Commentary by Steven Sedlis, MD Associate Professor of Medicine, Chief, Division of Cardiology Manhattan Veterans Administration Medical Center
The annual scientific session of the American Heart Association was held in New Orleans on November 8-12 2008, the second major cardiology meeting in New Orleans since Katrina. The city has obviously not recovered. The crowds on the streets are sparser and the lines at restaurants considerably shorter than they were before the hurricane. Charity Hospital is closed and a large sign for LSU Interim Hospital is a stark reminder that the health care system is also nowhere near back to normal.
It was hard to feel gloomy however under the blue skies with the temperature in the 70s. The cardiology fellows certainly enjoyed themselves a great deal. The fellows stayed at the JW Marriott on Canal Street, halfway between the convention center and the heart of Bourbon Street. Either way, they were at the heart. I can attest to that, having seen them at the meetings and having heard about all the fine dinners they enjoyed in the French Quarter. This posting will include accounts of the studies that the cardiology fellows thought were particularly interesting or important.
The big news from AHA was the JUPITER trial presented as a late breaking trial on Sunday and simultaneously published online in the New England Journal of Medicine. Eldad Einav presented the trial to our cardiology division and Tatyana Danilov presented the paper at journal club . JUPITER, a randomized trial of rosuvastatin in the prevention of cardiovascular events among 17,802 apparently healthy men and women with elevated levels of C – reactive protein (hsCRP) was an investigator initiated trial funded by Astra- Zeneca that compared outcomes in men over the age of 50 and women over the age of 60 with LDL cholesterol levels < 130 and hsCRP > 2 mg/dl randomized to rosuvastatin 20 mg or placebo. The study was stopped prematurely by the data safety monitoring board after a mean follow-up of less than 2 years because the pre-specified endpoint of first major cardiovascular event or death from any cause was met. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval 0.46 to 0.69; P<0.00001). As Paul Ridker, the principal investigator, pointed out in his late breaking trial presentation these data suggest that the number of patients needed to treat with rosuvastatin for 5 years to prevent one event is as low as 25.
JUPITER has sparked considerable controversy. Many have pointed out that Paul Ridker and Harvard hold a patent for the hsCRP assay. Does this financial incentive bias Ridker’s interpretation of the data? Others have pointed out that by stopping the trial early the data safety monitoring board may have overestimated the degree of benefit. On the other hand, many others (particularly in the field of prevention) say they would have prescribed statins to patients such as the ones enrolled in JUPITER irrespective of the hsCRP. So will JUPITER change practice? Will it change yours? A not particularly scientific survey of nearly 2500 physicians who responded to a poll in the New England Journal of Medicine indicated that the medical community is split nearly down the middle with 50% of respondents saying that the trial indicates that the approach to laboratory screening should be changed. Another 48% of voters responding to a second question thought that the trial provides a basis for a change in the therapeutic use of stains.
My own view is that JUPITER is an important study because it shows that 20 mg of rosuvastatin is a well tolerated and safe dose of a potent statin that will benefit many individuals at risk for atherothrombosis. There was no difference in the side effect profile of rosuvastatin and placebo except for a slight difference in glycemic control favoring placebo. My own bias is that difference is not clinically significant, but obviously some will differ. The importance of statin dose was underscored by a negative study presented at the AHA. The SEARCH trial randomized 12,000 patients with prior myocardial infarction to either 20 mg or 80 mg of simvastatin and found a non significant 6% reduction in vascular events with the higher dose at the cost of significantly more cases of myopathy (53 versus 3). In my view this was a predictable, but instructive finding. The Heart Protection Study showed that 40 mg of simvastatin was a safe and effective dose so I am sure that many patients in SEARCH randomized to the low dose ended up on 40 mg when they or their physicians noted suboptimal control of LDL. On the other hand, 80 mg of simvastatin is not a well tolerated dose and is associated with significant side effects. What this means to practitioners is that for most patients 40 mg of generic simvastatin is cost-effective treatment with 20 mg of rosuvastin or 80 mg of atorvastatin available for patients who do not reach goal with simvastatin and 40 mg of rosuvastatin reserved for patients who require the most potent statin. JUPITER did not address the higher dose of rosuvastatin, but taken together with other trials notably PROVE-IT, TNT, IDEAL and A to Z there is a growing body of evidence to suggest that intensive LDL lowering with statins is beneficial and now JUPITER confirms that 20 mg of rosuvastatin is a safe and effective means of achieving this goal.
Alex Natanson presented the findings of TIMACS (Timing of Intervention in Patients with Acute Coronary Syndromes). This was probably my favorite study from AHA because the findings mean that when I get a call about an ACS admission at night I can with a clear conscience and a happy heart go back to bed for a nice long snooze before I come to the hospital in the morning and take the patient to the cath lab. Now I am, and I hope you are too, a confirmed believer in an early invasive approach for most patients with ACS. The question is what does “early” mean? The TIMACS investigators randomized 3031 patients admitted with ACS to early angiography (within 24 hours) versus delayed angiography (greater than 36 hours) following hospital admission. The median time to cath was 14 hours for the early group and 50 hours for the delayed group. There was no significant difference in the primary endpoint of death, MI or stroke. Not surprisingly, there was a difference in the secondary endpoint of refractory ischemia requiring urgent cath. Clearly patients in the delayed group had more time when they were at risk for refractory ischemia than the early group that had undergone cath and revascularization. TIMACS did show benefit to early cath in their very high risk subgroup with ongoing ischemia or hemodynamic instability, but these are patients who most practitioners would take for early cath. A very important conclusion of TIMACS is that there is no benefit to waiting. There is no need to “cool down” patients – the same finding as in ISAR-COOL which showed no benefit and even harm from a strategy of intensive antiplatelet therapy for 72-120 hours prior to cath and intervention. So the moral is: don’t rush, but don’t delay – get your patient to the cath lab by the end of the day.
