December 6th, 2010
Ticagrelor Gets European Approval
Larry Husten, PHD
Ticagrelor has received approval for marketing in Europe, according to AstraZeneca. The drug, which will go under the brand name of Brilique in Europe, will not be available in most European countries until the second half of 2011, the company said. A decision about the approval of ticagrelor in the U.S., where it will be called Brilinta, is expected later this month.
December 4th, 2010
Rivaroxaban Found Safe and Effective for DVT
Larry Husten, PHD
In the EINSTEIN-DVT noninferiority study, 3449 patients with acute DVT were randomized to receive open label oral rivaroxaban or conventional therapy with enoxaparin followed by warfarin or acenocoumarol for 3, 6, or 12 months. The rate of recurrent VTE, the primary efficacy outcome, was lower with rivaroxaban treatment than with enoxaparin treatment, successfully demonstrating noninferiority for rivaroxaban. The rate of major and clinically relevant non-major bleeding, the primary safety outcome, was the same in both groups.
Here are the main results (rivaroxban versus conventional therapy):
- Recurrent VTE: 2.1% versus 3.0% (HR, 0.68; CI, 0.44 – 1.04; p<0.001)
- Major and clinically relevant non-major bleeding: 8.1% in each group
- 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)
In the EINSTEIN-Extension double-blind superiority study, 1196 patients who had completed the EINSTEIN-DVT study (or the similar EINSTEIN-PE study, which enrolled patients with acute pulmonary embolism) and had therefore received anticoagulant therapy for 6 or 12 months, were randomized to receive rivaroxaban or placebo for an additional 6 or 12 months. The rate of recurrent VTE was significantly lowered by rivaroxaban treatment, with a rate of 7.1% in the placebo group compared to 1.3% in the rivaroxaban group (HR, 0.18; CI, 0.09 – 0.39; p<0.001). There were four nonfatal major bleeds in the rivaroxban group, compared to none in the placebo group.
The EINSTEIN investigators concluded that rivaroxaban “may provide an effective, safe, single-drug approach to the initial and continued treatment of venous thrombosis.”
EINSTEIN-DVT and EINSTEIN-Extension were presented at the American Society of Hematology meeting and published simultaneously in the New England Journal of Medicine. The results of EINSTEIN-DVT were presented earlier this year in August at the ESC.
December 3rd, 2010
When the Hunter Becomes the Hunted
Andrew M. Kates, MD
One of the joys of running a fellowship program is watching Fellows mature and complete their training. The end of this process, of course, is the beginning of one’s professional career.
For many of you Fellows, as you finish your training, you will be recruited as never before. For the first time in your career, people will be actively seeking you out rather than vice versa. The hunter becomes the hunted. This is quite a change from your position in previous stages of your education — be it applying to medical school, residency, or fellowship. Now, your university may want you to stay as junior faculty, or practice groups want you, the well-trained Fellow, to join them.
I would like to open up the conversation at CardioExchange for you to share your thoughts on the job search process: What interesting encounters have you had? For those who are post-fellowship, do you have words of advice for those who are at these new frontiers? It’s a brave new world out there.…
December 2nd, 2010
AHA Releases Updated Stroke Prevention Guidelines
Larry Husten, PHD
Here’s the good news, according to Larry Goldstein, the chairman of the statement writing committee for the revised American Heart Association/American Stroke Association Guidelines for the Primary Prevention of Stroke:
“Between 1999 and 2006, there’s been over a 30 percent reduction in stroke death rates in the United States and we think the majority of the reduction is coming from better prevention,”
Here’s the bad news: Stroke remains the third leading cause of death in the U.S. And nearly 800,000 strokes occur each year, of which 77% are first events.
Here are a few key highlights from the new guidelines on how to prevent those first strokes:
- The risk of a first stroke can be reduced by as much as 80% with healthy lifestyle choices, including not smoking, eating a healthy diet, maintaining normal body weight, drinking in moderation, and exercising regularly.
- Genetic screening and carotid-artery screening are not recommended for the general population, but may be appropriate in some people.
