UK Politician Urges More Use Of Ticagrelor To Preserve AstraZeneca Jobs In UK 3

Use it or lose it. A UK politician is urging the National Health Service (NHS) to increase use of the antiplatelet drug ticagrelor (trade name Brilinta in the US, Brilique and Possia in the EU) in order to prevent the loss of British jobs.

Like nearly all the major pharmaceutical companies, AstraZeneca has been fighting a difficult cycle of patent expirations and unsuccessful new drugs, leading to repeated rounds of layoffs. But, according to the Manchester Evening News, the UK-based company, with the help of UK politicians, is  seeking to turn lemons into lemonade. Science Minister David Willetts is lobbying the National Health Service (NHS) “to increase its use of an AstraZeneca heart medicine, amid mounting political concern about the drugs company’s commitment to British jobs.

The minister, according to the paper, “has urged health officials to accelerate the uptake of Brilique [ticagrelor], a blood thinner used to treat patients suffering from severe angina or heart attacks, which has sold poorly despite winning a green light from the NHS’s cost-effectiveness watchdog in 2011.

AstraZeneca said although it invests heavily in producing new drugs in this country, it’s difficult to persuade primary healthcare trusts to adopt new costly medicines.

The group added: “Despite this recommendation and the NHS target of reducing the mortality rate from cardiovascular disease, it is currently only routinely available to patients in some parts of England.

“We share the NHS and the Government’s objective of broadening patient access to innovative medicines and continue to engage in dialogue.”

Hat tip: Lisa Jarvis (@lisamjarvis) and Matthew Herper (@matthewherper)

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Timing Of Heart Attacks Shifted In New Orleans After Katrina 3

Prior to Hurricane Katrina, heart attacks in New Orleans followed a well-known circadian and septadian (today’s word of the day, meaning day of the week) pattern, with predictable increases on Mondays and in the morning hours. Now a new study finds that the notorious 2005 hurricane dramatically altered that pattern for at least three years, shifting the pattern to a much greater than expected occurrence over nights and weekends.

Read my full story on Forbes.

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New Guidelines Define State-of-the-Art STEMI Care Reply

New guidelines published online today in Circulation and the Journal of the American College of Cardiology provide an efficient overview of the best treatments for STEMI patients. (Click here to download the PDFs of the full version (64 pages) or the executive summary  (27 pages) of the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction.)

“We’re looking to a future where more patients survive with less heart damage and function well for years thereafter,” said Patrick O’Gara, the chair of the guidelines writing committee, in a press release. “We hope the guidelines will clarify best practices for healthcare providers across the continuum of care of STEMI patients.”

The new document strongly supports the establishment and maintenance of regional systems to treat STEMI, which should include assessment and continuous quality improvement programs.

Primary PCI remains the preferred method of reperfusion when it can be performed by experienced operators in a timely fashion. For people who can’t receive primary PCI within 120 minutes of arrival, fibrinolytic therapy should be given within 12 hours of the the onset of symptoms.

The first medical contact (FMC)-to-device time should be 90 minutes at PCI-capable hospitals. Patients who arrive at non PCI-capable hospitals should be transported to a PCI-capable hospital within 30 minutes and should be treated with a FMC-to-device system goal of 120 minutes of less.

Drug-eluting stents should not be used in patients who can’t or won’t comply with long-term dual antiplatelet therapy (DAPT). After receiving a stent patients should receive DAPT with aspirin and either clopidogrel, prasugrel, or ticagrelor.

Click here to read the AHA press release…

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.

PCI Utilization Lower In States With Public Reporting Of Outcomes Reply

In patients with acute MI, utilization of percutaneous coronary intervention (PCI) is lower in states that publicly report outcomes data, according to a new study published in JAMA. Despite the difference in utilization, however, there was no difference in mortality between reporting and nonreporting states.

Karen Joynt and colleagues used Medicare data to analyze PCI utilization and mortality in acute MI patients in three states with public reporting of PCI outcomes (New York, Massachusetts, and Pennsylvania) and other states in the same region without public reporting. The differences in utilization were greatest in patients at highest risk, who presented with ST-segment elevation MI (STEMI), cardiogenic shock, or cardiac arrest.

  • Overall unadjusted PCI rate: 37.7% for reporting states versus 42.7% for nonreporting states
  • Risk-adjust odds ratio: 0.82, CI 0.71-0.93, p=0.003)

Overall mortality did not differ between the reporting and nonreporting states (12.8% and 12.1%, respectively; adjusted OR 1.08 (CI 0.96-1.20], p=0.20), although there was a significant mortality difference in the STEMI subgroup (13.5% vs. 11.0%; OR 1.35, CI 1.10-1.66, p=0.004).

In Massachusetts, where outcomes reporting was initiated during the course of the study period, PCI utilization was at first no different from the other nonreporting states, but was significantly lower than nonreporting states after the change.

The authors offer two potential explanations for the findings:

…the foregone procedures were futile or unnecessary, and public reporting focused clinicians on ensuring that only the most appropriate procedures were performed. Alternatively, public reporting may have led clinicians to avoid PCI in eligible patients because of concern over the risk of poor outcomes.

The mortality findings, they write, suggest “that the foregone procedures might have been a mix of appropriate and inappropriate PCIs.”

In an accompanying editorial, Mauro Mosucci writes that the mortality finding may be due to “a conscious or unconscious ‘futility assessment’” in states with public reporting,” leading to “avoidance of PCI for patients who are less likely to benefit.” Alternatively, “public reporting might have resulted in a drive toward improved quality of care and improved outcomes in patients receiving PCI, offsetting the adverse effect of not performing PCI in high-risk patients.” Mosucci also points out that the data may be skewed because public reporting might result in “gaming” the coding of cases.

