FDA Comes Out Against Aspirin To Prevent First Heart Attacks 1

In the latest development in a long-simmering debate, the FDA has announced that aspirin should not be marketed for the prevention of a first heart attack or stroke in people with no history of cardiovascular disease. The announcement follows FDA’s rejection on Friday of Bayer Healthcare’s decade-old  petition requesting approval of a primary prevention indication. [PDF of FDA rejection letter]

Click here to read the full post on Forbes.

 

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Aspirin and Clonidine Fail to Help Surgery Patients Reply

Heart attacks (myocardial infarctions) are among the most common and serious side effects of noncardiac surgery. An effective regimen to minimize this risk has been the subject of considerable debate in recent years. The controversy was recently exacerbated because the recommendation to use beta-blockers in this setting was based on research which has now been discredited. Substantial evidence against the use of perioperative beta blockers came from the original POISE trial.

Now a second POISE trial, the Perioperative Ischemic Evaluation 2 (POISE-2) trial, casts doubt on the value of two other proposed strategies to reduce death and MI in patients undergoing noncardiac surgery. Results of POISE-2 were presented at the American College of Cardiology meeting in Washington, DC and published simultaneously in two papers in the New England Journal of Medicine.

Click here to read the entire post on Forbes.

 

Some Patients With Minor Stroke Or TIA May Benefit From Early Clopidogrel And Aspirin Reply

Some people with minor ischemic stroke or transit ischemic attack (TIA) may benefit from dual antiplatelet therapy with aspirin and clopidogrel, according to a large new study from China published in the New England Journal of Medicine. In the immediate period following a TIA or minor stroke people are at high risk for having a major stroke. Aspirin is known to cause a modest reduction in recurrent events. More potent antiplatelet agents like clopidogrel may also be beneficial, but have not been well studied in the early phase and may increase the risk of bleeding complications, including the conversion of an ischemic stroke into a worse hemorrhagic stroke.

Investigators in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial randomized 5,170 patients within 24 hours of a minor ischemic stroke or high-risk TIA to three months of treatment with either clopidogrel and aspirin or placebo and aspirin. At 90 days the rate of stroke was 8.2% in the combination group versus 11.7% in the aspirin-alone group (hazard ratio 0.68, CI 0.57-0.81, p<0.001). There were also significant reductions…

Click here to read the full story on Forbes.

 

Study Suggests Aspirin Resistance May Not Be Real 1

Is it resistance or pseudoresistance? According to a new study published in Circulation, aspirin resistance may be a myth, an artifact of the enteric coating of most aspirin tablets. The coating, which is designed to prevent gastrointestinal side effects caused by aspirin, may delay or conceal the effects of the drug, the study suggests, but the antiplatelet effects of the drug will eventually emerge. According to the authors, the study raises new questions about the value of point-of-care tests designed to detect aspirin resistance.

Before and after  receiving a single 325 mg dose or either immediate or enteric coated aspirin, 400 healthy volunteers underwent testing to assess the effect of COX-1 on platelets, which is widely considered to be the basis for the cardiovascular effects of aspirin. In this first phase of the study there were no instances of apparent aspirin resistance in the group of 40 subjects who received plain aspirin. By contrast, 108 out of the 360 subjects who received coated aspirin qualified as non-responders when tested at either 4 hours or at 8 hours.

In the second phase of the study the non-responders underwent repeat testing, at which point the number of nonresponders decreased to 42. In the third phase of the study, no patients were found to be aspirin resistant after either a week of aspirin therapy or when aspirin was added ex vivo.

The study authors, led by Garret FitzGerald, said that their study “failed to find a single person who satisfied” the criteria for aspirin resistance. The results, they said, suggest that people who appear to be aspirin resistant instead exhibit “pseudoresistance, due to delayed and reduced drug absorption” due to the drug coating. “These observations question the value of seeking to diagnose aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition following enteric coated preparations of aspirin.”

In a comment given to the New York Times, Eric Topol disagreed with the study conclusions and pointed out that the study only used healthy volunteers, who are “very different” from people “who actually have heart disease or other chronic illnesses who are taking various medications.”

Sanjay Kaul sent the following comment:

In this elegantly designed study, the authors demonstrate that the prevalence of true aspirin resistance in a healthy cohort is rare and that the variability in aspirin responsiveness is mostly accounted for by variability in bioavailability (drug exposure) of enteric-coated aspirin. One should, however, exercise caution in not extrapolating from this study in healthy volunteers to patients with heart disease or chronic illnesses which might affect how aspirin works in the body. The concept of aspirin resistance rests on a shaky foundation. It is an unclear entity with unclear diagnosis, unclear mechanism, and unclear clinical relevance. It’s prevalence has been overblown, driven to a large extent by marketing considerations, i.e., development of tests to assess aspirin responsiveness, and availability of expensive alternatives to aspirin such as clopidogrel. Most guidelines appropriately do not endorse testing for aspirin resistance.

