September 1st, 2010
NEJM Editors Call for Removal of Sibutramine from U.S. Market
Larry Husten, PHD
Earlier this year, following the discovery of signals of potential danger in a large clinical trial, the weight loss drug sibutramine (Meridia) was withdrawn from the market in Europe while the FDA added a strongly worded contraindication to its use in people with cardiovascular disease. Now, 2 weeks before an FDA advisory panel will vote on whether the drug should remain on the market in the U.S., the results of the clinical trial that sparked the concerns have been published in the New England Journal of Medicine.
The Sibutramine Cardiovascular Outcomes (SCOUT) trial randomized 9804 overweight or obese subjects with preexisting cardiovascular disease and/or diabetes to either sibutramine or placebo. After 3.4 years of treatment, the combined rate of nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death was 11.4% with sibutramine versus 10.0% with placebo (HR, 1.16; 95% CI, 1.03-1.31; P=0.02). The differences in nonfatal MI (4.1% vs. 3.2%) and nonfatal stroke (2.6% vs. 1.9%) were significant themselves.
In an accompanying editorial, three NEJM editors — Gregory Curfman, Stephen Morrissey, and Jeffrey Drazen — take issue with the SCOUT investigators, who concluded that sibutramine should remain available, albeit limited to people without cardiovascular disease. They write:
We surely need safe and effective medications to help overweight and obese patients lose weight and improve their long-term health. But given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market.
September 1st, 2010
Long-Term Effect of Intensive BP Control in Blacks
Larry Husten, PHD
The African-American Study of Kidney Disease and Hypertension (AASK) investigated the role of intensive blood-pressure control in slowing the progression of chronic kidney disease in black patients. In the previously reported results of the randomized portion of AASK, intensive BP control had no effect on the progression of CKD. Now the AASK Collaborative Research Group reports the results of the cohort phase of the study, in which patients who completed the randomized phase were treated with a blood-presssure target of less than 130/80 mm Hg. The findings are presented in the New England Journal of Medicine.
In the cohort phase, the investigators once again found no difference between the groups in the primary trial outcome after a follow-up period of 8.8 to 12.2 years. However, a beneficial effect of intensive control was observed in subjects who had a protein-to-creatinine ratio of more than 0.22 (HR, 0.73; P=0.01).
In an accompanying editorial, Julie Ingelfinger writes that despite the somewhat mixed results in clinical trials, “the concept of intensive control has some data to support it and has been the basis of current guidelines of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative for a blood-pressure target of under 130/80 mm Hg in patients who have chronic kidney disease without diabetes.” She concludes that AASK “lends hope to the concept that intensive treatment will improve renal outcomes in black patients with hypertension, chronic kidney disease, and microalbuminuria.”
September 1st, 2010
Breathing Easier with Compression-Only CPR
Larry Husten, PHD
A recent NEJM study showed that out-of-hospital, cardiac-arrest patients who received compression-only CPR or traditional CPR had similar survival rates. We asked Mark Link, a member of the AHA Advanced Cardiac Life Support Committee, questions about this latest research. Read what he has to say, then ask him your own questions
August 31st, 2010
Apixaban Beats Aspirin for Stroke Prevention in AF
Larry Husten, PHD
The AVERROES (Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Strokes) trial randomized 5600 AF patients who were unable to take warfarin to receive either aspirin or apixaban, a factor Xa inhibitor. (Another trial still underway, ARISTOTLE, is a direct comparison of warfarin and apixaban in AF.) AVERROES was stopped early after the Data Monitoring Committee found clear evidence of clinically important benefit and an acceptable safety profile.
Stuart Connolly reported an annual rate of the primary endpoint — a composite of stroke or systemic embolism — of 3.6% per year in the aspirin group and 1.7% per year in the apixaban group (HR 0.46, CI: 0.33-0.64, p<0.001). The rate of major bleeding was 1.2% per year on aspirin and 1.4% per year on apixaban (HR 1.14, CI: 0.74–1.75, p=0.56). Hemorrhage stroke occurred at a rate of 0.2% per year in both treatment groups.
Connolly calculated that for every 1000 patients treated with apixaban for one year instead of aspirin, 18 strokes, 10 deaths, and 31 CV hospitalizations could be prevented, at a cost of 2 major bleeds.
Commenting on the results in an ESC press release, Connolly said: “The results of AVERROES are truly impressive. The reduction in stroke and systemic embolism is very important and the increased risk of haemorrhage is small. It appears that apixaban will be an excellent treatment for the many patients with atrial fibrillation who are unsuitable for warfarin. These findings will reduce the burden of stroke in society.”
The designated discussant at the Hot Line presentation, Harald Arnesen, said AVERROES was a “landmark study that will affect guidelines,” and he predicted that aspirin use would diminish after apixaban becomes available.
