June 19th, 2014
Genetic Studies May Help Unravel the Triglyceride Problem
Larry Husten, PHD
The precise role of triglycerides in heart disease has been very difficult to determine. To help untangle the knotty problem two research groups studied large populations and identified rare variations in a gene (APOC3) that encodes for apolipoprotein C3, which is known to increase triglyceride levels.
In the first paper, published in the New England Journal of Medicine, an NHLBI working group sequenced the genes of 3,734 people and identified several rare loss-of-function variants of APOC3. As expected, people with the variants had significantly lower triglyceride levels. The researchers then analyzed data from more than 110,000 participants in 14 studies and observed that people with the same loss-of-function mutations had a 40% lower risk for coronary heart disease.
The results, write the authors, “show that loss of APOC3 function confers protection against clinical coronary heart disease,” though they were unable to identify a primary mechanism linking APOC3 to heart disease.
In the second paper, also published in the New England Journal of Medicine, researchers used data from more than 75,000 participants in two large Danish prospective studies to explore the role of APOC3. People with APOC3 loss-of-function mutations had triglyceride levels reduced by 44%, with corresponding risk reductions of 41% for ischemic vascular disease and 36% for ischemic heart disease.
In both studies the APOC3 mutations were also linked to elevated HDL levels and other changes in lipid values. The authors of both papers write that their findings suggest that APOC3 might make for an attractive drug target.
Additional reading:
- Matthew Herper in Forbes: Mutations That Prevent Heart Attacks Upend The Search For New Drugs
- Gina Kolata in the New York Times: In Single Gene, a Path to Fight Heart Attacks
June 18th, 2014
Yet Another Delay for Boston Scientific’s Watchman Device
Larry Husten, PHD
Boston Scientific hopes the third time will be the charm. The company disclosed on Tuesday yet another obstacle in the path to approval for its novel Watchman left atrial appendage closure device for the prevention of stroke in patients with atrial fibrillation. Although it has already been before two FDA advisory panels, the company said that it had been informed by the FDA that it will need to undergo yet another advisory panel before gaining approval. The news was announced by Boston Scientific’s chief financial officer at a Wells Fargo investor’s conference.
Watchman has already travelled a long and rocky road. In 2010, the FDA issued a complete response letter following the first advisory panel. Last year, a scandal broke out when the American College of Cardiology cancelled a prestigious late-breaking clinical trial presentation of the PREVAIL trial, after the company broke an embargo by giving study results to investors. Last December, the FDA’s Circulatory System Devices Panel voted 13-1 in favor of the device, but as I reported at the time, the lopsided vote did not provide a full indication of lingering concerns about the device by panel members. In particular, panel members repeatedly expressed concern about the potential for overuse of the device. They also had trouble interpreting the major clinical trials with the device.
A date has not been set for the third panel. The company now anticipates approval of Watchman in the first half of 2015.
June 17th, 2014
FDA Approves Second-Generation Heart Valve from Edwards Lifesciences
Larry Husten, PHD
The next phase of the burgeoning and rapidly maturing transcatheter aortic valve replacement (TAVR) market has begun. Edwards Lifesciences announced on Monday afternoon that the FDA had approved its second-generation Sapien XT TAVR device for the treatment of high-risk and inoperable patients suffering from severe symptomatic aortic stenosis (AS).
The Sapien XT is the successor to the first-generation Sapien device, which offered the first nonsurgical approach to aortic valve replacement. A competing device, Medtronic’s CoreValve, was approved earlier this year and has gained considerable interest. The Sapien XT is expected to be more competitive, in part because of its lower profile and the availability of a 29-mm valve size for patients with a larger native annulus.
Edwards said the Sapien XT will be immediately available along with its accompanying transfemoral, transapical, and transaortic delivery systems.
“There is a substantial and growing body of evidence that the SAPIEN XT valve benefits both high-risk and inoperable patients, and clinicians have documented these consistently positive results in both randomized studies and European country registries,” said Martin Leon, the co-principal investigator for the PARTNER II Trial, which evaluated the SAPIEN XT valve, in a press release. “The results from the PARTNER II Trial in treating U.S. inoperable patients with the SAPIEN XT valve demonstrated a reduction in complications with the TAVR procedure, and improved patient outcomes over earlier trials.”
June 17th, 2014
A Meta-Look at Thrombolysis vs. Conventional Anticoagulation for PE
Jay Giri, MD, MPH and Saurav Chatterjee, MD
CardioExchange’s John Ryan interviews Jay Giri and Saurav Chatterjee about their meta-analysis of trials comparing thrombolytic therapy and conventional anticoagulation in patients at intermediate risk for pulmonary embolism (PE). The study is published in JAMA. Further details are available in CardioExchange’s news coverage.
