By Steven Sedlis, MD
The 2010 Scientific Sessions of the American Heart Association were held on November 13-17 in Chicago, IL. Details of all the late breaking trials including presentation slides and commentary are available on the newly redesigned and user friendly meeting web site: http://scientificsessions.americanheart.org/portal/scientificsessions/ss/. The cardiology fellows stayed at the W in the Loop and had a raucous party Monday night hosted by Barry Rosenzweig and Glenn Fishman to which the faculty was invited. There was plenty to celebrate. Two of the fellows received honors and the meetings featured numerous landmark trials, some of which will have an immediate and major impact on practice and some which may lead to revolutionary changes in therapy for cardiovascular disease. The results of all the major trials were announced in advance of the actual presentations—available on Facebook and Twitter and sometimes even published online in the New England Journal of Medicine. This did not seem to decrease attendance at the meeting; on the contrary, the presentations were packed. I found the presentations far more interesting when I had the opportunity to view the results on my Droid prior to the presentation since I was able to focus on the details, the discussion and the implications of the research rather than just wait impatiently for the summary slides. The final attendance figures are not yet available but I am sure that there were far more attendees than the paltry total of 20,946 for the meetings in Orlando in 2009.
Of course, the highlights of the meetings as far as I am concerned were the honors garnered by our fellows. Our very own Binita Shah won an AHA Women in Cardiology Trainee Award for Excellence and our very own Anu Lala was a finalist in the Elizabeth Barrett-Connor Research Award in Epidemiology and Prevention competition. Anu’s presentation of her abstract entitled “Aspirin for the Prevention of Cardiovascular Events in Patients without Clinical Cardiovascular Disease: A Meta-Analysis of Randomized Trials” was attended by a large and enthusiastic NYU cheering section and was very well received by the panel of judges. Anu performed a rigorous meta-analysis of 9 primary prevention trials enrolling a total of 102,621 patients and showed that for every 1,000 healthy individuals treated for 5 years, aspirin would prevent 2.9 major cardiovascular events which was offset by an additional 2.8 major bleeds caused by aspirin. My conclusion is that for healthy folks like me, aspirin should be used exclusively for hangovers.
One of the first late breaking trials presented at the meeting will have an immediate effect on practice and is of particular relevance to medical residents. EMPHASIS HF evaluated the effect of the aldosterone receptor antagonist eplerenone on cardiovascular endpoints in patients with class II heart failure. The study was stopped prematurely by the data safety and monitoring board because of the striking beneficial effects of the intervention. In 2,737 patients with mild to moderate heart failure randomized to eplerenone or placebo, there was a 37% reduction in the primary endpoint (p < 0.00001), a composite of cardiovascular death or heart failure hospital admission and a 24% reduction in all cause mortality in the eplerenone arm. The number needed to treat for one year to prevent one patient from reaching the primary endpoint was 19 and the number needed to treat for one year to prevent one death was 52. Taken together with the results of the landmark RALES and EPHESUS trials, there is now a clear and persuasive mandate to use aldosterone receptor antagonists (spironolactone or eplerenone) in virtually all heart failure patients with systolic dysfunction.
Clinicians will need to make sure that their patients with appropriate indications are provided the benefits of this live-saving, inexpensive (both drugs are now generic) and widely under-used class of drugs. Clearly, care must be taken to avoid hyperkalemia in patients treated with these agents, but the benefits of therapy far out-weigh the risks. The importance of aldosterone receptor blockade was underscored by a number of trials presented at the sessions. For example, the PROTECT trial, a single center unblinded study from the Massachusetts General Hospital, randomly assigned 151 patients with heart failure to either routine care or tailored therapy guided by N terminal-proBNP levels. There were better outcomes in the tailored therapy arm, but what struck me about this trial was not the conclusion concerning the benefits of tailored therapy (it’s hard to draw conclusions from a small unblinded trial) but the fact that the main difference in actual treatment was 62.7% use of aldosterone antagonists in the tailored arm versus 44.7% in the control group (p < 0.01),
Another trial that should have an immediate impact on therapy was RAFT (The Resynchronization/Defibrillation for Ambulatory Heart Failure Trial) which evaluated the benefits of biventricular pacing in a mildly symptomatic patient population similar to that of the EMPHASIS trial. This multicenter randomized double blind trial, funded by the Canadian Institutes of Health Research with additional financial support from industry, randomized 1798 patients with mild heart failure, primary prevention indications for ICD and QRS duration > 120 ms or paced QRS > 200 ms to either ICD alone or ICD plus cardiac resynchronization therapy (CRT). The 5 year heart failure free survival was 57.6% in the CRT group versus 48.7% with ICD alone (p < 0.0002). There was also a 6% difference in all cause mortality at 5 years—14 patients treated for 5 years to prevent one death. Not surprisingly, subgroup analysis showed there was no difference in outcome in patients with QRS < 150.