- The use of carotid stenting or carotid endarterectomy in patients without symptoms is “unclear.” The relative benefits of the two procedures are also “still uncertain.”
- Aspirin will not prevent a stroke in low-risk individuals, including those with diabetes or asymptomatic peripheral artery disease.
December 1st, 2010
Study Links Tricyclic Antidepressants to Increased Risk for CVD
Larry Husten, PHD
A survey from Scotland has found an increased risk for cardiovascular disease in people taking tricyclic antidepressants (TCAs). In an article in the European Heart Journal, the researchers write that they failed to find any increased risk with selective serotonin reuptake inhibitors (SSRIs).
Nearly 15,000 Scottish adults without known histories of CVD were followed for 8 years. After adjustment for other risk factors, TCA use was associated with a significant, 35% increase in CVD. (The authors note that most previous studies in this field have been based on people with preexisting CVD, while this study contained a representative sample of adults in the community.)
Because the association between drug and disease appeared to be “independent of psychiatric symptoms,” the authors speculate that “there may be some characteristic of TCA that is raising CVD risk.” But, they note, it is equally “plausible that an elevated rate of CVD of 35% could be explained by residual confounding due to unmeasured or unknown risk factors.”
November 30th, 2010
New Performance Measures for Peripheral Artery Disease Issued
Larry Husten, PHD
Performance measures to improve the diagnosis and treatment of peripheral artery disease (PAD) in adults have been published for the first time. The document was produced by the ACC, the AHA, and several other medical organizations. Here are a few key details of the performance measures:
- Measuring the ankle brachial index (ABI) is an easy and inexpensive way to screen for PAD.
- Statin therapy should be used to lower LD below 100 mg/dL.
- Smokers should receive support to quit smoking.
- Antiplatelet therapy should be used in people with a history of symptomatic PAD.
- Supervised exercise programs, like cardiac rehabilitation programs for MI or CABG patients, increase walking distance and reduce cardiovascular risk.
- People with a lower extremity vein bypass graft should undergo periodic ABI measurement and ultrasound to determine whether the conduit continues to function.
- Abdominal aortic aneurysms should be monitored.
“Patients with peripheral artery disease have the highest rate of heart attacks, stroke and cardiovascular death — higher than people with coronary artery disease — yet they remain undertreated,” said Jeffrey Olin, chair of the writing committee, in an ACC press release. “Therapies simply aren’t given with the same intensity. These patients receive antiplatelet therapy (aspirin or clopidogrel) or statin therapy (cholesterol-lowering medications) much less frequently than patients with coronary artery disease despite their high cardiovascular event rate.”
Olin also emphasized the value of, and the difficulty of delivering, exercise therapy for PAD patients: “The most effective therapy for PAD — a supervised exercise program — is not reimbursed by most third party payers, even though virtually every randomized trial has shown that when used for patients with claudication, they are able to increase their walking distance by up to 200 percent and their walking speed also increases…. This is more than can be achieved with any medication that is available on the market.”
November 30th, 2010
ASCENDing Into the Depths of the Nesiritide Controversy: Questions for Eugene Braunwald
CardioExchange Editors, Staff
Results of ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial), presented as a late-breaking clinical trial at the AHA meeting, showed that there were no significant differences in the pre-specified endpoint of dyspnea among some 7,000 patients with acute, decompensated HF randomized to receive standard therapy and either continuous intravenous nesiritide or placebo.
This trial was started in response to considerable controversy sparked by two meta-analyses (one in Circulation and the other published in JAMA) over the safety and efficacy of nesiritide, which was being used in growing numbers of heart failure patients. Click here for our news summary and here for the late breaker presentation.
Dr. Eugene Braunwald answers our questions about this trial, this drug, and this controversy. What are your questions or conclusions?
CardioExchange: Despite the subgroup analysis of patients with GFR <60 versus >60, the majority of ASCEND-HF patients appeared to have normal or near-normal creatinines at baseline. Given all the studies to date on nesiritide and renal outcomes, do you think that the use of nesiritide in even mild renal dysfunction should be further investigated or simply avoided altogether?