August 31st, 2010
Positive Results for Rivaroxaban in EINSTEIN-DVT
Larry Husten, PHD
The EINSTEIN-DVT study tested the effect of the new oral anticoagulant rivaroxaban in the setting of DVT. The open-label, non-inferiority study randomized more than 3,400 patients with acute, symptomatic DVT to either oral rivaroxaban or conventional therapy with enoxaparin followed by warfarin or acenocoumarol for 3, 6, or 12 months, based on the attending physician’s assessment at baseline.
Dr. Harry Büller reported that recurrent symptomatic venous thromboembolism took place in 2.1% of patients in the rivaroxaban group compared to 3.0% of the subjects on conventional therapy (p<0.0001 for non-inferiority). The rate of major and clinically relevant non-major bleeding was 8.1% in each group. Büller reported there were no signals of liver toxicity and that the drug was well-tolerated during the trial.
Here are additional results (rivaroxban versus conventional therapy):
- Net clinical benefit (the composite of the primary efficacy outcome plus major bleeding): 2.9% vs. 4.2% (HR 0.67, CI: 0.47 – 0.95).
- All-cause mortality: 2.2% vs. 2.9% (HR 0.67, CI: 0.44 – 1.02)
- Cardiovascular events: 0.7% vs. 0.8% (HR 0.79, CI: 0.36 – 1.71)
“The single-drug approach with rivaroxaban will provide clinicians and patients with an attractive, simple, alternative regimen for the initial and long-term treatment of deep vein thrombosis.” said Büller, in an ESC press release. The results of ROCKET-AF, which is testing the efficacy of rivaroxaban for stroke prevention in AF, are scheduled to be presented in November at the AHA.
August 31st, 2010
The CURE for Clopidogrel Genotyping?
Guillaume Pare, MD, MSc
CardioExchange welcomes Guillaume Paré to discuss his team’s work on the utility of clopidogrel genotyping. The researchers genotyped for CYP2C19 alleles associated with loss-of-function or gain-of-function of clopidogrel in some 5,000 patients with ACS or A-fib from two large randomized trials. In both studies, clopidogrel had similar efficacy over placebo regardless of whether patients had loss-of-function alleles. In contrast, clopidogrel-treated patients with gain-of-function alleles derived more benefit over placebo recipients than did clopidogrel recipients with standard genotype. The findings were presented at the European Society of Cardiology Congress and published online simultaneously in the New England Journal of Medicine.
In contrast to previous research, your study found that CYP2C19 loss-of-function alleles had no effect on cardiovascular risk among clopidogrel recipients with ACS or A-fib. Why the discordance between what might be expected from the basic science studies and the results of the trial?
Guillaume Paré: Our understanding of the clopidogrel dose-response curve is limited with regards to outcomes, both ischemic and hemorrhagic. While carriers of loss-of-function alleles are expected to have approximately 30% less active metabolite than noncarriers, it is not entirely clear how such a decrease will impact on clinical outcomes. It is quite reasonable to assume that in certain individuals modest changes in active metabolite concentration will not materially alter the benefit of clopidogrel, for example if a dose-response plateau is reached.
What are you now recommending to practitioners? To the clinician who is doing genotyping or who was considering doing it?
Guillaume Paré: Clinical decisions must be made using all available information. Our data show that there is no effect of loss-of-function alleles in conservatively managed ACS and AF patients and provide a convincing argument against genotyping in these populations, but these data may not be applicable to other patient populations. At this point, we can only speculate on reasons behind differences between our study and previous reports. Whether the effect of loss-of-function alleles on active metabolite concentration varies from one population to the other, or the concentration of active metabolite necessary for clinical benefit varies, these important questions will have to be resolved to define which patient populations are likely to benefit from genetic testing.
Clearly, more data will be necessary to better understand the pharmacological effects underlying these results. Ultimately, randomized clinical trials including genetic information will be needed (and are underway) to determine the best treatment option for individual patients.
What’s the potential significance—if any—to your finding that ACS patients with the gain-of-function alleles had better outcomes over ACS patients with wild-type or loss-of-function alleles?
Guillaume Paré: Taken together with recent data from Sibbing and colleagues demonstrating increased bleeding in gain-of-function carriers, our data confirm the importance of the gain-of-function allele in clopidogrel-treated patients. Nevertheless, there is still much to learn about this association and other populations will have to be investigated to fully characterize its effect. If anything, this finding emphasizes the complexity of pharmacogenetic associations. There are undoubtedly factors that need to be identified to explain why this allele seems to be associated with outcomes in certain populations but not others.
August 31st, 2010
No Benefits for Low-Dose Heparin Over Standard Heparin in FUTURA/OASIS-8
Larry Husten, PHD
FUTURA (Fondaparinux Trial With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes)/OASIS-8 is the first trial to compare low-dose unfractionated heparin with conventional heparin dosing in PCI patients receiving fondaparinux. Sanjit Jolly and colleagues randomized 2026 non-STEMI high-risk patients undergoing PCI within 72 hours to either low-dose unfractionated heparin or a standard dose of heparin adjusted by activated clotting time (ACT), in addition to fondaparinux. The results were presented at the ESC in Stockholm and published simultaneously in JAMA.
