December 10th, 2012
Selections from Richard Lehman’s Literature Review: December 10th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 6 Dec 2012 Vol 367
Aliskiren for Type 2 Diabetes (pg. 2204): Renin starts off the renin-angiotensin-aldosterone cascade, and it was inevitable that it would become a target for pharmacological blockade; just odd that it took so long. Had ACE inhibitors and angiotensin receptor blockers and aldosterone antagonists not got there first, renin antagonists like aliskiren would undoubtedly have become first-line drugs for hypertension and heart failure. In this RCT, the drug is compared with placebo in diabetic patients with cardiovascular disease and/or renal impairment who were already on treatment with an ACEI or ARB. The initial results were good: aliskiren lowers blood pressure and reduces albuminuria. So why don’t we prescribe it for all our high-risk diabetic patients, as we do other drugs for which we have only these end-points to go by? But wait: this Novartis trial actually measured death and cardiovascular events; and by the second interim analysis, these had become significantly more frequent in the aliskiren group. Oops: if only the trial had stuck to surrogates, all would have been well. But now there will be no market for aliskiren: she arrived too late on the scene, and was too well investigated.
Lancet 8 Dec 2012 Vol 380
Monoclonal Antibody to PCSK9 in Patients with Hypercholesterolemia (pg. 1995): The Lancet seems to have adopted a policy of filling its research section with reports of phase 2 trials. This is decidedly odd, since these trials are by definition useless to practising clinicians, dealing with preliminary safety issues and dose-finding in compounds which may be years away from licensing. Take the two Amgen-funded trials in this week’s Lancet: they deal with a new monoclonal antibody AMG145 which reduces low density lipoprotein cholesterol. Of course, the drugs of choice we use when we want to reduce LDL-C are the statins, which are so cheap, safe and effective that any other intervention is going to have a very hard time finding a market. The first of these trials was conducted in 52 centres and recruited 411 participants: “For ethical reasons related to conducting a placebo-controlled study in which some patients would receive no active antihyperlipidaemia treatment, we enrolled patients with low cardiovascular risk who did not require cholesterol lowering therapy.” OK, so these people were not actually “patients” at all but healthy volunteers with highish levels of LDL-C. And sure enough, AMG145, the new antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), resulted in lowering of LDL-C and seems not to have had any adverse effects in the short term.
Monoclonal Antibody to PCSK9 Plus Statin in Patients with Hypercholesterolemia (pg. 2007): The other Amgen phase 2 trial looked at the dosing and safety of AMG145 in 631 patients with hyperlipidaemia and a fasting LDL-C level above 2.2 mmol/L despite treatment with a statin and/or ezetimibe. Again, fortnightly or monthly injections of AMG145 reduced LDL-C levels. So the paper concludes that the next requirement is “a large phase 3 clinical trial with several years of follow-up to investigate the long-term clinical efficacy and safety of AMG 145 in patients at increased risk of cardiovascular events.” Yes indeed: a trial with real end-points and an active comparator, which may with luck be completed and reported by 2020. Until then, this drug is of absolutely no interest to 99% of readers of the Lancet. So what are these lengthy reports doing in the UK’s leading medical journal? Is the reprint income they may bring from Amgen really sufficient to justify such a waste of space? Exactly what is this journal supposed to be for?
Ann Intern Med 4 Dec 2012 Vol 157
Warfarin vs. New Oral Anticoagulants for Management of AF and VTE (pg. 796): For many years now I’ve been tracking the progress towards fixed-dose anticoagulation without INR monitoring in these columns. It’s a nice idea and of course an enormous market for drug companies: there are many agents and many RCTs. I’m amazed that the authors of this systematic review of their comparative effectiveness against warfarin could narrow the field down to just six, including trials for both atrial fibrillation and venous thromboembolism. Their conclusion is prosaic and rather obvious: “Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment.” If you have an excellent system for INR control, and patients are compliant, then the extra cost of these agents is not warranted at present. But when they come off patent, things may change, and INR testing may disappear and become one cost less for all health systems.
December 8th, 2012
Prolonged Anticoagulation with Apixaban Beneficial in Venous Thromboembolism
Larry Husten, PHD
A new study suggests that extending anticoagulant therapy for an additional year may be beneficial after patients with venous thromboembolism complete their initial course of therapy. The results of AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment) were presented at the annual meeting of the American Society of Hematology meeting in Atlanta and published simultaneously in the New England Journal of Medicine.
After completing a standard anticoagulation regimen for 6 to 12 months, 2486 VTE patients were randomized to either placebo or apixaban (2.5 or 5 mg twice daily) for an additional 12 months. At both doses, apixaban treatment was associated with a large reduction in clinical events and no increase in major bleeding events.
