Faculty Peer Reviewed
The 59th Annual Scientific Sessions of the American College of Cardiology (ACC) took place in Atlanta on March 14-16, 2010. Despite inclement weather in the northeast causing the cancellation of many flights, a large number of NYU faculty, fellows, and others made it to Atlanta to give talks, presentations, or simply attend the conference.
As usual, the Sessions presented us with many important studies from around the world, some of which may change our clinical practice for years to come. While it is obviously impossible to cover even a small portion of the many important works that were presented, I would like to highlight a few “late-breaking trials”.
The first official day of the meetings was referred to by some as “Negative Sunday” because of the many “negative” trials that were presented. As some pointed out, however, a “negative” trial may be very positive for our patients (and their treating physicians) by providing essential information for their care.
Two trials relating to the Action to Control Cardiovascular Risk (ACCORD) trial were presented: the ACCORD lipid and the ACCORD BP  trials.
First, the accord lipid trial investigated the effects of adding fenofibrate to a statin (simvastatin) in all patients with type 2 diabetes at “high risk” for cardiovascular disease with a mean follow-up of 4.7 years. 5,518 diabetics were randomized to statin plus placebo (control group) or statin plus fenofibrate. The study results showed no significant difference in cardiovascular (CV) events—major fatal and nonfatal CV event rates/year were 2.2 in fenofibrate group and 2.4 in control group (p=NS). In a subgroup analysis, a trend toward benefit of fenofibrate was shown in the group of diabetics that had a significant dyslipidemia (low HDL and high triglycerides). Additional subgroup analysis showed a trend toward harm in women (but not men) in the fenofibrate group.
Comment: This trial, while providing very important information, will likely not change current clinical practice as fibrates are generally not used routinely in this population. Given the results from the subgroup analysis in those with elevated triglycerides and low HDL, addition of fibrates in this group of diabetics is reasonable (which is often done currently in clinical practice). The trend toward harm in women is of obvious concern, and should be investigated in future studies.
The second ACCORD trial was the ACCORD blood pressure (BP) trial. This was the first of 2 trials presented on Sunday regarding BP control in diabetics.
This trial randomized 4,733 type 2 diabetics to “intensive” (goal systolic BP <120 mmHg) vs. “standard” (goal systolic BP <140mmHg) BP control arms. Surprising to many, there was no benefit of intensive BP control over standard control regarding the primary endpoint of major fatal and nonfatal cardiovascular (CV) events. There was a reduction in strokes in the intensive control arm, however since the incidence of stroke was very low (less than 0.5% per year), the number needed to treat to prevent one stroke would be 89 patients over 5 years. In addition, the intensive group suffered significantly more adverse effects related to anti-hypertensive treatment than the standard group (3.3% vs. 1.3%).
The second trial presented on Sunday was a retrospective analysis of the INVEST trial  which originally investigated the effects of a calcium channel blocker versus beta-blocker (in addition to other BP meds) in 6,400 diabetics with coronary disease, with a goal BP of 130/85. It is important to point out that INVEST did not randomize patients into BP control “strategy” arms, so this analysis was done by dividing the patients into groups based on what BP was achieved with treatment (retrospectively). In this analysis, the investigators found that those patients with uncontrolled BP (>140mmHg) suffered the most cardiovascular events, however those in the “usual” control group (130-140mmHg) did not suffer any more events than those in the “tight” (<130mmHg) control group. And, in fact, there was an increased risk for mortality in the tight group compared to the usual control group, which on further analysis appears to be only significant in those achieving BP of <115mgHg.
Comment: These trials provide extremely valuable clinical information and may impact clinical practice for many physicians. The data suggest that BP control in diabetics is extremely important to a level below 140mmHg. However, a goal lower than 120mmHg may not carry significant benefit and may even cause harm in high risk diabetics. Given the difficulty in clinical practice of pushing BP below 120mmHg and the growing problem of polypharmacy, this is welcome news for physicians and patients alike. Still, some may argue that the stroke benefit in ACCORD was significant and that certain subgroups of diabetics might benefit from tighter control as opposed to a strategy for all diabetics, however further analysis of these trials and others will be necessary to confirm these hypotheses.
Another trial presented on Sunday was the Everest II trial  which randomized 279 patients with severe mitral valve regurgitation to either surgery (repair or replacement) or percutaneous repair using the “MitraClip”. Investigators found that the 30 day adverse event rate was significantly lower in the percutaneous group, although the majority of this reduction was related to blood transfusions, which some argue should not be considered a major event. Clinical success, defined as freedom from mitral surgery/reoperation and mitral regurgitation less than or equal to 2+ at 12 months, was 72% in the percutaneous group and 88% in the surgery group (p = 0.0012).
