday but is now available, along with extensive support material, on the American Heart Association website.)
The third universal definition of MI establishes the troponin levels required to make a diagnosis of MI in various situations. In a press release, Kristian Thygesen, the co-chair of the document task force, discussed the difficulties the task force encountered in reaching a consensus. Setting a troponin level for procedure-related MIs is difficult “because interventional cardiologists and surgeons do not want myocardial infarction as a complication,” he said. “It means that they want to set the levels of troponin as high as possible. It was also difficult to reach a consensus because it’s impossible to conduct a clinical trial to find the answer.”
The task force also expects the new definition will be adopted by the FDA and will be used in clinical trial protocols accepted by the FDA. Said Thygesen, “This is significant because it will help to standardize the way myocardial infarction is defined in clinical trials, making comparisons between trials more meaningful. Steering committees that write protocols for clinical trials do follow FDA requirements.”
Here is a summary of the new definition from an FAQ published by the AHA:
The preferred biomarker overall and for each specific category of MI is cardiac troponin (cTn) (I or T), which has high myocardial tissue specificity as well as high clinical sensitivity. An increased cTn concentration is defined as a value exceeding the 99th percentile of a normal reference population (upper reference limit, URL).
Myocardial infarction is determined by the specified cTn value, and at least one of the five following diagnostic criteria:
- Symptoms of ischemia
- New (or presumably new) significant ST/T-wave changes or LBBB
- Development of pathological Q waves on ECG
- Imaging evidence of new loss of viable myocardium or regional wall-motion abnormality
- Identification of intracoronary thrombus by angiography or autopsy
August 24th, 2012
Is Bad News About Fibrates Getting Buried?
Harlan M. Krumholz, MD, SM
This week JAMA published a meta-analysis on lipid-modifying therapies and the risk for pancreatitis. It was conducted by an honor roll of investigators, including LaRosa, Pedersen, Ridker, Kjekshus, McMurray, and others. The conclusion of the abstract says, “In a pooled analysis of randomized trial data, use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels.”
A casual reader might miss something even more interesting. The authors also looked at the much-maligned fibrates. You know, the drugs that many people touted to prevent pancreatitis in patients with elevated triglyceride levels. Well, the curious thing is that in the pooled analysis of the fibrate trials, these drugs were associated with a borderline significant 39% increase in the risk of pancreatitis (risk ratio, 1.39; 95% CI, 1.00–1.95) — a concerning finding, even if merely hypothesis-generating. Compare that with the 23% reduction in risk with statin therapy (RR, 0.77; 95% CI, 0.62–0.97).
The discussion notes that “no convincing trial data exist to support use of any agents for prevention of pancreatitis in this situation” (moderate elevation in triglyceride levels). The authors also acknowledge, appropriately, that their results should indeed be considered hypothesis-generating.
I agree this analysis has limitations, but what evidence we do have suggests, at least, that fibrates may be associated with a higher — not a lower — risk for pancreatitis. Fibrates, with about $2 billion dollars in sales annually, have yet to be shown in a trial to reduce risk. The results of the current meta-analysis therefore raise questions about their use.
What’s your view on the use of fibrates? Do you think the fibrate data in this meta-analysis get enough play in the article?
August 24th, 2012
Topol: The Clinical Trial World Is “Contrived”
Harlan M. Krumholz, MD, SM
I was intrigued by an email that touted a piece by Eric Topol. The startling headline: “Get Rid of the Randomized Trial.” Eric is one of the pioneers of the large, simple randomized trial and contributed many landmark studies that have shaped the practice of cardiology. His TAMI studies and GUSTO influenced so many of us who were in training during that era. Every AHA and ACC annual meeting was marked by Eric at the podium describing another important randomized trial that he had led, often with Rob Califf. So you can imagine my surprise. I skip most of these types of emails, but this title and its author compelled me to click through.
What I found was a 5-minute video of Topol making an argument that randomized trials are an anachronism and no longer fit what we need. He describes a trial using crenezumab, to prevent Alzheimer’s disease in high-risk individuals, that depends on surrogate endpoints. He says that these are the trials of the future — restricted to patients at risk and using surrogate markers. I cannot find this trial by searching for crenezumab on clinicaltrials.gov, but I assume from the press release Eric references that it is randomized.
Then he says what we need is surveillance of every patient in a trial — that we should have conditional approval of a new drug or device (without a trial?) and then monitor everyone treated. He goes on to decry the “contrived clinical trial environment” and says we “need to get to the real world.”
Because it is Eric Topol presenting this argument, this piece on Medscape is worth a viewing. It would be a big change to approve first and evaluate later — and to get rid of the randomized trial.
What’s your view of Topol’s proposal?
August 22nd, 2012
NHLBI Announces 7000-Patient Trial to Test Inflammation Hypothesis
Larry Husten, PHD
The National Heart, Lung, and Blood Institute (NHLBI) has announced the launch of a large clinical trial testing the inflammation hypothesis. Paul Ridker is the principal investigator of the trial, which will be known as the Cardiovascular Inflammation Reduction Trial (CIRT).
CIRT will enroll 7,000 patients who are stable following a heart attack but are at high risk for a recurrent event because they have either type 2 diabetes or metabolic syndrome. Trial subjects will be randomized to low-dose methotrexate or placebo. The primary outcome measure is the rate of recurrent major cardiovascular events (MI, stroke, or cardiovascular death). Low-dose methotrexate is now used to treat rheumatoid arthritis.
“If this generic drug, which is already on the market at low cost, proves effective for reducing risk of heart attacks, stroke, or death, it has the potential for broad public health impact in saving lives and reducing disease,” said Ridker, in an NHLBI press release.