The primary endpoint, the composite of death or symptomatic recurrent VTE, was significantly lower in the low-dose and high-dose apixaban groups (3.8% and 4.2%, respectively) than in the placebo group (11.6%).
Very few major bleeding events occurred: 4 (0.5%) in the placebo group, 2 (0.2%) in the low-dose apixaban group, and 1 (0.1%) in the high-dose apixaban group. Clinically relevant nonmajor bleeds occurred in 2.3% of the placebo group, 3.0% of the low-dose apixaban group, and 4.2% of the high-dose apixaban group.
The investigators concluded that the results of the study “provide a rationale for continuing anticoagulation therapy” in VTE patients for whom there is uncertainty about the worth of continued anticoagulant therapy. They calculated that 14 patients would need to be treated to prevent one VTE case.
December 8th, 2012
ECG Screening via iPhone — Game Changer or Just a Game?
Shengshou Hu, M.D.
On my blog, Dr. Wes, I recently shared my experiences using AliveCor’s ECG Case for iPhone, for which I was a beta-tester. This device’s ease of use will, I think, make it a game changer for physicians and medically savvy patients. I have no commercial interest in AliveCor (frankly, I wish I did), so I share my thoughts with you here just as an honest observer.
Here, in brief, are what I consider to be the strengths and limitations of the device, which has now been approved by the FDA.
Strengths
- Ease of use (no technician), compelling design, handsome appearance
- Real-time recording
- Versatility of recording method (grasping electrodes by hand or placement of the device on the skin of the chest)
- ECG tracings can be uploaded, sent, and stored in a variety of formats
- My fellow physicians see it as a useful complement to the stethoscope
- Instant differentiation of atrial fibrillation from premature atrial or ventricular beats (or even from atrial flutter with variable AV conduction)
- The device can replicate most limb leads
- Patients are transfixed by what the device shows them
Limitations
- Case could be sturdier
- Alcohol prep may be needed for reading via placement on the skin
- Recordings from the device cannot yet be easily incorporated into an electronic medical record
- Single-lead device (multiple ECG leads are not collected simultaneously), so subtle indicators of a heart attack could be missed
- Patient information, including demographics, must be entered manually (the biggest minus, in my opinion)
- Ease of use outside a medical setting poses confidentiality challenges
As a member of the CardioExchange community, I am curious to hear your thoughts about how, if at all, this device will change practice.
December 7th, 2012
Heparin Labels Will Be Revised to Reduce Dosing Miscalculations
Kristin J. Kelley, CardioExchange Staff
Heparin manufacturers will now be required to state the total drug strength of the entire container on their labels, the FDA announced on Thursday. The revisions, proposed by the United States Pharmacopeia (USP) in order to avoid medication errors caused by dosing miscalculations, will take effect on May 1, 2013.
The new labels for heparin lock flush solution and sodium injection vials containing more than 1 mL must prominently display the drug strength per total volume, followed by the strength per mL in parentheses. For vials with less than 1 mL of heparin, the strength per fraction of a mL should be the only expression of strength on the label.
December 7th, 2012
Should Body Weight Influence Choice of Antihypertensive Therapy?
Larry Husten, PHD
The hypertension field has been troubled by repeated observations that normal weight patients have more cardiovascular (CV) events than obese patients. Now a new analysis of a large hypertension trial confirms this finding but also suggests that it may be explained by either an adverse effect of diuretics or a protective effect of calcium-channel blockers in non-obese hypertensives.
Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem. In 2008, the main results of the trial showed that the combination of benazepril and amlodipine (calcium channel blocker group, CCB) was superior to the combination of benazepril and hydrochlorothiazide (diuretic group) in reducing CV events in high-risk hypertensive patients.
The new analysis, published online in the Lancet, confirmed earlier observations and found significant differences in outcome based on weight. However, the differences in outcome occurred mostly in the diuretic group. In the diuretic group, the rate for the primary endpoint was significantly different between the groups (30.7 events per 1,000 patient-years in normal weight patients, 21.9 in overweight patients, and 18.2 in obese patients, p=0.0034). In the CCB group, the rates were not significantly different (18.2, 16.9, and 16.5).
To explain their finding, the investigators proposed that “hypertension in obese and lean patients is probably mediated by different forms of underlying pathophysiology.” Obese patients, who are more likely to have increased plasma volume and cardiac output, will be responsive to diuretics, while lean patients are more likely to have involvement of the sympathetic and renin-angiotensin systems. They concluded that “diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment, but thiazides are clearly less protective against cardiovascular events in patients who are lean. An alternative therapeutic regimen that includes a calcium channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”
In an accompanying comment, Franz Messerli and Sripal Bangalore write that the effectiveness of hydrochlorothiazide in obese people in ACCOMPLISH “has little if anything to do with obesity per se, but simply reflects the fact that among obese patients there was a preponderance of individuals at risk for heart failure who were prone to respond well to diuretic treatment.” They argue that “amlodipine-based treatment should be used irrespective of body size” for the indication of hypertension. Diuretics, on the other hand, should be used for the prevention of left-ventricular dysfunction.