Click here to read the press release from JAMA…

Registry Study Raises Questions About Cardioprotective Effect Of Beta Blockers 1

Although beta-blockers have been a cornerstone of therapy for patients with coronary artery disease for more than a generation, a new study published in JAMA suggests that that in the modern era beta blockers may not improve outcomes.

Sriapl Bangalore and colleagues analyzed data from 44,708 patients enrolled in the Reduction of Atherothrombosis for Continued Health (REACH registry), 31% of whom had a prior MI, 27% of whom had documented CAD without MI, and 42% of whom only had CAD risk factors. Patients who received beta blockers were compared with matched controls and were followed for a median of 44 months.

Beta-blocker use was not associated with a significant difference in the rate of cardiovascular death, nonfatal MI, or nonfatal stroke:

CAD patients with prior MI:

  • 16.93% in the beta-blocker group versus 18.60% in the controls, hazard ratio [HR] 0.90, CI 0.79-1.03, p = 0.14

CAD patients without prior MI:

  • 12.94% versus 13.55%, HR 0.92, CI 0.79-1.08, p= 0.31

Patients with risk factors only:

  • 14.22% versus 12.11%, HR 1.18, CI 1.02-1.36, p = 0.02

In their paper the REACH investigators point out that the evidence supporting beta blocker use after MI is now quite old, with most of the trials having been performed prior to the widespread use of modern reperfusion strategies and medical therapy. The presumed “cardioprotective” effect of beta blockers in patients without MI did not have an evidence base and was an extrapolation from heart failure trials and older post-MI trials. on the other hand, they note, current evidence does support the use of beta blockers in acute MI patients without shock or heart block.
Click here to read the press release from JAMA…

“Dramatic” Increase In Bleeding Accompanies Addition Of Oral Anticoagulant Therapy In ACS Reply

The newer oral anticoagulants may help reduce ischemic events after an acute coronary syndrome (ACS), but only at the cost of a “dramatic” increase in bleeding complications, according to a new meta-analysis published in the Archives of Internal Medicine.

Hungarian researchers performed a systematic review and meta-analysis of seven trials in which 31,286 ACS patients were randomized to placebo or a new oral anticoagulant, either an anti-Xa or direct thrombin inhibitor. All patients also received antiplatelet therapy. Here are the odds ratios for bleeding events and important clinical endpoints with the newer agents:

  • TIMI major bleeding events: OR 3.03 (2.20-4.16)
  • Overall mortality: OR 0.90 (0.76-1.06)
  • Composite ischemic events: OR 0.86 (0.79-0.94)
  • Stent thrombosis (definite or probable): OR 0.73 (0.54-0.98)

“These results suggest that the unrestricted use of new-generation oral anticoagulant agents as an adjunct to dual antiplatelet therapy after an ACS cannot be recommended,” the authors concluded. However, they left open the possibility that the newer oral anticoagulants may be beneficial in the 6%-21% of ACS patients who require long-term anticoagulation for atrial fibrillation and other conditions.

In an accompanying comment, Adrian Hernandez writes that “the conclusions of the meta-analysis seem to be robust.” He points out that the large differences in the relative risk of bleeding and clinical events found in the meta-analysis translate into smaller differences in absolute risk. Nevertheless, he writes, “the benefit is largely canceled by the harm; therefore, the routine use of [novel oral anticoagulants] among patients with ACS is unwarranted.”

 

News Briefs: Cholesterol Trends, AHA Late-Breakers, FDA Updates On Rivaroxaban And Heartware HVAD Reply

Cholesterol Trends

The Centers for Disease Control issued a new report with the latest details about the prevalence of cholesterol screening and high blood cholesterol in US adults. Here is their summary of the key findings:

…cholesterol screening increased from 72.7% in 2005 to 76.0% in 2009, whereas the percentage of those screened who reported being told they had high cholesterol increased from 33.2% to 35.0%. Previously identified demographic disparities persist.

AHA Previews LBCTs

The American Heart Association has published a preview of the late-breaking clinical trials scheduled for presentation in November at the scientific sessions in Los Angeles. 28 LBCTs have been selected, including the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial and the controversial Trial to Assess Chelation Therapy (TACT).

J&J Provides More Information To FDA About Rivaroxaban

Johnson & Johnson said today that it had fully responded to the FDA’s request for more information about the use of rivaroxaban (Xarelto) in patients with acute coronary syndromes. The company also said it had resubmitted its supplemental New Drug Application (sNDA) for the drug to reduce the risk of stent thrombosis in ACS patients.

Heartware HVAD Close To FDA Approval

The Heartware HVAD ventricular assist system may be approved soon by the FDA, according to Wells Fargo analyst Larry Biegelsen. Robert Kormos, a cardiothoracic surgeon at the University of Pittsburgh, who also consults for Heartware,  said during a session at a Society of Thoracic Surgeons symposium that the device would be approved in the next few weeks.

Republished with permission from CardioExchange, a NEJM group publication.

Unrecognized MI: More Prevalent And Dangerous Than Previously Suspected 2

Unrecognized myocardial infarction (UMI) is more prevalent, and is associated with a worse prognosis, than may be generally understood, according to a new study published in JAMA.