Ryan: Although you find a mortality benefit from thrombolytics, the number needed to treat (NNT) is 59. How do you discuss the potential benefits and harms with a patient when considering thrombolytic therapy?
Giri: As you suggest, clinical decision making about thrombolysis should be individualized on the basis of the risks and benefits for each patient rather than a one-size-fits-all approach to intermediate-risk PE. For example, both PEITHO, the largest randomized trial of this issue in intermediate-risk PE patients, and our analysis point to attenuated risks of bleeding in younger patients (75 or younger in PEITHO, 65 or younger in our meta-analysis). The most feared harm of thrombolytics, intracranial hemorrhage, appears to be significantly less likely in younger patients.
I favor a clear discussion with patients about whether to choose thrombolytic therapy for PE in selected cases. In most of those cases, patients are quite symptomatic and understand that a slightly increased risk for intracranial hemorrhage may accompany the possibility of more-rapid symptom resolution and other benefits, possibly even the mortality benefit suggested by our analysis.
Chatterjee: This is indeed a delicate issue. To aid clinicians in having such a discussion with patients, we outlined the different absolute-risk metrics in Table 2 of our article. We noted that for all patients presenting with PE, the NNT is 59 for preventing one death with thrombolytics, 78 for preventing one intracerebral hemorrhage (ICH), and 18 for preventing one episode of major bleeding (the definitions of which, unfortunately, varied across the studies, ranging from relatively more-common “drops in hemoglobin” to life-threatening ICH events). However, with effective thrombolysis, there is always a high risk for bleeding. To help make a balanced decision, we performed a formal, weighted risk–benefit analysis that showed, for all comers with PE who were potential candidates for thrombolytic therapy, a 0.81% weighted mortality benefit compared with the risk for ICH (an outcome comparable with the risk for death); this benefit persisted in the intermediate-risk population as well.
Ryan: RV dysfunction is defined in your paper as echocardiogram abnormalities and/or abnormal biomarkers (BNP, troponin). How useful do you find these parameters in determining treatment options for intermediate PE? (I find it difficult to justify thrombolytics in a hemodynamically stable patient.)
Giri: Prior research has shown that patients with echocardiographic markers of RV dysfunction or biomarkers indicating RV strain suffer worse outcomes than patients who don’t meet those criteria. Some people argue for treating those patients more aggressively with thrombolysis, but no trial to date had clearly justified that approach. Our analysis suggests that there is a group of hemodynamically stable patients who benefit acutely from thrombolysis.
The clinical factors I consider in making an individualized decision for a patient include the above parameters as well as heart rate, hypoxia, age, and bleeding risk. In intermediate-risk PE patients with advanced age or any increased bleeding risks (recent surgery/trauma, thrombocytopenia, history of stroke), I tend to take a more conservative approach, with anticoagulation alone as an initial strategy. However, for intermediate-risk patients who are younger without key relative bleeding contraindications, I consider thrombolysis to be a therapy that leads to faster symptom resolution, more-rapid normalization of pulmonary pressures and RV dysfunction, reduced chances of acute hemodynamic decompensation, and a potential mortality benefit. Of course, significant additional research must clarify quantitative risk-stratification strategies in this intermediate-risk cohort for both mortality and bleeding risks.
Chatterjee: This is an interesting question that merits further research. As you correctly note, RV dysfunction has been defined with various echocardiographic parameters (RV hypokinesis, RV dilatation, and pulmonary hypertension), as well as elevated biomarkers such as BNP and troponins. To our knowledge, the relative merits of the individual markers in identifying an optimal candidate for thrombolysis have not been determined. However, given our analysis of mortality benefits with thrombolytic therapy in intermediate-risk PE, any patients with PE who have features of RV dysfunction should at least be considered for thrombolytic therapy and should require a good reason for being precluded from a potentially life-saving therapy.
Ryan: Do you search for trials that are registered but unpublished, as on clinicaltrials.gov?
Giri: Yes, we used clincaltrials.gov and several other sources to search for unpublished data. In fact, in our original draft meta-analysis, the two most recent trials, PEITHO and TOPCOAT, had been presented but remained unpublished. However, during the peer-review process, those trials were published, leading our final accepted manuscript to include only published trials.