As pointed out by the discussant, Clyde Yancy, the immediate past president of the AHA, RAFT adds to the growing and compelling evidence from a suite of randomized trials including COMPANION, CARE-HF, MADIT CRT and REVERSE that CRT is effective for heart failure. CRT is an expensive technology and is associated with some risk and some complications, but the benefits are so great that this is a cost-effective treatment. Guidelines will likely change in the near future and CRT will be the standard of care for the majority of patients with mild heart failure, severe systolic dysfunction and markedly prolonged QRS duration. Electrophysiologists are already implanting CRT devices in many patients with relatively mild symptoms and very prolonged QRS duration. Patients with LBBB and patients with LVEF < 20% benefit the most for CRT so there is still work to be done to better define which mildly symptomatic heart failure patients really need CRT and which ones should be spared the risk and cost of an upgrade from an ICD alone to a bi-V ICD.
There were of course a number of negative or inconclusive trials, but some of these will also have an immediate impact on practice. ACT (Acetylcysteine for the Prevention of Contrast-Induced Nephropathy) evaluated the common practice of using Mucomyst to prevent contrast nephropathy. This 48 center Brazilian trial randomized 2,308 patients at risk for contrast nephropathy to N-acetylcysteine 1200 mg orally BID or matching placebo (same odor and taste) before and after cardiac cath. There was absolutely no difference in outcome. The primary endpoint (>25% elevation in serum creatinine 48-96 hours after angiography) and the secondary outcomes including total mortality, cardiovascular mortality, need for dialysis, doubling of serum creatinine and side effects were identical. This trial will have an immediate impact on clinical practice. I can’t say that I mourn the demise of NAC. I never believed that it could be effective for the prevention of contrast nephropathy (the bioavailability of an oral dose is miniscule) and it gave physicians a false sense of security when dealing with patients at risk for this dreaded complication of angiography. Physicians, including medical housestaff, should concentrate on the factors that can make a major impact on the incidence of contrast nephropathy including careful patient selection and most important of all, vigorous hydration before and after angiography.
Another disappointing trial was GRAVITAS (Gauging Responsiveness with a VerifyNow Assay-Impact on Thrombosis and Safety). This trial randomized patients undergoing coronary stenting who had high on treatment platelet reactivity after clopidogrel loading as measured by the Accumetrics VerifyNow assay to either standard dose clopidogrel (75 mg daily) or high dose clopidogrel (repeat loading dose followed by 150 mg daily). The VerifyNow assay is used widely and patients with high on treatment platelet reactivity (PRU = platelet reactivity units > 320) are known to suffer from significantly more thrombotic complications including stent thrombosis than patients without clopidogrel resistance. Clinicians often use BID clopidogrel or switch to prasugrel for patients with PRU > 230, but the efficacy of this strategy had never been tested. For GRAVITAS, 5,429 patients were screened and 41% were found to have high residual platelet reactivity and were randomized. High dose clopidogrel had a significant effect on pharmacodynamics at 30 days and 6 month, PRU > 230 was seen in only 41% of patients treated with 150 mg versus 61% treated with 75 mg (p<0.001), but this did not translate into any clinical benefit. The primary endpoint of cardiovascular death, MI or stent thrombosis occurred in 2.3% of both groups. As expected, the event rate was lower in patients with baseline PRU < 230 who were not randomized, but were followed as part of a secondary analysis. An effective strategy to lower cardiac events without an increase in bleeding in patients with on treatment PRU > 230 is needed and is being actively investigated.
An eagerly awaited and ultimately disappointing trial was ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial).Nesiritide, a recombinant B-type natriuretic, was widely touted as a miracle drug when it was first released in 2001 and then vilified as a dangerous agent that caused kidney damage and death based on two meta-analyses published in 2005. None of these conclusions was justified by adequately powered studies. To settle the issue, the manufacturer sponsored a definitive trial that randomized 7,141 patients with acute heart failure to intravenous nesiritide or placebo. The drug was shown to be safe, there was no difference in survival or kidney function at 30 days, but there was very little benefit observed. There was a modest reduction in dyspnea but not at the pre-specified time points of 6 and 24 hours and there was no effect on readmission for heart failure. It does not appear that this drug will be a major part of our armamentarium for heart failure in the future.