ARCTIC Blows A Cold Wind On Platelet Function Tests 1

The use of platelet-function tests to monitor and guide antiplatelet therapy in PCI patients has sparked heated debate. Cardiologists have sought to reconcile biological plausibility with the absence of clinical evidence. Now the ARCTIC (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation versus Continuation One Year after Stenting) trial brings cold comfort to supporters of the monitoring strategy.

The ARCTIC investigators randomized 2440 PCI patients either to a strategy in which antiplatelet therapy was guided by platelet-function monitoring, or to conventional therapy without monitoring. The VerifyNow P2Y12 and aspirin point-of-care assay was used in the monitoring group. Results of the trial were presented at the American Heart Association scientific sessions in Los Angeles on Sunday and published simultaneously in the New England Journal of Medicine.

The primary endpoint was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization at 1 year:

  • 31.1% in the conventional group and 34.6% in the monitoring group (HR 1.13, CI 0.98-1.29, p=0.10)

The ARCTIC investigators also reported a main secondary endpoint consisting of stent thrombosis, revascularized or not, or any urgent revascularization:

  • 4.6% and 4.9% (HR 1.06, CI 0.74-1.52, p=0.77)

In the monitoring group, 7.6% of patients were found to be poor responders to aspirin and 34.5% were poor responders to clopidogrel. The authors conclude that platelet-function testing with antiplatelet therapy adjustment does not improve clinical outcomes as compared with standard treatment and that their results “do not support the routine use of platelet-function testing in patients undergoing coronary stenting.”

A second arm of the trial, studying whether clopidogrel therapy should be continued after 1 year, is ongoing. In addition, a follow-up study, ANTARCTIC, is evaluating the value of platelet-function testing in an elderly population “with a paradigm shift towards safety.”

ASPIRE: Aspirin An Attractive Alternative After First VTE Reply

It is unclear what the best approach is for the long-term treatment of people who have had a first unprovoked episode of venous thromboembolism (VTE). Although warfarin is effective at preventing a recurrence, it is inconvenient and raises the risk for bleeding. Newer anticoagulants have not been tested or approved for this population.

The ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) trial randomized 822 patients who had finished an initial course of anticoagulant therapy after a first unprovoked case of VTE to either aspirin (100 mg daily) or placebo for 4 years. Although the reduction in the rate for recurrent VTE with aspirin did not reach statistical significance, there were significant reductions in secondary outcomes of clinical events:

26% reduction in the yearly rate of VTE recurrence (primary endpoint):

  • 6.5% for placebo and 4.8% for aspirin (HR 0.74, CI 0.52-1.05, p=0.09)

34% reduction in the yearly rate of major vascular events (VTE, MI, stroke, or CV death):

  • 8.0% versus 5.2% (HR 0.66, CI 0.48-0.92, p=0.01)

33% reduction in the yearly rate of VTE, MI, stroke, major bleeding, or all-cause mortality (net clinical benefit):

  • 9.0% versus 6.0% (HR 0.67, CI 0.49-0.91, p=0.01)

The ASPIRE investigators calculated that for every 1000 patients treated for 1 year, aspirin would prevent 17 episodes of VTE and 28 major thrombotic events, at a cost of 5 nonfatal bleeding episodes.

Reporting in the New England Journal of Medicine, the investigators write that although aspirin is “substantially less effective than warfarin,” it is “an attractive alternative because it is simple and inexpensive and its safety profile is well documented.”

In an accompanying editorial, Theodore Warkentin combined the ASPIRE results with findings from the recent WARFASA trial and calculated that aspirin results in a 32% reduction in the rate of recurrent VTE and a 34% reduction in the rate of major vascular events. He concludes that aspirin is “a reasonable option” for patients who wish to stop anticoagulation:

Aspirin is inexpensive, does not require monitoring (in contrast to warfarin), and does not accumulate in patients with renal insufficiency (in contrast to dabigatran and rivaroxaban); in addition, if major bleeding occurs or the patient requires urgent surgery, the antiplatelet effects of aspirin can be reversed…”

WOEST: Get Rid Of The Aspirin In Triple Therapy 1

According to current guidelines and clinical practice, PCI patients already taking an oral anticoagulant generally end up on triple therapy comprising the anticoagulant plus clopidogrel and aspirin. However, there is no supporting evidence base for this approach and the triple therapy regimen is known to increase bleeding complications. Now a new study– the first randomized trial to address this situation, according to the investigators–  may have a large impact on clinical practice by demonstrating that the omission of aspirin in this context appears to be safe and may reduce adverse events.