Studying an elderly (67-93 years of age) population in Iceland, Erik Schelbert and colleagues used ECG and cardiac magnetic resonance (CMR) to detect UMI. CMR was more effective than ECG at detecting UMI. The study established that UMI was twice as prevalent as recognized MI (RMI):

  • No MI: 74%
  • RMI: 10%
  • Unrecognized MI by ECG: 5%
  • Unrecognized MI by CMR: 17%

Diabetics were more likely to have UMI detected by CMR than by ECG. After 6.4 years of followup, mortality was higher in the RMI and UMI groups than in the group without MI:

  • RMI: 33% (CI 23% to 43%)
  • UMI: 28% (CI 21% to 35%)
  • No MI: 17%, (CI 15% to 20%)

After adjusting for other factors, UMI by CMR, but not UMI by ECG, significantly improved risk stratification for mortality. People with UMI by CMR were less likely than people with RMI to take cardiac drugs.

According to the authors, the large percentage of UMIs has not been understood in the past due to previous reliance on ECG data; thus “a significant public health burden” has not been fully appreciated.

Click here to read the JAMA press release…

Danish Survey Finds Clopidogrel Less Effective In Diabetics Reply

A large nationwide survey of MI survivors in Denmark provides new information about the efficacy of antiplatelet therapy with clopdiogrel in patients with diabetes. In a paper published in JAMACharlotte Andersson reports on 58,851 MI patients, 12% of whom had diabetes and 60% of whom received clopidogrel.

As expected, diabetics had a worse outcome than nondiabetics: the composite endpoint of recurrent MI and all-cause mortality occurred in 25% of diabetics compared with 15% of the nondiabetics. Overall mortality was 17% in the diabetic group compared with 10% in the nondiabetic group.

Clopidogrel was less effective in diabetics than in nondiabetics in reducing all-cause mortality and CV mortality:

  • All-cause mortality risk reduction: 11%for diabetics versus 25% for nondiabetics (p value for interaction = .001)
  • CV mortality risk reduction: 7% (nonsignificant) for diabetics versus 23% for nondiabetics (p value for interaction = .01)

The results lend support to the hypothesis that “there may be a difference of effect of clopidogrel among those with diabetes compared with those without it,” wrote the authors. After acknowledging that “use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes,” they then raise the “possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes.”

In an accompanying editorial, Deepak Bhatt lends support to their suggestion, writing that it is plausible to suspect that there is “something about patients with diabetes that makes them less likely to respond to standard antiplatelet therapy.” Compared with nondiabetics, diabetics with coronary artery disease have increased platelet reactivity.  Bhatt writes that the newer and more potent antiplatelet agents prasugrel and ticagrelor may be more effective in diabetics, though they may also cause an increase in the risk of bleeding, and they cost more than clopidogrel, which has now gone generic.
Click here to read the press release from JAMA…

ESC: Trial Finds No Benefit For Intraaortic Balloon Counterpulsation In Cardiogenic Shock 2

Despite a lack of evidence, circulatory support with intraaortic balloon counterpulsation (IABP) has a class 1 recommendation in the guidelines and is often used in patients in cardiogenic shock following myocardial infarction for whom early revascularization is planned. That situation may change soon, as no benefit was found for the use of IABP in the first large trial of the strategy.

The IABP-SHOCK II (Intraaortic Balloon Pup in Cardiogenic Shock II) was presented at the ESC and published simultaneously in the New England Journal of Medicine. Trial investigators, led by Holger Thiele, randomized 600 acute MI patients in cardiogenic shock to either IABP or no IABP. At 30 days there were no significant differences in mortality, the primary endpoint of the study:

  • Mortality: 39.7% in the IABP group versus 41.3% in the control group (relative risk with IABP 0.96, CI 0.79-1.17, p=0.69)

There were no significant differences between the groups in secondary endpoints, process-of-care outcomes, or safety endpoints, including stroke and bleeding.

In an accompanying editorial, Christopher O’Connor and Joseph Rogers write that the trial “could have affirmed contemporary clinical practice and guidelines” but, “instead, it revealed surprising results.”

“Members of guidelines committees and clinicians should take note of another example of a recommendation that is based on insufficient data,” they wrote.

Click here to read an interview on CardioExchange with the principal investigator Holger Thiele.

Republished with permission from CardioExchange, a NEJM group publication.

TRILOGY At ESC: No Advantage For Prasugrel Over Clopidogrel In Medical ACS Patients Reply

The newer antiplatelet agent prasugrel was no better than the old standby clopidogrel for treating patients with acute coronary syndrome (ACS) who are not undergoing revascularization. The results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial were presented by Matt Roe at the European Society of Cardiology meeting in Munich and published simultaneously in the New England Journal of Medicine.

In the primary analysis of the trial, prasugrel (10 mg daily) was compared with clopidogrel (75 mg daily) in 7243 ACS patients younger than age 75. At 17 months, the rate of CV death, MI, or stroke did not differ significantly between the two groups:

  • 13.9% in the prasugrel group versus 16.0% in the clopidogrel group (hazard ratio [HR] for prasugrel, 0.91; 95% CI, 0.79-1.05, P=0.21)

The results were similar in a secondary analysis, which also included 2083 patients who were age 75 or older and who received either  low-dose prasugrel (5 mg daily) or the standard clopidogrel dose.

In a separate prespecified analysis, prausgrel patients under age 75 had a decreased risk for multiple recurrent ischemic events (HR, o.85; 95% CI, 0.72-1.00, P=0.04). According to the TRILOGY investigators, this finding is consistent with results from the earlier TRITON trial. TRITON compared prasugrel with clopidogrel in ACS patients undergoing revascularization; recurrent ischemic events in the prasugrel group were reduced by 30%, with most of the reduction occurring later in the trial. “Although this observation is exploratory,” the TRILOGY investigators wrote, ” it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional” in previous studies.