Chatterjee: We conducted a comprehensive search to identify all studies, including various databases and conference abstracts. In fact, we were able to identify two studies that had been reported at national conferences but had not made it to the publication stage by the time we first submitted our paper. During the JAMA peer-review process, the quality of the trials that had been presented but not published in peer-reviewed journals paved way for a debate on whether to include these studies in the final manuscript. Fortunately, the two trials were published in the interim, and a sensitivity analysis excluding them showed similar findings to those in the overall analysis, indicating robustness of the data (the sensitivity analysis was not included in the accepted final version). We did search clinicaltrials.gov to identify unpublished and ongoing studies, but we did not identify any controlled trials that would be reported in the near future and could further influence the results of our analysis.
Ryan: Is it proper to include so many older studies?
Giri: To avoid selection bias, we had our primary analysis incorporate all trials that met our inclusion criteria (randomization between anticoagulation and thrombolytics for acute PE). However, we agree that trials that are several decades old may not properly reflect the risks and benefits in contemporary practice. As such, we prespecified a secondary analysis of only the 6 most recent trials of thrombolysis (all published in the past 5 years and all including intermediate-risk PE patients). We discovered that the associated mortality benefit was strongly evident in this group of modern trials.
Chatterjee: This is a very valid issue, as many of the older thrombolytic trials were conducted in an era when standards of care were different. To prevent this issue from leading us to erroneous results, we performed a sensitivity analysis of the 6 trials published from 2009 to 2014 (since the last Cochrane review on this topic). We found that the mortality benefits actually were largely derived from these contemporary trials — a further reassuring message that should prompt clinicians to consider thrombolytics in PE. However, we did not want selection bias to affect our overall results, so we included all trials from all time periods for the overall analysis.
JOIN THE DISCUSSION
Do Giri and Chatterjee’s insights about their meta-analysis affect your view of the role of thrombolytic therapy for PE?
June 17th, 2014
Mixed Results for Thrombolysis in Pulmonary Embolism
Larry Husten, PHD
The role of thrombolytic therapy for the treatment of pulmonary embolism has been unclear, as it has been difficult to measure the precise balance between enhanced clot-dissolving efficacy and greater bleeding risk produced by thrombolysis when compared with conventional anticoagulation.
A new meta-analysis published in JAMA analyzed data from 16 randomized trials including 2115 patients. Overall, there was a significant, 47% reduction in mortality with thrombolysis relative to standard anticoagulation, but this was accompanied by significant increases in major bleeding, including intracranial hemorrhage. The increased risk in bleeding was significant only in patients over 65 years of age.
- Mortality: 2.17% with thrombolysis versus 3.89% with standard anticoagulation (odds ratio, 0.53, CI 0.32-0.88)
- Major bleeding: 9.24% versus 3.42% (OR, 2.73, CI 1.91-3.91)
- Intracranial hemorrhage: 1.46% versus 0.19% (OR 4.63, CI 1.78-12.04)
A similar pattern was observed in the large subgroup (1775 patients) deemed to be at intermediate risk.
The mortality benefit, the authors write, “must be tempered by the finding of significantly increased risk of major bleeding and ICH associated with thrombolytic therapy, particularly for patients older than 65 years.” They advise that risk stratification for bleeding should be performed in all patients, especially the elderly, to identify those at high risk for bleeding complications.
In an accompanying editorial, Joshua Beckman writes that “the net clinical benefit of thrombolysis suggests evidence of modest efficacy for thrombolysis in intermediate-risk PE, rendering the need for decision making on a patient-by-patient basis.”
CardioExchange’s John Ryan interviews study authors Saurav Chatterjee and Jay Giri about their findings. Join the conversation.
June 16th, 2014
Selections from Richard Lehman’s Literature Review: June 16th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection 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 12 June 2014 Vol 370
CPAP, Weight Loss, or Both for Obstructive Sleep Apnea (pg. 2265): Obstructive sleep apnoea is often a result of weight gain, and unfortunately, once it is established, losing weight does not reduce it. But losing weight has benefits of its own (he sighs wistfully), as this trial of weight reduction, continuous positive airways pressure, or both for OSA demonstrates. I carry my flabby, insulin resistant, borderline hypertensive, tired all the time body around until the happy moment when I can put on my mask and feel the cool whoosh of air that signals sleep time. Would I do better to lose weight? Oh yes. It would not reduce my C-reactive protein (assuming it needs reducing), but it would certainly help reduce my triglycerides and insulin resistance (not that I have much idea about them either).
CPAP vs. Oxygen in Obstructive Sleep Apnea (pg. 2276): In OSA, CPAP reduces BP. Nice to be able to use these abbreviations, because I have spelt them out above; well actually I haven’t spelt out BP. It stands for blood pressure. In a cohort of people with OSA and high BP, supplemental nocturnal oxygen was tried instead of CPAP for 12 weeks. Result: O2 a no-no for lowering BP in OSA.