The NHLBI said that site selection will begin in November 2012 and that patient recruitment will start in March 2013. Patients will be followed for an average of 2.5 years.
Resources:
- CIRT on the ClinicalTrials.Gov website
- CIRT website (including information for potential sites)
- NHLBI press release
August 21st, 2012
Cardiovascular Risk Prediction: Two More Studies, Little Progress
Larry Husten, PHD
Two studies published in JAMA provide new data — and, perhaps, some additional clarity — about using additional markers to help improve risk prediction for coronary heart disease (CHD) and cardiovascular disease (CVD).
In one study, Joseph Yeboah and colleagues used data from 1330 intermediate-risk participants in the Multi-Ethnic Study of Atherosclerosis (MESA) to analyze the prognostic value of 6 risk markers: coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of CHD.
After a median follow-up of 7.6 years, four risk markers (CAC, ABI, CRP, and family history) were found to be independent risk factors for CHD. CAC provided “the highest improvement in discrimination” over traditional risk scores. “The present study,” wrote the authors, “provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk.” However, “broad recommendations” about CAC should not be made until the associated problems of radiation exposure and incidental findings are addressed, they cautioned.
In the other study, Hester Den Ruijter and colleagues focused on CIMT, performing a meta-analysis in which they analyzed individual patient data from 14 studies and 45,828 patients. They found that adding CIMT provided only a small improvement in net reclassification which, they concluded, was “unlikely to be of clinical importance.”
In an accompanying editorial, J. Michael Gaziano and Peter Wilson write that “although there has been a great deal of work on the improvement in prediction modeling, less work has been done in 2 areas: the cost and risk in the screened population and risk prediction over time.” Using the example of an intermediate-risk patient who is a possible candidate for lipid-lowering therapy, they note that although CAC improves classification “at a single point in time,” most physicians evaluate patients over time and will often repeat tests to track trends over time. In this context, radiation exposure and costs may limit the utility of CAC.
August 21st, 2012
New Questions About Latest-Generation ICD Leads from St. Jude
Edward J. Schloss, MD
A highly anticipated study analyzing failures of St. Jude Durata and Riata ST Optim ICD leads has been published online in Europace by prominent electrophysiologist and ICD critic Dr. Robert Hauser along with associates from the Minneapolis Heart Institute.
Over the past year St. Jude Medical has been beset with bad news about its ICD leads. Until recently, the criticism was confined to the older-generation Riata and Riata ST leads. These leads have been shown to be prone to both structural and electrical failures at an increased rate compared with competitive leads. St. Jude has staunchly defended its newer-generation Durata and Riata ST Optim leads, which have an additional layer of Optim copolymer insulation coating, which St. Jude believes will reduce failures by improving abrasion resistance. Last week, however, the FDA issued a new request for postmarketing studies, including X-ray surveillance of these leads, calling them “sufficiently similar” to Riata and Riata ST to merit increased scrutiny.
Today’s study from Hauser serves as another blow to St. Jude and may affect implanter confidence in current-generation Durata leads. In the study, Hauser queried the FDA MAUDE database for “abrasion analysis” and reported detailed results. He found 15 Riata ST Optim and 37 Durata reports. The predominant abnormality in both groups was external abrasion (i.e., can/lead or lead/lead), although several internal abrasions were also found. Most of these abrasions resulted in clinically relevant electrical abnormalities such as low voltage oversensing leading to inappropriate shocks. One high-voltage failure during a spontaneous ventricular arrhythmia resulted in an ineffective shock and subsequent patient death.
Hauser shied away from making comparisons with other leads in the current study and did not make any attempt to calculate an incidence of lead failure, recognizing the limitations inherent in analysis of a voluntary database. This stands in contrast to his last Riata/Riata ST MAUDE analysis, which provoked a firestorm of criticism including a request for article retraction from St. Jude Medical.
In comments in the New York Times, Hauser expresses a lack of confidence with Durata: “There is no need to use this lead until we have more confidence in its performance.” Hauser goes on to level direct criticism at Optim insulation, stating “I’m afraid that this material is not going to perform as advertised.”
As a practicing cardiac electrophysiologist and ICD implanter who has followed this matter closely, I’d like to add a few comments of my own. It’s important for all to realize that no ICD lead is bulletproof. All will have an incidence of failure including the types of abrasion reported in Hauser’s current study. It is critical to realize that even poor performing ICD lead models in patients with an appropriate implant indication confer lifesaving protection against sudden cardiac arrest that exceeds medical therapy alone.
St Jude has taken an aggressive stance defending the Durata lead, and from a business standpoint, it is not hard to see why. Along with others who have closely followed this situation, I have criticized this lead, given its significant similarity to the Riata ST lead and have chosen not to implant it. Today’s study is a direct blow to the Optim insulation that St. Jude holds is the key to Durata’s relative performance. If Optim proves to have long-term bio-instability, we can expect this lead to behave similarly to Riata ST.
It is naive to think that any insulation, including Optim, will be 100% immune to abrasion. Today’s study reminds us of that fact. Note, though, that it is impossible to make any assumptions about the overall incidence of Durata and Riata ST Optim failures on the basis of this data. For that reason, I agree that it would be inappropriate to replace or extract these leads in the absence of electrical failure.
Because it is unlikely that Optim will worsen ICD lead performance, it should be reasonable to expect these leads to behave like Riata ST in their early life. Failures in these leads tend to accelerate about four years after implantation. As the first implanted Durata leads are only now reaching that stage, the jury on this lead will remain out for some time.