Binita Shah, having done a good deal of work on outcomes of patients with diabetes and metabolic syndrome undergoing PCI was interested in the findings from the Massachusetts Data Analysis Center Registry of Drug Eluting and Bare Metal Stenting for Diabetes Mellitus. The authors of this study compared risk adjusted survival of 3,341 patients with diabetes treated in Massachusetts non-federal hospitals from April 2003 through September 2004 with drug eluting stents (DES) to that of 1,710 similar patients treated with bare metal stents (BMS). In a propensity matched analysis of 2952 patients treated with DES or BMS, there were decreased rates of death, MI, and TVR associated with DES at 3 years. Of course the problem with propensity scores is that they do not take into account unmeasured variables. We know that patients with diabetes are prone to restenosis. Why were some selected for treatment with BMS? Were there socioeconomic issues that precluded long-term treatment with clopidogrel? Were there serious life-threatening conditions or need for urgent non-cardiac surgery? So this study is encouraging for patients with diabetes treated with DES, but is still far from the final word on this important topic.
Chad Kliger presented a study entitled “Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Reduce Early Stent Thrombosis” which evaluated the utility of a vasodilator-associated stimulated phosphoprotein (VASP) index to guide management in patients undergoing PCI for non-emergent causes. This study showed a significant difference in rates of stent thrombosis, myocardial infarction and major adverse cardiac events between groups treated with a tailored versus conventional approach. Unfortunately, the VASP test remains a research tool only and the tailored approach which took up to 4 days to achieve platelet inhibition is not a practical alternative to standard clopidogrel loading. This study does support the concept of better platelet inhibition to improve outcomes of PCI. New commercially available platelet function assays and newer ADP receptor antagonists will clearly play a role here.
Late breaking trials presented at AHA that evaluated new therapies included ATLAS TIMI 46 which tested a novel anti-Xa therapy for patients with ACS and BICC which evaluated beta-interferon for chronic viral cardiomyopathy. TIMI 46 was a phase 2 dose finding study of rivaroxaban an oral direct factor Xa inhibitor in patients with ACS. This drug has been evaluated for prophylaxis of DVT in patients undergoing orthopedic surgery (RECORD 1-3) and appears to be a promising alternative to warfarin. The results of ATLAS were far from conclusive, but the study showed a benefit with respect to a composite secondary endpoint (death or myocardial infarction or stroke) at the cost of excess bleeding. BICC was a phase 2 study evaluating the use of beta interferon to reduce viral load in patients with biopsy proven chronic viral cardiomyopathy and infection with adenovirus, enterovirus and/or parvovirus. A total of 143 patients were randomized to high dose or low dose interferon versus placebo. The study showed that interferon does decrease viral load and there were some encouraging preliminary clinical data suggesting that this may be beneficial. A larger phase 3 study is planned, but considerable clinical benefit would be need to be shown to justify the high costs of therapy with interferon and the risks of routine myocardial biopsy.
A promising new biomarker Mid-Regional pro-Adrenomedullin (MR-pro-ADM) was featured in the presentation of the BACH trial which compared the usefulness of MR-pro-ADM versus BNP and NT-proBNP in patients presenting to the emergency room with shortness of breath. The novel marker had better prognostic accuracy than the older markers for prognostication of 30 day mortality. Milt Packer, who discussed the study at the late breaking trials session was dismissive of these findings pointing out that prognostication alone does not change therapy and serves little clinical purpose. I am a bit less pessimistic about the future utility of this biomarker. It would be important to determine whether there are differential effects of therapies such as beta blockers depending on MR-pro-ADM levels and to determine whether changes in biomarker levels predict response to therapy.
There were of course the usual number of negative trials. SEARCH and The Physicians’ Health Study II were enormous studies that have convincingly shown that antioxidant vitamins and folate do not have a role in prevention of heart disease. Thumbs up for statins, thumbs down for multivitamins. I-PRESERVE showed that there was mo benefit to therapy with ARBS for heart failure with preserved LV function. APPROACH was an intravascular ultrasound study which showed that among type 2 diabetic patients the use of rosiglitazone did not reduce percent atheroma volume compared to glipizide. Not very encouraging news for TZDs.
So what are the take home messages from AHA? Visit New Orleans, for sure. High dose potent statins for all, maybe. Routine measurement of hsCRP, perhaps. Early cath for ACS, yes, but no real rush unless patients are high risk and truly unstable. Drug eluting stents for diabetics, seems to be the way to go. Tailored ADP receptor blocker therapy is not quite ready for prime time. And stay alert to the possibility of very different take home messages from future meetings as new trials are completed, paradigms shift and the practice of cardiology continues to evolve.
Please see the cardiology fellows’ summaries of the AHA presentations below:
Drug Eluting and Bare Metal Stenting for Diabetes Mellitus
Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Reduce Early Stent Thrombosis