The prasugrel and clopidogrel groups did not differ significantly in the rate of severe and intracranial bleeding. However, within the younger subgroup (taking the higher prasugrel dose), prasugrel recipients had more major and minor bleeding complications than clopidogrel recipients did — a reflection, the authors wrote, of “the more intense platelet inhibition with prasugrel.”

An exploratory analysis found that in the main group of patients under the age of 75, the Kaplan-Meier curves for the primary endpoint and for the individual components of the endpoint were not different for the first year but diverged afterward in favor of prasugrel. “The reasons for this finding remain uncertain,” the investigators wrote.

A subgroup analysis suggested the possibility that prasugrel might be more effective than clopidogrel in current or recent smokers, in patients who underwent angiography prior to randomization, and in patients taking a proton-pump inhibitor.

Sanjay Kaul provided the following comment:

“I find the TRILOGY investigators’ focus on time-dependent treatment effect (greater benefit after 12 months of treatment exposure) and recurrent events, both of which favor prasugrel, an attempt at cherry picking the data that portray prasugrel in the best light. The bottom line is that given the lack of a statistically discernible difference in the primary efficacy endpoint coupled with an increase in TIMI major or minor bleeding and increased cost associated with prasugrel, it is hard to make a case for prasugrel over clopidogrel treatment in low- to moderate-risk patients with unstable angina and NSTEMI who do not undergo revascularization. Although TRILOGY was not adequately powered to detect a cancer signal, the lack of increase in new nonbenign neoplasms is somewhat reassuring.”

Republished with permission from CardioExchange, a NEJM group publication.

New Universal Definition Of MI Unveiled At ESC 2012 1

A new universal definition of myocardial infarction (MI) was unveiled today at the European Society of Cardiology meeting in Munich. The document was developed jointly by the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA) and the World Heart Federation (WHF) and will be published in five journals: the European Heart Journal, the Journal of the American College of CardiologyCirculationGlobal Heart and Nature Reviews Cardiology. (The document  was scheduled to go online on Sunday but is now available, along with extensive support material, on the American Heart Association website.)

The third universal definition of MI establishes the troponin levels required to make a diagnosis of MI in various situations. In a press release, Kristian Thygesen, the co-chair of the document task force, discussed the difficulties the task force encountered in reaching a consensus. Setting a troponin level for procedure-related MIs is difficult “because interventional cardiologists and surgeons do not want myocardial infarction as a complication,” he said. “It means that they want to set the levels of troponin as high as possible. It was also difficult to reach a consensus because it’s impossible to conduct a clinical trial to find the answer.”

The Task Force also expects the new definition will be adopted by the FDA and will be used in clinical trial protocols accepted by the FDA. Said Thygesen, “this is significant because it will help to standardize the way myocardial infarction is defined in clinical trials, making comparisons between trials more meaningful. Steering committees that write protocols for clinical trials do follow FDA requirements.”

Here is a summary of the new definition from a FAQ published by the AHA:

The preferred biomarker overall and for each specific category of MI is cardiac troponin (cTn) (I or T), which has high myocardial tissue specificity as well as high clinical sensitivity. An increased cTn concentration is defined as a value exceeding the 99th percentile of a normal reference population (upper reference limit, URL).

Myocardial infarction is determined by the specified cTn value, and at least one of the five following diagnostic criteria:

  1. Symptoms of ischemia
  2. New (or presumably new) significant ST/T wave changes or LBBB
  3. Development of pathological Q waves on ECG
  4. Imaging evidence of new loss of viable myocardium or regional wall motion abnormality
  5. Identification of intracoronary thrombus by angiography or autopsy

NHLBI Announces 7000 Patient Trial Testing Inflammation Hypothesis 2

The National Heart, Lung, and Blood Institute (NHLBI) has announced the launch of a large  clinical trial testing the inflammation hypothesis. Paul Ridker is the principal investigator of the trial, which will be known as  the Cardiovascular Inflammation Reduction Trial (CIRT).

CIRT will enroll 7,000 patients who are stable following a heart attack but are at high risk for a recurrent event because they have either type 2 diabetes or metabolic syndrome. Trial subjects will be randomized to low dose methotrexate or placebo. The primary outcome measure is the rate of recurrent major cardiovascular events (MI, stroke, and cardiovascular death). Low dose methotrexate is now used to treat rheumatoid arthritis.

“If this generic drug, which is already on the market at low cost, proves effective for reducing risk of heart attacks, stroke, or death, it has the potential for broad public health impact in saving lives and reducing disease,” said Ridker, in an NHLBI press release.

The NHLBI said that site selection will begin in November 2012 and patient recruitment will start in March 2013. Patients will be followed for an average of 2.5 years.

Resources:

Click here to read the NHLBI press release…

TNF Inhibitors Linked To MI Reduction In Psoriasis Patients 1

Psoriasis patients who take TNF inhibitors have a significant reduction in the risk for myocardial infarction (MI), according to a retrospective cohort study published in Archives of Dermatology. Although previous research suggested that the anti-inflammatory effects of methotrexate, an older therapy, may be beneficial in this population, the cardiovascular effects of TNF inhibitors had not been well studied.

Researchers identified 8845 patients who were diagnosed with psoriasis or psoriatric arthritis within the Kaiser Permanente Southern California health plan. After a median of 4.3 years of observation, the overall rate of MI was 5.21 per 1000 patient-years.