A disappointing trial in the field of structural heart disease was CLOSURE I: A Prospective, Multicenter, Randomized Controlled Trial to Evaluate the Safety and Efficacy of the STARFlex® Septal Closure System Versus Best Medical Therapy in Patients with a Stroke or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale. This trial randomized 910 patients between the ages of 18 and 60 with history of cryptogenic stroke to PFO closure versus medical therapy. The primary endpoint of death or recurrent stroke occurred in 5.9% of patients treated with the device versus 7.7% for medical therapy (p = 0.30). The non-significant trend in favor of the device was driven mainly by TIA and not stroke. There were 13 recurrent strokes in the medical arm and 12 recurrent strokes in the device arm. Importantly, in 80% of patients in the study with recurrent stroke, a cause other than PFO could be implicated (atrial fibrillation, vasculitis etc.)
The final day of the meeting featured novel therapies which may have a profound impact on the practice of medicine in the future. The preliminary results of the DEFINE trial: Determining the Efficacy and Tolerability of CETP Inhibition with AnacEtrapib was published in the New England Journal of Medicine on the morning of the presentation. CETP (cholesterol ester transfer protein) inhibition elevates plasma HDL and lowers plasma LDL and so should have a beneficial effect on cardiovascular endpoints. Previous studies of the CETP inhibitor torcetrapib however actually showed worse outcomes with treatment as compared to placebo. This has been ascribed to off-target effects on the adrenals with elevation in aldosterone levels leading to hypertension. Anacetrapib is a more potent and specific CEPT inhibitor than torcetrapib and has no measurable effects on the adrenals. DEFINE was a safety trial that enrolled 1623 patients with coronary artery disease or at high risk for coronary artery disease and all treated with statins. Patients were randomized to 100 mg daily of Anacetrapib or placebo. There was no effect on blood pressure, plasma aldosterone or any other safety parameters, but the effect on plasma lipids was nothing short of astounding. Mean LDL in the treated patients fell from 89 mg/dL at baseline to 41 mg/dL at 24 weeks and mean HDL rose from 40 mg/dL to 101 mg/dL! Furthermore, in-vitro HDL functional assays of HDL particles isolated from anacetrapib treated patients have been shown to have preserved (and possibly enhanced) cholesterol efflux properties. Such optimal lipid profiles should translate into enormous clinical benefits—it may not be too farfetched to dream that the end of the atherosclerosis epidemic is in sight, but of course we will need to wait for the results of trials with clinical endpoints before coming to any firm conclusions. Such a trial is on the way. The DEFINE presentation closed with an announcement of a definitive 30,000 patient trial run jointly by the Oxford and Harvard groups entitled REVEAL Heart Protection study III/TIMI 55. Stay tuned—we should have the answer in about 5 years.
The final study presented at the late breaking trials suggests that there soon may be a powerful new therapy (perhaps even a cure) for hypertension. The Symplicity HTN-2 Trial of renal sympathetic denervation in patients with treatment-resistant hypertension was published online in Lancet simultaneous with presentation. It has long been known that there is activation of the renal sympathetic nerves in patients with hypertension, especially in younger patients with “essential hypertension.” Furthermore, renal denervation prevents or delays the development of hypertension in many experimental models. Surgical approaches were tried in the past, but abandoned when newer and more effective drugs became available. Since the renal sympathetic nerves course in the adventitia of the renal arteries, it is theoretically possible to ablate them with radiofrequency energy. A catheter based system very similar to that used for electrophysiologic procedures and that can be delivered through a standard 6F sheath was recently developed and the first in man results were reported last year in Lancet. Symplicity HTN-2, the first randomized trial of this new technology, enrolled 190 patients in Australia and Europe with systolic blood pressure > 160 (or in diabetics > 150) on > 3 drugs and randomized 106 of them to ablation versus control. At 6 month systolic blood pressure as measured in the office was 33 mmHg lower in the treated patients than in control and diastolic blood pressure was 12 mmHg diastolic lower in the treated patients than in control (p < 0.0001). The device has now been approved in Europe and a large pivotal trial including patients from the United States is in the planning stages.
In summary, the AHA meeting is still very much alive, even in the age of the blog. There is much to be gained from face to face discussion and there is a special energy associated with presentations before large groups. This AHA meeting will lead to changes in the practice of medicine. Some old ideas such as the usefulness of aspirin for primary prevention of ischemic events and NAC for prevention of contrast nephropathy have been debunked and some old ideas such as the importance of aldosterone and renal sympathetic tone in the pathogenesis of hypertension and heart failure have gained new clinical relevance. Some new ideas such as the utility of platelet function testing and the benefit of PFO closure have been brought into question and other new ideas such as CEPT inhibition seem poised to deliver therapeutic breakthroughs. I am already very much looking forward to the next meeting.
Dr. Sedlis is Associate Professor of Medicine, and Chief, Division of Cardiology Manhattan Veterans Administration Medical Center