The primary endpoint — a composite of major bleeding, minor bleeding, or major vascular access-site complications in the 48 hours after PCI — occurred in 4.7% of patients in the low-dose group compared with 5.8% of the conventional-dose group. This difference did not achieve statistical significance. The researchers also observed a nonsignificant increase in the low-dose group in the composite secondary endpoint of periprocedural major bleeding or 30-day death, MI, or target vessel revascularization.
The authors conclude: “The finding that adding ACT-guided unfractionated heparin to fondaparinux while treating patients with acute coronary syndromes does not increase major bleeding is important in the context of modern PCI practice…. These findings support using the currently recommended standard ACT-guided dose of unfractionated heparin when performing PCI in patients with non-ST segment elevation acute coronary syndromes who are treated with fondaparinux.”
August 31st, 2010
ESC: The Good, the Bad, and the Better
Susan Cheng, MD
As far as conferences go, I’m impressed. It’s only day two for me, but I can already say that I would come back. The workshops and clinical sessions are solid. The original science being presented is plentiful and of good quality. One Austrian colleague mentioned he was particularly pleased with the growth of basic science and translational content.
What’s bad is the venue layout for oral presentations. Most of the action is along a single corridor with entrances to the different speaking halls on one side. We all know by this point that if you want a fighting chance of getting into a popular session, you’d better start stalking the doorway at least 15 minutes early. But even so, there’s still the risk of being shut out. This afternoon, there was an especially dense aggregation of people around the doorway to a session on pulmonary hypertension. Trying to get through that crowd was enough to drive up anybody’s RVSP.
A much better experience was the poster sessions. In fact, this was actually the surprise hit of the day for me. Unlike the rooms for most oral presentations, the poster halls are huge and spacious. The poster boards are actually stainless steel sheets suspended from the ceiling, with each poster neatly cornered by round silver magnets. Featured posters are strategically located, set against a soft pillar of back-lit white sheets. Wandering through the hall was like walking through a hallowed section of high-end Ikea wares, but with science. Now I really want the Swedes to re-design my workspace. I always enjoy the poster sessions, given the opportunities to interact directly with presenters and run into colleagues — but this setup manages to improve on the experience.
Tomorrow, posters for sure, more gravlax, more attempts at getting into talks, and the much-touted Viking museum.
August 30th, 2010
Study Finds African-Americans at Increased Risk for Stent Thrombosis
Larry Husten, PHD
African-Americans are nearly three times more likely than other races to develop stent thrombosis after receiving a drug-eluting stent, according to a new study appearing in Circulation. Ron Waksman and colleagues analyzed data from a large, single-center registry of 7,236 patients who received a DES and found that African-American race was the single strongest predictor of late stent thrombosis — even after accounting for other known risk factors, and even though African-Americans were more likely to comply with their prescriptions for antiplatelet therapy. The rates of stent thrombosis for African-Americans, compared with non-African-Americans, were:
- 1.71% vs. 0.59% at 30 days;
- 2.25% vs. 0.79% at 1 year;
- 2.78% vs. 1.09% at 2 years;
- 3.67% vs. 1.25% at 3 years.
Overall mortality at 3 years was also higher among African-Americans: 24.9% versus 13.1% for other races.
In the discussion section, the authors write: “Because the traditional socioeconomic factors that plague racial disparities in health care have been accounted for in our study, further mechanisms such as genetic differences by which black race predicts ST [stent thrombosis] must be pursued.”
August 30th, 2010
4-Year Findings from the REACH Registry
Larry Husten, PHD
“Not all atherothrombosis is equal.” That’s the message from the latest findings of the international REACH (Reduction of Atherothrombosis for Continued Health) registry of more than 45,000 patients with “various manifestations” of atherothrombosis. According to the REACH investigators, “easily demarcated subgroups of atherothrombotic patients had widely varying risks [for future ischemic events], ranging from 7% in nondiabetic patients with other risk factors for atherothrombosis to 25% in patients with polyvascular disease and prior ischemic events.”
The findings were presented by Deepak Bhatt at the ESC in Stockholm and published simultaneously in JAMA. Other key findings include:
- People with prior ischemic events were at higher risk than people with stable CAD but no history of ischemia, while people with risk factors alone had the lowest risk.
- An ischemic event within the past year raised risk more than a remote event did.
- Diabetes substantially increased risk across all categories of patients.
- Polyvascular disease was even stronger than diabetes in predicting risk in people with established atherothrombosis.
NEJM Journal Watch — Recent Cardiology Articles- Optimal Management of NSTEMI in Older Adults: A Meta-Analysis
- Which Cardiovascular Risk Calculator Is Best in Older Adults?
- A New Indication for Finerenone, a Mineralocorticoid-Receptor Antagonist
- Should Patients Take Once-Daily Antihypertensive Drugs in the Morning or the Evening?
- Exercise as Medicine for Preventing Colon Cancer Recurrence