  • In the 1673 patients who received a TNF inhibitor (etanercept, infliximab, or adalimumab), the MI rate was 3.05 per 1000 patient-years.
  • In the 2097 patients who received oral therapy or phototherapy, the MI rate was 3.85 per 1000 patient-years.
  • In the 5075 patients who received topical therapy, the MI rate was 6.73 per 1000 patient-years.

TNF inhibitors and oral therapy/phototherapy were each superior to topical therapy, but the difference between TNF inhibitors and oral therapy/phototherapy was not significant. Compared with topical agents, TNF inhibitors and oral agents/phototherapy had hazard ratios (adjusted for other risk factors) of 0.50 and 0.54, respectively.

The authors write, “This is the first large scale retrospective cohort study to show that the use of TNF inhibitors for psoriasis is associated with a clinically and statistically significant reduction in MI risk and incident rate compared with psoriatic patients treated with topical agents.” However, they note that “prospective studies are needed and warranted to determine whether the use of TNF inhibitors may reduce the risk of major adverse cardiovascular events in patients with systemic inflammatory conditions.”

Click here to read the press release from Archives of Dermatology…

Troponin Test May Allow Rapid MI Rule-Out in the Emergency Department Reply

More than three-quarters of people with chest pain can be triaged within an hour of arrival at the emergency department with a novel strategy utilizing high-sensitivity cardiac troponin (hs-cTnT), according to a study from Switzerland published in the Archives of Internal Medicine. The strategy is promising, according to anaccompanying editorial, but much work remains before it can be implemented in clinical practice.

Tobias Reichlin and colleagues first studied 436 patients and developed a treatment algorithm utilizing hs-cTnT baseline changes and absolute changes over the initial hour. The algorithm was then tested in a second validation cohort of 436 patients, with the following results:

  • 60% were classified as “rule-out”
  • 17% were classified as “rule-in”
  • 23% required further observation
  • Overall sensitivity and negative predictive value: 100% for rule-out
  • Specificity for rule-in: 97%
  • Positive predictive value for rule-in: 84%
  • Prevalence of MI in the observational group:  8%
  • 30-day survival: 99.8% in the rule-out group, 98.6% in the observational group, and 95.3% in the rule-in group

The authors claim that their strategy “may obviate the need for prolonged monitoring and serial blood sampling in 3 of 4 patients.”

In an accompanying comment, L. Kristin Newby writes that the Swiss study “is a major advance in understanding the application of hsTn testing that with continued development could substantially improve evaluation of ED patients with suspected MI.” However, she notes that the excellent results obtained in this initial study will probably not be equalled in the real world. In addition, she writes, “although touted as ‘simple’ by the authors, the need for multicomponent algorithms that are different for rule-in and rule-out and that vary by age group or other parameters will challenge application by busy clinicians unlikely to remember or accurately process the proposed algorithm. As such, it will be imperative that hsTn algorithms, if validated, are built into clinical decision support layered onto electronic health records so that testing results are provided electronically to physicians along with the algorithmic interpretation to allow systematic application in triage and treatment.”
Click here to read the press release from Archives…

RIFLE-STEACS: Radial Access Improves Outcome In Early Invasive Therapy Reply

For early invasive therapy for  ST-segment elevation acute coronary syndrome (STEACS), the use of radial access instead of femoral access reduces bleeding complications and improves outcomes, according to the results of the first large randomized trial testing the two approaches in this population. The results of the Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome (RIFLE-STEACS) study were published online in the Journal of the American College of Cardiology.

Investigators in Italy and the Netherlands randomized 1,001 patients with acute STEACS to either the radial or femoral approach. At 30 days the composite of cardiac death, stroke, myocardial infarction, target lesion revascularization, and bleeding (net adverse clinical events, or NACEs) was significantly lower in the radial group than in the femoral group. Cardiac deaths, bleeding complications were also reduced in the radial group, though there were no significant differences in MI, target lesion revascularization, or stroke. Hospital stay was shorter in the radial group.

  • NACEs: 13.6% in the radial group vs 21% in the femoral group, p= 0.003
  • cardiac deaths: 5.2% vs 9.2%, p =0.020)
  • bleeding: 7.8% vs 12.2%, p =0.026
  • hospital stay: 5 days vs 6 , p =0.03

The door-to-balloon time was similar in the two groups, but radial access slightly prolonged the time from artery puncture to first balloon inflation.

The result, said the authors, “corroborates the link between mortality and ‘clinically relevant’ access site bleeding.” They speculated that the beneficial effect of the radial approach may be due to reductions in bleeding-related hemodynamic compromise, the need for blood transfusion, and lifesaving drug discontinuation. More rapid mobilization of the patient may also play a role.

Radial access, the authors concluded, “should become the recommended approach in these patients, provided adequate operator and center expertise is present.”

ROMICAT-II Provokes Opposing Views On CT Angiography In The Emergency Department 1

For patients with suspected acute coronary syndromes (ACS) CT angiography (CTA) compared to standard treatment can reduce the time in the emergency department (ED), according to results of the ROMICAT-II (Rule Out Myocardial Infarction/Ischemia Using Computer-Assisted Tomography) trial published in the New England Journal of Medicine. However, CTA resulted in more tests being performed and increased radiation exposure.

1000 patients with possible ACS but without ECG signs of ischemia or a positive troponin test were randomized to either CTA or standard treatment. The primary endpoint of the study, the mean length of hospital stay, was reduced from 30.8 hours in the standard evaluation group to 23.2 hours in the CTA group, a highly significant reduction of 7.6 hours (p<<0.001). In addition, many more patients in the CTA group were discharged directly from the ED (47% vs 12%, P<0.001). There were no cases of undetected ACS in either group and very few major adverse cardiovascular events (2 vs 6, p=0.18). Half of the patients in the CTA group were discharged within 8.6 hours, compared with only 10% of the controls.