Braunwald: There is no contraindication to the administration of nesiritide to patients with mild renal dysfunction.
CardioExchange: In light of this trial’s results, are there specific situations where you would recommend that nesiritide be used in addition to standard care at this point in time?
Braunwald: Yes, but only in a limited number of patients. Those with extreme dyspnea who have not responded to intravenous loop diuretics and generic vasodilators (sublingual or IV nitroglycerine or IV Na nitroprusside) but who are not hypotensive.
CardioExchange: What would you consider to be the most important next step that investigators should take in order better define the most appropriate role of nesiritide in clinical practice? And, with what (if any) caveats?
Braunwald: I might consider a trial of low dose nesiritide (0.005 ug/kg/min) in acute pulmonary edema.
CardioExchange: Do you think a controversy like the nesiritide one could happen again? If so, what needs to be done to prevent such an occurrence?
Braunwald: I don’t think that the scenario with nesiritide and the ASCEND-HF trial could have been avoided. The drug was approved for the relief of dyspnea in acute heart failure, and not for reduction of mortality and/or rehospitalization for heart failure. Two meta-analyses of small trials suggested that nesiritide increased mortality and caused worsening of renal function. Once these meta-analyses were published the company that produced nesiritide (Scios) had to choose between taking the drug off the market or sponsoring a huge, expensive clinical outcome trial. They selected the latter course and showed that the results of the meta-analyses were misleading. Other than hypotension, the drug was well tolerated, and did not increase mortality or renal dysfunction. It did reduce dyspnea but not sufficiently to reach the high statistical levels that were pre-specified.
I don’t see much of a future for nesiritide.
November 29th, 2010
Study Finds No Link Between Cancer and Antihypertensives, Except for ARB-ACE Inhibitor Combo
Larry Husten, PHD
A new meta-analysis has found no evidence of a large cancer risk for most common antihypertensive agents, but did find strong evidence, largely based on one trial, for at least a 10% increase in cancer risk with the rarely used angiotensin-converting-enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARB) combination. In a paper in the Lancet Oncology, Sripal Bangalore and colleagues report on multiple analyses of data taken from 70 trials and including almost 325,000 patients.
The results, write the authors, refute a 5% to 10% “increase in either cancer or cancer-related death with most antihypertensive drug classes.” In contrast to a previous study, the new meta-analysis did not find an increased risk for ARBs in general or for telmisartan specifically. For the ARB-ACE inhibitor combination, however, the investigators note “a consistent harmful effect,” though they point out that “the finding was driven largely by the ONTARGET trial.”
Click here for previous coverage of cancer and antihypertensive agents on CardioExchange.
November 23rd, 2010
Greek Study Offers Reassurance About Statin Usage in Patients with Abnormal Liver Tests
Larry Husten, PHD
In the GREACE (Greek Atorvastatin and Coronary Heart Disease Evaluation) study, 1600 patients with coronary heart disease were randomized to atorvastatin or usual care; of these, 437 had moderately abnormal liver tests at baseline, suggesting non-alcoholic fatty liver disease (NAFLD).
In a post-hoc analysis of this subset of patients, published in the Lancet, the GREACE Study Collaborative Group reported a dramatic 68% reduction in the rate of cardiovascular events in the statin group. Cardiovascular events occurred in 30% of patients in the non-statin group (63 out of 210) compared to 10% of patients in the statin group (22 of 227). The authors say their results mean that “statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease.” In addition, the authors note that statin treatment was associated with improvement in liver tests.
Finally, the authors acknowledge that the benefits of statins in these patients “might be attributable to the presence of NAFLD, since alcohol misuse and other liver diseases were excluded.”