Comment: The results from this trial are very encouraging regarding the potential use of percutaneous valve repair, but they must be interpreted with caution. This study does show that this new percutaneous technique is safe and relatively effective out to 1 year. This is a very short follow-up time, however, and extrapolating this technique over a longer term is not warranted from these data, especially given the fairly high number of patients with residual mitral regurgitation after this procedure. One of the most important pieces of information that we will need to examine in the future will be whether mitral valve repair (as opposed to replacement) will still be feasible if the MitraClip device fails. With a short term failure, we know repair is usually possible, however after the clip has been in place for 1 or more years the effect of scar tissue, etc. on valve repair is unknown. Nonetheless, with this safety and efficacy data, this study gives us a new treatment option for severe mitral regurgitation, which may become especially important in those who would otherwise not be candidates for surgical repair. FDA approval for this device is pending.
Another late-breaking trial presentation set out to answer a very important and controversial question in the cardiology community: how long to continue clopidogrel after the implantation of a drug-eluting stent (DES). This study combined 2 Korean trials (REAL-LATE and ZEST-LATE)  in which all patients received both aspirin and clopidogrel following implantation of a DES for 12 months. After 12 months, patients were then randomized to either continue this dual anti-platelet regimen or continue aspirin alone without clopidogrel. After a 19.2 month median follow up, the investigators found no significant difference in the two groups relating to the primary endpoint of nonfatal MI or cardiac death (1.8% in dual drug group vs. 1.2% in aspirin alone group, p=NS).
Comment: This study is very important, but does suffer several limitations. In addition to methodological concerns of combining 2 trials, the event rate was markedly lower than expected, thus reducing the power of the study results. Another limitation was the fact that some patients were randomized after 18 months of dual anti-platelet therapy instead of 12. And finally, the duration of follow up was relatively short. Despite all of these shortcomings, this trial provides evidence that continued dual antiplatelet therapy beyond 1 year in patients with DES may not be warranted (although this is still frequently done in clinical practice). Fortunately, larger trials looking at this question are underway currently and should help to clarify the evidence presented here.
The last trial I will mention is the RACE-2 trial . This trial randomly assigned 614 patients with permanent atrial fibrillation (AF) to 2 different rate control strategies: the “strict” control group (resting heart rate [HR] < 80 bpm and <110 bpm on limited exercise) and the “lenient” control group (resting HR <110 bpm). The primary outcome was a composite of cardiovascular death, stroke, hospitalization for heart failure, systemic embolic event, pacemaker/ICD implantation, life-threatening arrhythmic event, bleeding and adverse events of rate-control drugs. The results demonstrated no significant difference in the primary endpoint between the two treatment groups after 3 years follow-up, with 12.9% vs. 14.9% in the lenient vs strict group, respectively. Health care provider visits were much higher in the strict group (684 vs 75 visits).
Comment: Given the difficulty in achieving strict HR control, these results are again good news for both patients with atrial fibrillation and their providers. While the results may be surprising to some, it is important to point out that post-hoc analysis from previous trials (AFFIRM and RACE) suggested this lack of benefit to stricter HR control in atrial fibrillation. As with all of these trials, however, it is important to keep in mind that care must be individualized and those that remain symptomatic or are at higher risk of heart failure may indeed require tighter rate control. Further analysis and details of this data including quality of life measures will be very important in fine tuning any conclusions from this study.
Final thoughts: Several of the above presentations, while “negative” are actually extremely important for the treatment of our patients. They remind us that, while aggressive patient management is essential to preventing serious clinical events, there is a point at which we reach diminishing returns and may even cause harm with overtreatment. One reason for this almost certainly involves polypharmacy, which is becoming an increasingly important point of concern for all of our patients, especially the elderly and those with multiple co-morbidities. It should also be pointed out that treating (or overtreating) patients with a “one-size-fits-all” approach may not be appropriate and may explain the lack of benefit seen in some of the above presentations. Determining the subset of patients, if any, that might benefit from more intensive control (e.g. of BP, HR, glucose, etc.) will be the goal of future clinical research.
Dr. Donnino is a Section Editor, Cardiology, Clinical Correlations
Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations
Image of blood pressure exam courtesy of Wikimedia Commons.
 ACCORD study group. Effects of combination lipid therapy in type 2 diabetes mellitus. NEJM 2010 (published online http://www.nejm.org/)
 ACCORD study group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. NEJM 2010 (published online www.nejm.org)
 Presented by Rhonda Cooper-DeHoff at the ACC.10/i2 Summit, Atlanta, GA, March 2010
 Presented by Dr. Ted Feldman at the ACC.10/i2 Summit, Atlanta, GA, March 2010
 Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. NEJM 2010 (published online http://www.nejm.org/)
 Van Gelder CI, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. NEJM 2010 (published online http://www.nejm.org/)