ED and hospital costs were similar in both groups. Radiation exposure was increased in the CTA group (13.9 mSv vs 4.7 mSv) and more diagnostic tests were performed  in the CTA group.

The authors concluded that their “data should allow providers and patients to make informed decisions about the use of this technology as an option for evaluation when symptoms are suggestive of an acute coronary syndrome.”

Schrödinger’s ROMICAT

In contrast to the neutral presentation of the authors in the NEJM paper, strikingly different positions about the utility of CT angiography were taken in an accompanying editorial by Rita Redberg and a press release issued by the National Heart Lung and Blood Institute, which sponsored the study.

In her editorial, Redberg writes:

 Although shorter lengths of stay in the hospital are highly desirable, especially from the patient’s point of view, the ROMICAT-II study reveals a deeper flaw in the approach to chest pain in the emergency department. The underlying assumption… is that some diagnostic test must be performed before discharging these low-to-intermediate-risk patients from the emergency department. This assumption is unproven and probably unwarranted. The rationale for any test, as compared with no testing, should be that it will lead to an improved outcome, and here there is no evidence that the tests performed led to improved outcomes.

Redberg points out that the very low (under 1%) rate of patients who actually had an MI in the study means “that it is impossible to know whether the CCTA groups received any benefit whatsoever.” Further, factoring in radiation doses  both from CTA and nuclear stress tests and adverse reactions to contrast dye, “clinicians may legitimately ask whether the tests did more harm than good.”

For patients like those in ROMICAT II, with normal ECG findings and negative troponin tests, “multiple studies show no evidence that any additional testing further reduces that risk.”Although CTA can reduce length of stay in the hospital compared to standard care, “it is even faster to discharge these patients without any additional diagnostic test after determining that their ECG findings and troponin levels are normal.” She concludes:

In short, the question is not which test leads to faster discharge of patients from the emergency department, but whether a test is needed at all.”

By contrast, the NHLBI press release focuses exclusively on the benefits of CTA and lacks any significant discussion of its potential limitations, as presented in the NEJM paper and as discussed in detail by Redberg. The press release quotes Susan Shurin, the acting director of the NHLBI:

Identifying the underlying cause of chest pain more quickly with CT scans could allow medical care providers to better allocate limited resources to the patients who are most in need of treatment.

The principal investigator of the study, Udo Hoffmann, says that ROMICAT II can “help health care providers and patients make better informed decisions by knowing the risks and potential benefits of using CT scans to more quickly diagnose acute coronary syndrome,” but he glosses over the risks and then focuses on the benefits:

“It can be a relief to patients with chest pain to quickly know they are not having a heart attack and that they can spend the night at home, instead of in a hospital bed.”

Finally, the press release gives short shrift to the radiation issue:

Participants in the CT group were exposed to more radiation than those in the standard screening group, though the study authors suggested that future CT scans could be done using less radiation, which could help lower exposure without sacrificing accuracy.

Click here to read the NHLBI press release…

Elevated Risk of Acute MI Following Total Hip And Knee Replacement Surgery 1

A large study reports a high increased risk for acute MI (AMI) in the first 6 weeks after total-hip replacement (THR) or total-knee replacement (TKR) surgery. Analyzing a nationwide cohort from Denmark that included 95,227 patients who underwent THR or TKR and matched controls, Arief Lalmohamed and colleagues calculated the adjusted hazard ratios (HR) for AMI. Their results are published in the Archives of Internal Medicine.

The risk for AMI was significantly higher in the first two postoperative weeks for both THR and TKR, but the risk was higher only in the THR group for weeks 2 through 6.

Adjusted HR, Weeks 1 to 2:

  • THR: 25.5 (95% CI, 17.1-37.9)
  • TKR: 30.9 (95% CI, 11.1-85.5)

Adjusted HR, Weeks 2 to 6:

  • THR: 5.05 (95% CI, 3.58-7.13)
  • TKR: 0.81 (95% CI, 0.37-1.77)

At 6 weeks, the absolute rate of AMI was 0.51% in the THR group and 0.21% in the TKR group. The only significant effect modifier identified by the investigators was age, with the greatest excess risk found in patients age 80 or older. By contrast, no increase in risk was found in patients younger than 60 years.

In an accompanying commentary, Arthur Wallace writes that the study “once again confirms that the perioperative period increases cardiac risk. Physicians must go further than establishing risk factors; physicians must actively work to reduce perioperative risk.” Risk can be reduced with the appropriate use of preoperative beta-blockers, clonidine, statins, and aspirin, he writes. Despite level 1 evidence supporting the use of antiischemic agents, many physicians discontinue their use in the perioperative period, he notes.
Click here to read the press release from Archives…

Ticagrelor Joins Clopidogrel And Prasugrel In Updated NSTEMI Guidelines Reply

Ticagrelor (Brilinta, AstraZeneca) gains equal standing with prasugrel (Effient, Lilly) and clopdiogrel in the newly released focused update of the ACCF/AHA guidelines for unstable angina and non-ST-elevation myocardial infarction (NSTEMI). The change had been widely anticipated since last year’s FDA approval of ticagrelor.

“We have put it on equal footing with two other antiplatelet medications, clopidogrel and prasugrel,” said Hani Jneid, the, lead author of the update, in a press release issued by the AHA.