December 5th, 2012
Aspirin Resistance May Not Be Real
Larry Husten, PHD
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 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 of 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, no instances of apparent aspirin resistance occurred in the group of 40 subjects who received plain aspirin. By contrast, 108 of the 360 subjects who received coated aspirin qualified as nonresponders when tested at either 4 hours or at 8 hours.
In the second phase of the study, the nonresponders 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” related 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 to the New York Times, Eric Topol disagreed with the study conclusions and pointed out that the study used only 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 of 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.
December 3rd, 2012
Selections from Richard Lehman’s Literature Review: December 3rd
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 28 Nov 2012 Vol 308
Aldosterone Antagonist Therapy, Mortality, and Readmission Among Patients with HF and Reduced EF (pg. 2097): Heart failure is a common process of dying which mostly affects people over the age of 75. Living with heart failure can be burdensome and unpredictable, and dying from heart failure can be awful, unless you are lucky enough to die suddenly. I thought I’d get those sentences out of the way first, because when we look at the evidence base for treating heart failure it’s easy to regard it as a “disease” rather than a process, and to regard death and hospitalization as the most important aspects of it, and as things that are potentially avoidable. Most people in their late seventies expect to have something wrong with them and to die before too many more years have gone by: their fear is not so much death itself as what they will have to go through before they die. So when I look at a paper about heart failure, I first check out the age of the population and then see if there are any clues about what the patients experienced as a result of the intervention, other than death and hospitalization.
The patients in this study of associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction had a mean age of 77: they were the same age as the real patients you and I deal with all the time. And in this observational study, it didn’t make a jot of difference to either end point whether they were taking aldosterone antagonists or not. They died and went to hospital at exactly the same rate, unlike the patients in the original landmark randomized trials of spironolactone and eplerenone, who showed a 30% decrease in both endpoints during these trials, which were both stopped early because of the magnitude of the effect. So why is there such a difference between the benefit in those studies and the lack of benefit we seem to observe here? There could be several reasons. The patients in the RALES trial were younger (mean age 65) and 45% of them had a non-ischaemic cause for their heart failure, whereas in this study it was less than 30%. The same applies to a lesser extent to the eplerenone trials. But I think the main clue in this observational study is that the patients who were taking these drugs were already taking higher doses of ACE inhibitors and ß-blockers than the comparison group. In other words, they were at a later stage of the heart failure process, and that’s why they had been given what most clinicians regard as third-stage treatment. And whether they felt any better on it is a question this study can’t answer: very few studies have ever bothered to ask.
Renin-Angiotensin System Antagonists and Mortality in Patients with HF and Preserved EF (pg. 2108): Half of all the elderly patients who have heart failure do not have a reduced systolic ejection fraction, and they live in a diagnostic and therapeutic no-mans land, despite being just as likely to die. Attempts to treat this kind of heart failure with renin-angiotensin system inhibitors have met with no success in randomized trials. But in this Swedish database study of patients with heart failure and preserved ejection fraction (defined as over 40%), the use of RAS antagonists was associated with lower all-cause mortality. A good editorial by James Fang speculates as to why this might be so, and sensibly suggests that rather than trying out RSA antagonists on everyone with this form of HF, we should use them preferentially to treat the large number who have elevated blood pressure.
Warfarin Therapy Duration After Bioprosthetic AVR and Risk of Mortality, Thromboembolic Complications, and Bleeding (pg. 2118): Travelling south across the straits from Sweden to Denmark, we turn to another registry-based study for cardiovascular enlightenment. “Through a search in the Danish National Patient Registry, 4075 patients were identified who had bioprosthetic aortic valve replacement surgery performed between January 1, 1997, and December 31, 2009. Concomitant comorbidity and medication were retrieved. Poisson regression models were used to determine risk.” The question here is whether warfarin therapy can safely be stopped at three months, as is common practice. But the analysis convincingly demonstrates that discontinuation of warfarin treatment within 6 months after bioprosthetic AVR surgery was associated with increased cardiovascular death. Usual practice may need to change.