Results of the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting) trial were presented by Willem Dewilde at the ESC in Munich today. Investigators in the Netherlands and Belgium randomized 573 patients to triple therapy or dual therapy of an anticoagulant plus clopidogrel for at least one month after implantation of a bare-metal stent or one year after a drug-eluting stent. Two-thirds of the patients were receiving oral anticoagulation for atrial fibrillation.

The primary endpoint, the total number of bleeding events, was dramatically reduced in the dual therapy group at one year:

  • 44.9% in the triple therapy group versus 19.5% (HR 0.36, CI 0.26-0.50)

There were 3 intracranial bleeds in each group. Most of the difference in bleeding occurred in TIMI minor and minimal bleeding. The difference in TIMI major bleeding (3.3% versus 5.8%) did not achieve statistical significance.

Clinical events, the trials’s secondary endpoint, were numerically lower in the dual therapy group. The difference in mortality achieved statistical significance.

  • Mortality: 7 deaths (2.6%) in the dual therapy group versus 18 deaths (6.4%) in the triple therapy group, p=0.027
  • MI: 3.3% versus 4.7%, p=0.382
  • TVR: 7.3% versus 6.8%, p=0.876
  • Stroke: 1.1% versus 2.9%, p=0.128)
  • Stent thrombosis: 1.5% versus 3.2%, p=0.165

“The WOEST study demonstrates that omitting aspirin leads to less bleedings but does not increase the risk of stent thrombosis, stroke or myocardial infarction,” said Dewilde in an ESC press release. “Although the number of patients in the trial is limited, this is an important finding with implications for future treatment and guidelines in this group of patients known to be at high risk of bleeding and thrombotic complications.”

David Holmes said the trial addressed “an incredibly important issue” and predicted that it would “change the way we practice medicine, it will change practice right away.” Keith Fox said that the evidence base prior to WOEST was extremely limited and that the trial showed that there was no hazard in doing without aspirin. The ESC discussant, Marco Valgimigli, said the trial showed it was safe to drop aspirin and provided another demonstration that “we have hit the wall” with anticoagulation.

Republished with permission from CardioExchange, a NEJM group publication.

Real World Bleeding Risk Of Aspirin In Primary Prevention Examined Reply

A new study published in JAMA provides substantial new evidence about the real world effects of aspirin, including the risk of  bleeding, in a broad  population. The study also sheds important new light on the effects of aspirin in a diabetic population.

Giorgia De Berardis and colleagues analyzed data from more than 4 million people in Puglia, Italy and compared 186,425 people taking low-dose aspirin with the same number of matched controls not taking aspirin.

Major bleeding events requiring hospitalization:

  • aspirin: 5.58 (5.39-5.77) per 1000 person-years
  • controls: 3.60 ( 3.48-3.72) per 1000 person-years
  • Incidence rate ratio (IRR) 1.55 (1.48-1.63)

Diabetics overall had an increased risk of major bleeding episodes but this increased risk was not significantly associated with aspirin use:

  • Hemorrhagic events in diabetics overall (compared with non diabetics): IRR 1.36 (1.28-1.44)
  • Hemorrhagic events in diabetics taking aspirin compared with diabetics not taking aspirin: IRR 1.09 (0.97-1.22)

The authors wrote that their findings demonstrate that bleeding events occur more frequently than had been observed in clinical trials. They calculated that for individuals with a 10-year risk of cardiovascular events between 10% and 20% the risks and benefits of aspirin therapy are similar, causing 2 excess bleeds, and preventing 2 CV events, for every 1,000 people treated each year.

In an accompanying editorial, Jolanta Siller-Matula writes that the benefits of aspirin in secondary prevention are “not disputed,” since aspirin can prevent 6 major vascular events at the expense of 1 major bleeding event. But there is no such consensus for primary prevention, and Siller-Matula writes that the findings of the Italian study reinforce current European guidelines which do not recommend aspirin for primary prevention.

The JAMA study provides far more information about aspirin use in diabetics than had been previously available. Nevertheless, writes Siller-Matural, the decision whether to use aspirin for primary prevention in this population is still not clear, and will require additional data from ongoing studies.

Click here to read the JAMA press release…

Aspirin Found To Prevent Recurrent Venous Thromboembolism 1

Aspirin can help prevent the recurrence of venous thromboembolism (VTE) after discontinuation of anticoagulation therapy, according to results of the WARFASA (the Warfarin and Aspirin) study published in the New England Journal of Medicine.

Following 6 to 18 months of oral anticoagulation, 403 patients with first-time unprovoked VTE were randomized to aspirin (100 mg daily) or placebo for two years. Aspirin therapy resulted in a significant reduction in VTE but did not cause an increase in the risk of bleeding:

  • VTE recurrence: 6.6% per year in the aspirin group versus 11.2% in the placebo group (hazard ratio 0.58, CI 0.36 to 0.93, p=0.02).
  • Major bleeding occurred in one patient in each treatment group.