As part of the standard of dual-antiplatelet therapy (DAPT), aspirin should be given immediately to patients with unstable angina and NSTEMI. Aspirin use should be continued for “as long as it is tolerated.”

The document offers a highly detailed, near-Talmudic analysis of the literature, with a great deal of attention devoted to analysis of the  TRITON-TIMI 38 trial of prasugrel and the PLATO trial of ticagrelor. Overall, the committee concluded:

This guideline explicitly does not endorse one of the P2Y12 receptor inhibitors over the other.

However, based on data from the trials, the document provide ssome advice about the selection of the P2Y12 receptor inhibitors in specific situations, and related issues involving clopidogrel resistance.

–Because prasugrel was administered only after PCI had been planned, the writing group “does not recommend that prasugrel be administered routinely to patients with UA/NSTEMI before angiography.”

–The writing group cautions “clinicians about the potential increased bleeding risks associated with prasugrel and ticagrelor compared with clopidogrel in specific settings and especially among the subgroups identified in the package insert and clinical trials.”

–The document reviews at length the issue of clopidogrel resistance, but concludes “there is little information about the use of strategies to select patients who might do better with newer P2Y12 receptor inhibitors.”

–On genotype testing for loss-of-function CYP2c19 alleles: “On the basis of the current evidence, it is difficult to strongly recommend genotype testing routinely in patients with ACS, but it might be considered on a case-by-case basis, especially in patients who experience recurrent ACS events despite ongoing therapy with clopidogrel.”

–On platelet function testing: “any strong recommendation regarding more widespread use of such testing must await the results” of ongoing trials…. the prudent physician should maintain an open yet critical mind-set about the concept until data are available…”

–On the use of proton pump inhibitors and clopidogrel: “The expert consensus statement does not prohibit the use of PPI agents in appropriate clinical settings, yet highlights the potential risks and benefits from use of PPI agents in combination with clopidogrel.”

Click here to read the press release from the AHA…

Stem Cell Therapy Company Hypes Preliminary Results 3

Update (July 6)–  I have heard from several investigators in the trial that the Osiris press release was issued without any input or consultation from the site investigators. In fact, the site investigators, including several who are  extremely experienced clinical trialists, have expressed frustration and disappointment because their input has not been sought at any point during the trial. In most multi-center trials it is common practice to consult with the sites, and in particular the top-enrolling sites. In this case, the highest enrolling sites have had no significant involvement in the trial design or conduct. One investigator said he “had never worked with a company like this.”

Another member of the steering committee told me that the committee had not met in a long time and has not seen the trial data. In fact, steering committee members were not even aware that Mark Vesely, an assistant professor at the University of Maryland, was the principal investigator of the study. One steering committee member said he’d never heard of him before reading the press release.

A biotech company has been accused of releasing preliminary and misleading information about a clinical trial. The company, Osiris Therapeutics, is the manufacturer of  a cultured mesenchymal stem cell therapy called Prochymal, which is being studied in a phase 2, placebo-controlled study in post-MI patients. Earlier this week Osiris issued a press release announcing preliminary results from the trial, in which 220 patients have been randomized, claiming that Prochymal “significantly reduces hypertrophy, arrhythmia and progression to heart failure in patients suffering a heart attack.” But Adam Feuerstein, a veteran biotech reporter for The Street, accuses the company of distorting the truth about the trial.

Osiris “disappeared” important data in its press release, Feuerstein writes in his detailed analysis of the press release. He quotes the press release:

Patients receiving Prochymal had significantly less cardiac hypertrophy, as measured by cardiac MRI, compared to patients receiving placebo (p [less than] 0.05). Patients treated with Prochymal also experienced significantly less stress-induced ventricular arrhythmia (p [less than] 0.05).

Feuerstein comments:

Sounds impressive except none of the Prochymal benefits disclosed by Osiris are predefined endpoints in the phase II trial.

Osiris appears to have thrown out the real endpoints called for in the phase II trial and replaced them with new endpoints which just happen to show Prochymal in the best light. Why would Osiris do this? Perhaps the pre-defined endpoints in the study all failed? That’s a pretty safe assumption when companies decide to swap out trial endpoints with no disclosure or explanation.

Feuerstein points out that the primary endpoint of the trial, as listed on Clinicaltrials.gov, is left ventricular end systolic volume (ESV), while the secondary endpoints are  left ventricular ejection fraction (LVEF), infarct size and major adverse cardiovascular events (MACE). Writes Feuerstein: “Osiris’ silence on the outcomes of these two important endpoints (ESV and LVEF) should be deafening to investors — and not in a good way.”

The Osiris press release also claims “a statistically significant reduction in heart failure”:

In the study, seven patients who were treated with placebo have progressed to heart failure requiring treatment with intravenous diuretics, compared to none of the Prochymal patients (p=0.01). Furthermore, patients receiving placebo tended to require re-hospitalization for cardiac issues sooner than the patients receiving Prochymal (median 27.5 days vs. 85.5 days).

However, as Feuerstein writes, “these weren’t predefined endpoints”:

Importantly, Osiris doesn’t disclose the time point at which these purported benefits occurred, nor does the company tell us anything about the number of patients analyzed. How was heart failure defined? Osiris doesn’t say. What was the baseline incidence of heart failure in the study? Osiris doesn’t say. The study only allowed for a single infusion of Prochymal or a placebo immediately after the first heart attack but patients were followed for six months or a year, so how do follow-up therapies in each arm of the study compare? Were they balanced? Again, Osiris doesn’t say.