In an accompanying comment, Ted Bader estimates that 10% to 30% of patients who need statins might be denied treatment because of liver functions tests. “Statin-induced hepatotoxicity is a myth,” he writes. He recommends that statin manufacturers request FDA approval to remove language about liver toxicity from drug labels. “For too long,” he writes, “a raised ALT after starting a statin has been erroneously thought to represent liver disease. For too long, patients with liver disease have been denied statins for their hypercholesterolemia.”
November 23rd, 2010
How Should We DEFINE Anacetrapib’s Success?
Philip John Barter, MD, PhD and Christopher Paul Cannon, MD
CardioExchange welcomes Philip Barter and Christopher P. Cannon, two of the investigators for the DEFINE trial, which was recently published in the New England Journal of Medicine. Here, they answer questions posed by CardioExchange’s editors. First, some background about the trial:
In DEFINE, 1623 patients with or at high risk for coronary disease were randomized to receive either 100 mg of anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, or placebo daily for 18 months. By week 24, the mean LDL level had dropped significantly more with anacetrapib (from 81 to 45 mg/dL) than with placebo (from 82 to 77 mg/dL), and the mean HDL level had increased significantly more with anacetrapib (from 41 to 101 mg/dL) than with placebo (from 40 to 46 mg/dL). The incidence of prespecified cardiovascular events was similar in the two groups (2.0% with the drug, 2.6% with placebo; P=0.40). Anacetrapib’s manufacturer funded the study.
Q: You performed a prespecified Bayesian analysis with respect to the incidence of cardiovascular events. What does that analysis indicate regarding a reduction in those events with anacetrapib?
A: The prespecified Bayesian analysis indicated with 94% confidence that anacetrapib would not be associated with a 25% increase in cardiovascular events — an increase previously documented with torcetrapib. The analysis does not tell us anything with respect to a decrease in cardiovascular events. In fact, the trial was not designed (or powered) to assess efficacy. The observed possible reduction in events should be interpreted with this in mind. The results should instead simply offer comfort about going ahead with a very large clinical-outcomes trial that is designed (and powered) to test the hypothesis that inhibiting CETP will limit the incidence of cardiovascular events.
Q: In terms of anacetrapib’s potential benefit, how important is the change in HDL relative to the change in LDL?
A: It’s not possible to say from this trial, but the results of a large clinical-outcomes trial might provide an answer.
Q: Given the same change in LDL from using a statin, what would the adjudicated cardiovascular events have looked like? In other words, why didn’t we see a greater reduction in events with the drug, just from the LDL lowering alone? Would a statin-related reduction in LDL like this have a stronger effect?
A: The DEFINE trial was too small and too short (and thus seriously underpowered) to provide a sensible answer to this question.
Q: Anacetrapib yielded a roughly 40% reduction in LDL but only a roughly 20% reduction in apolipoprotein B (apoB). Did the treated group have more small, dense LDL particles? If so, is that a good or a bad thing? And could it account for the lack of significant improvement in cardiovascular events?
A: The LDL reduction resulted from at least two mechanisms. First, inhibiting CETP reduces the amount of cholesterol transferred from HDL to LDL and, thus, reduces the cholesterol content of the LDL particle. Second, there is evidence that inhibiting CETP up-regulates the LDL receptor (by an unknown mechanism) and, therefore, increases the removal of LDL particles (and thus apoB) from plasma. The enhanced LDL removal reduces the concentration of both apoB and LDL; the inhibition of CETP reduces LDL but not apoB. Hence, the reduction in LDL was greater than that in apoB. The implication that the LDL particle size may have been smaller is probably of little consequence when you consider that the number of LDL particles was clearly reduced. But, again, we will not know the clinical significance of these details until we have data from a large clinical-outcomes trial.
Q: A few CETP inhibitors are being developed. Are there important differences among them that we should know about?
A: Ongoing research should provide answers. For now, we just don’t know.
Pose your own questions to Drs. Barter and Cannon, and share your thoughts about the DEFINE trial here on CardioExchange.
NEJM Journal Watch — Recent Cardiology Articles- 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
- Intensive Blood Pressure Control: Do the Benefits and Harms Vary with Baseline Cardiovascular Risk?