In an accompanying editorial, Richard Becker writes that the results of WARFASA “are compelling and may signal an important step in the evolution of care” but calls for additional studies to more precisely define the role of aspirin in preventing recurrent VTE. The results of a larger trial, the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study, will be reported this year, according to Becker, and, in conjunction with WARFASA, “may provide more reliable evidence of the effect of aspirin in patients with first unprovoked venous thromboembolism.”

WARCEF: No Advantage For Warfarin Over Aspirin In Heart Failure 1

A new study offers “no compelling reason” to use warfarin instead of aspirin in heart failure patients who don’t have atrial fibrillation. In a paper published in the New England Journal of Medicine, Shunichi Homma and members of the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) study group report the results of a trial in which 2,305 patients with left ventricular dysfunction were randomized to warfarin or placebo and followed for up to six years.

No significant differences were observed in the primary endpoint (the composite of death, ischemic stroke, or intracerebral hemorrhage) or its individual components. Warfarin was superior to aspirin in reducing the rate of ischemic stroke, but this advantage was offset by an increased incidence of major hemorrhage in the warfarin group.

  • Primary endpoint: 26.4% for warfarin versus 27.5% for aspirin, HR 0.93, CI 0.79-1.10
  • Ischemic stroke: 1.8% versus 3.5%, HR 0.55, CI 0.32-0.96)
  • Major hemorrhage: 5.8% versus 2.7%, OR2.21, CI 1.42-3.47

The authors concluded:

Given the finding that warfarin did not provide an overall benefit and was associated with an increased risk of bleeding, there is no compelling reason to use warfarin rather than aspirin in patients with a reduced LVEF who are in sinus rhythm.

In an accompanying editorial, John Eikelboom and Stuart Connolly agree with the study authors that there is no justification for the “routine clinical use of warfarin in most patients with heart failure” but write that warfarin is still “most likely to benefit” heart failure patients with atrial fibrillation or with a history of cardioembolic stroke or formation of LV thrombus. They leave open the possibility that warfarin may also benefit heart failure patients with underlying coronary artery disease, and recommend that future studies of anticoagulants in heart failure focus on this population.

Meta-Analysis Adds New Evidence For Cancer Benefits Of Daily Aspirin 1

Although daily aspirin was originally proposed to reduce cardiovascular events, the effects on cancer of daily aspirin have become increasingly apparent while the vascular benefits, especially in primary prevention, have become less clear. Now a new meta-analysis in the Lancet adds significantly new details to our understanding about the effects of aspirin and increases the evidence in support of a long-term beneficial effect of aspirin in preventing cancer.

Peter Rothwell and colleagues analyzed data from 51 primary and secondary prevention trials including more than 80,000 patients. They reported several key findings

  • Daily aspirin reduced deaths from cancer by 15% (p=0·008).
  • After 5 years, there was a particularly striking 37% reduction in cancer deaths (p=0·0005), which largely accounted for a reduction in non-vascular deaths overall (p=0·003).
  • Aspirin was associated with an initial reduction in major vascular events, but this was offset by increases in major bleeding. With longer followup the vascular effects diminished, so that after 3 years only the reduced risk of cancer was significant.

The authors wrote that “in view of the very low rates of vascular events in recent and ongoing trials of aspirin in primary prevention, prevention of cancer could become the main justification for aspirin use in this setting…”

In an accompanying comment, Andrew Chan and Nancy Cook point out that the meta-analysis did not include the two largest primary prevention studies, the Women’s Health Study and the Physician’s Health Study, because they used alternate-day aspirin rather than daily aspirin. Both trials failed to find an effect on cancer. Nevertheless, they write, the researchers “show quite convincingly that aspirin seems to reduce cancer incidence and death across different subgroups and cancer sites, with an apparent delayed effect.”

“For most individuals, the risk-benefit calculus of aspirin seems to favour aspirin’s long-term anticancer benefit,” they state. However, current evidence does not support “a definitive conclusion about population-based recommendations regarding routine use of aspirin for cancer prevention.” They conclude that in the future guidelines “can no longer consider the use of aspirin for the prevention of vascular disease in isolation from cancer prevention.”
Click here to read the press release from the Lancet…

Metaanalysis Raises More Questions About Routine Use of Aspirin for Primary Prevention Reply

Although aspirin can reduce the risk of cardiovascular (CV) events, the associated increase in bleeding suggests that it should not be used routinely in  people without prior CV disease, say the authors of a new meta-analysis published in Archives of Internal Medicine.

Sreenivasa Rao Kondapally Seshasai and colleagues combined data from 9 clinical studies including more than 100,000 participants who were followed for a mean of 6 years. They found a significant reduction in CV events, but not CV mortality, and an increased risk of important bleeding events:
Click to continue reading…