NEJM 29 Nov 2012 Vol 367
Dalcetrapib in Patients with a Recent ACS (pg. 2089): The new blockbuster drugs to follow the statins were going to be high density lipoprotein cholesterol increasing drugs, such as the rapibs—inhibitors of cholesteryl ester transfer protein (CETP). But we are rapibly becoming disillusioned. First torcetrapib bit the dust, and now it is the turn of dalcetrapib. In this trial it increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events in patients who had recently had an acute coronary syndrome. The manufacturers of the last CETP inhibitor standing, anacetrapib, continue to pour money into a massive trial being organised by Oxford’s Clinical Trials Support Unit, which will not REVEAL its results until 2017. I am not holding my breath.
Bedside Monitoring to Adjust Antiplatelet Therapy for Coronary Stenting (pg. 2100): Another great money-spinner was going to be platelet function monitoring at the bedside to individualize treatment with the latest antiplatelet therapies: but this too is proving a dead end. “This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring” say the investigators of this large French trial. So it’s clopidogrel all round folks, and remember that it is now a very cheap drug.
November 29th, 2012
Following Earlier Recall, Ranbaxy Halts Manufacturing of Atorvastatin
Larry Husten, PHD
Ranbaxy, the often-troubled manufacturer of generic drugs, will temporarily stop manufacturing generic atorvastatin. On November 9, 2012, the company announced a voluntary recall of some lots of atorvastatin because of possible contamination with glass particles. An FDA statement today said that Ranbaxy will discontinue making the drug “until it has thoroughly investigated the cause of the glass particulates and remedied the problem.”
To date, no reports of harm from the contamination have been received by the FDA. Both FDA and Ranbaxy believe there is only a low likelihood that there will be adverse events related to the problem.
The FDA said it does not anticipate a shortage of atorvastatin because of the recall, but that it “is working with other manufacturers of atorvastatin to ensure adequate market supply.”
November 29th, 2012
European Medicines Agency Destroys the Dam: Slight Dampness Results
Richard Lehman, BM, BCh, MRCGP
It is odd how a dam can burst with hardly anyone noticing. For decades, the pharmaceutical industry has been conducting trials on its own products that have never been made public, though many of them have been disclosed to licensing agencies such as the FDA and the European Medicines Agency (EMA). These agencies have also received huge volumes of clinical study reports, trial protocols, and individual patient data that have been kept confidential. Until this year, the EMA has been dismissive of any attempts by researchers to gain access to such data. However, in the face of criticism from the European Ombudsman and the European Parliament, the EMA announced in April 2012 that it would be henceforth allowing access to all data submitted to it in applications for drug licensing in Europe, whether those applications were successful or not, and that it would be holding a workshop on data transparency in November to discuss the best methods of carrying out such disclosure proactively.
Many of us rushed to book places at this workshop, and it was so over-subscribed that months went by before we knew whether we had a seat for the meeting, which took place last week on November 22nd, at a time when most of you were getting up to face a day of family togetherness culminating in a turkey dinner.
Some of us were elated to hear the EMA’s Executive Director state at the beginning of the meeting that the EMA’s decision was irrevocable and that we were here to discuss how all data submitted to the EMA could be shared, not if. There was then a panel discussion in which two representatives of the European Federation of Pharmaceutical Industries and Associations expressed considerable disquiet about this decision, repeatedly citing considerations of commercial sensitivity and competitive disadvantage. Other members of the panel countered these objections and invited the pharma representatives to put their case to the public: Do people want trial data to be used for the commercial advantage of drug manufacturers, or for the public and health professionals to gain better information about the harms and benefits of the drugs that they use on millions of people every day?
In the second part of the meeting, similar arguments went back and forth, and there were few respondents who actually addressed the purpose of the meeting by offering concrete suggestions on how to optimize the proactive release of data submitted to the EMA from January 2014 onwards.
So the meeting was lively, momentous even, but not very productive. What most of us — including the panelists — had failed to notice was that the EMA is already releasing huge quantities of data. If you would like to see everything that has been submitted to the EMA relating to a drug already on the European market, simply apply while providing the purpose of your inquiry, and you will be given the whole file.
Yes, you read that right. The dam is already bust, and lies in pieces in Europe. The data that industry is trying so hard to fence in with legal restrictions, careful vetting of applicants, clauses about indemnity against commercial losses, etc., is in large part out there for open use if you have a reasonable case for accessing it. Moreover, the agency is trying to make the process more comprehensive, better structured, and proactive.
There is a clear challenge here to other licensing agencies such as the FDA. It is also a challenge to medical editors, and one that the BMJ has already decided to address by insisting that all authors disclose their full data for studies that it publishes from January 2013 onwards. Other leading journals will need to take note: the EMA decision calls time on the current model by which pharmaceutical companies design, conduct, and report phase-3 trials of their own new products in leading journals, and then buy up large numbers of reprints for promotional purposes. Products will henceforth be judged on the totality of data relating to the human trials in which they have been used — and about time, too.