In the press release a company official announces an extension of the trials duration:

Given the quality of the data and highly encouraging results observed thus far, we are extending the trial’s duration to capture a better understanding of the long-term clinical benefits of MSCs.”

But the company offers no explanation for the extension. Writes Feuerstein:

Perhaps Osiris is extending the phase II study to delay the reporting of negative results? Again, that’s a pretty safe assumption absent a better explanation.

Note: I’ve requested comments from Osiris and from several trial investigators.

FDA Rejects ACS Indication for Rivaroxaban (Xarelto) 2

The FDA has issued a complete response letter to the supplemental new drug application (NDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) in patients with acute coronary syndrome (ACS). The action was expected, since last month the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against recommending the new indication, which was based on the pivotal ATLAS ACS 2-TIMI 51 trial.

In a press release a J&J company official said the company remains “confident in the robust results of the ATLAS ACS 2 TIMI 51 trial and the positive benefit-risk profile of rivaroxaban in patients with ACS. We will continue to work with the FDA to fully address their questions as quickly as possible.” Rivaroxaban is currently approved for the prevention of clots following knee replacement and hip replacement surgery and for the prevention of strokes and blood clots in people with atrial fibrillation.

Click here to read the press release from J&J…

Live Blog: The FDA Advisory Panel For Rixaroxaban for ACS 1

Here’s my live-blogg of the FDA’s Cardiovascular and Renal Drugs Advisory Committee meeting to consider the supplemental new drug application (sNDA) for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. Here is a link to the FDA briefing documents.

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4:48: Meeting adjourned! J&J has just issued a press release saying they will “ensure the questions raised today are addressed with the FDA.”

4:45: Temple is raising the possibility that the FDA might ultimately approve rivaroxaban for ACS. I would not be shocked if this were to happen.

4:38: Now discussing whether the FDA should say about the use of rivaroxaban with thienopyridine. All agree that people should be on a thienopyridine. What about prasugrel and ticagrelor? Nissen says the reality is that rivaroxaban will be given with these drugs, even though there’s no evidence. This was part of his reasoning in voting no. Sager said he would be more concerned about prasugrel, because of the excess risk of bleeding associated with prasugrel. But he notes there is no evidence to support use with either drug.

4:33: Moving on to questions about what to do if rivaroxaban is approved. Everyone agrees that the 2.5 dose is the dose that would get approved.

4:30: Kaul said he wished he had had the courage to abstain (to general laughter) and said he agrees with Fleming that he’d rather advise than vote, and that there was a very fine line between yes and no today.

4:24: Nissen thinks the decision to use mITT– which is counting events at 30 days after stopping treatment– is what doomed ATLAS. With mITT, he says, you’re telling the investigators and the patients that you don’t care so much about what happens to them long term. Nissen thinks the drug could be approvable if there were a second trial, but he also says its possible that the mortality benefit would not be replicated. He’s worried about exposing hundreds of thousands of patients to a three-drug regimen and causing lots of bleeding complications.

4:18: Results: Yes 4, No 6, 1 Abstain!

Voting breakdown:
Click to continue reading…

Rivaroxaban For ACS Gets Positive FDA Review, But Questions About ATLAS Trial Conduct Persist 2

The FDA will offer generally positive but also highly mixed advice to the FDA’s Cardiovascular and Renal Drugs Advisory Committee  when it meets on Wednesday to consider the supplemental new drug application for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. The FDA posted the briefing documents on its website this morning.

Although the primary clinical review and the statistical review support approval for the new indication (the drug is already approved for venous thromboembolism prophylaxis and stroke prevention in AF), one reviewer, Thomas Marciniak, the Medical Team Leader, issued a blistering memorandum suggesting that the supporting data, plagued by missing and inconsistent records in the pivotal ATLAS ACS 2-TIMI 51 trial, “may not support the favorable statistical results.”

The primary clinical reviewer, Karen Hicks, recommended approval for the 2.5 mg BID dose (but not the 5 mg dose) of rivaroxaban for ACS. She noted that the lower dose reduced the combined endpoint of CV death, nonfatal MI, or nonfatal stroke  in the ATLAS trial, with most of the benefit driven by a reduction in CV death, with little or no difference in MI or stroke. The higher 5 mg dose increased bleeding risk in the trial without providing additional efficacy, she concluded. She did not recommend a mortality indication for the label. Her views generally coincide with the reception of the ATLAS trial following its presentation and publication in the New England Journal of Medicine.

It should be noted that Hicks hedged her endorsement with a potentially significant caveat:
Click to continue reading…

The Medicines Company Collaborates with AstraZeneca To Sell Brilinta (ticagrelor) Reply

The Medicines Company will collaborate with AstraZeneca to help sell Brilinta (ticagrelor), AstraZeneca’s struggling oral antiplatelet drug. The collaboration is the first stage of  “a global collaboration for acute ischemic heart disease compound” announced by the two companies today.

AstraZeneca will pay $15 million per year for The Medicines Company’s Brilinta-related sales activities, scheduled to begin in May. The two companies also plan to collaborate on two other drugs from The Medicines Company, Angiomax (bivalirudin), the direct thrombin inhibitor, and cangrelor, an acute intravenous antiplatelet agent. Details of these collaborations have not yet been established.

Like many other large pharmaceutical companies, AstraZeneca has been seeking new sources of revenue after the expiration of patents for many of its key drugs. Initial hopes that Brilinta would provide a much-needed boost to the company have so far not been realized. The Medicines Company has also sought to find a successor to Angiomax, which has been the company’s mainstay.

Click here to read the press release from AstraZeneca and The Medicines Company…