JAMA 11 Jun 2014 Vol 311
Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and CV Events and All-Cause Mortality Among Patients With Diabetes (pg. 2288): This issue of JAMA is all about diabetes. Why does that make me want to run away and hide? Nobody in the field had ever heard of me until I entered the fray in 2009 with an editorial in The BMJ, shared with Harlan Krumholz, about the new QOF target for HbA1c. It drew 25 rapid responses, and ever since then I have been dragged back into commenting on diabetes, although I had said pretty much all I have to say in that short piece. Which is simply that the management of diabetes is a mess, and won’t be sorted out until we give patient-important outcomes a higher rank than surrogate outcomes. Alas, this implies that we need new long term trials of considerable complexity.
In the meantime, we have to go by what evidence we have, which is almost entirely observational. We would like to know if adding insulin to metformin is a better strategy than adding a sulfonylurea. Enter the Veterans’ Administration database and some cutting edge statistical wizardry. Not just propensity scores, but also marginal structural Cox proportional hazards models, inverse probability weights, and estimates of the magnitude of imbalance in unmeasured confounders, which might skew the results. What could possibly go wrong? Well, just about anything, as a very good editorial by Monika Safford explains. The conclusion of the study is that, among patients with diabetes who were receiving metformin, the addition of insulin rather than a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all cause mortality. But short of a randomised trial, we just can’t know for sure.
JAMA Internal Med Jun 2014
Statins and Physical Activity in Older Men (OL): “When you are old and grey and full of sleep, A dosset box of statins you shall keep.” This comes from the poetic language summary of the latest NICE guidance on statins. The prose version says “Offer a statin to all individuals aged 85 or over,” which sounds entirely bonkers to me, though I am generally in favour of offering statins to everyone. But by the time I get to 85, I think I might want to die of something, to save further trouble. The benefits of statins are certain and accrue over many years; the harms are less certain, and generally stop as soon as you stop the statin. The trouble is that the main adverse effect of statins is to make muscles ache, and this is so common in old age that people may not put it down to their tablets. This could be the reason that a new analysis of data, collected for the Osteoporotic Fractures in Men study, finds that men who take statins have slightly lower rates of physical activity. Or maybe not. There may be a hidden confounder to account for these minor differences. If you are looking for a stick to beat statins with, this is more like a twig.
Ann Intern Med 3 Jun 2014
Transitional Care Interventions to Prevent Readmissions for Persons With Heart Failure (pg. 774): “Heart failure (HF) is a leading cause of hospitalization and health care costs in the United States. Up to 25% of patients hospitalized with HF are readmitted within 30 days. Readmissions after an index hospitalization for HF are related to various conditions. An analysis of Medicare claims data from 2007 to 2009 found that 35% of readmissions within 30 days were for HF; the remainder were for diverse indications (for example, renal disorders, pneumonia, and arrhythmias).” There are a lot of people who are working on this, trying out new models of care, such as the so-called “transitional care interventions” that form the basis of this review. In the context of the USA, anything that promoted primary care and team working reduced admissions and mortality. What about the UK? I have been thinking about this for 20 years, and I don’t know, for the simple reason that I have not properly asked people with HF and their carers what would be of greatest help to them. I’d suggest that somebody does this, rather than working from a cost reduction perspective and asking cardiologists, just because that is the easiest way to get a grant. I suspect that if I get heart failure, I will just want a place of safety when I am weak and breathless and feel like I’m about to die: which may happen a lot before I actually do.
Lancet 14 Jun 2014 Vol 383
Differential Clinical Outcomes After 1 Year vs. 5 Years in a Randomised Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Coronary Stents (pg. 2047): Well Dave, you can hear the anticipation in the capacity crowd here at Rio as these two great teams line up in the tunnel. The last time these titans met at a World Cup, it was Sirolimus that came away one-nil, but four years later can Zotarolimus even the honours? We know this pitch is not in perfect shape—it looks like an open label job to me—and we’re hoping there won’t be any of those questionable decisions by the ref and the linesmen that marred previous clashes. Oh, and they’re off. (Five years seem to elapse). Well that was 90 minutes of pure magic, ending in a goalless draw! Still, both managers will have something to take away from this. Alfonso Medtronico of Zotarolimus has brought the side into major surplus, and his old rival Johnson Johnson on the Sirolimus side won’t be too unhappy either. It’s the fans I feel sorry for. In the old bare metal days, a stent match used to be a family affair, when you could bring your small lads along and ten bob would cover the game and a pie afterwards. Some of these fans have paid over a thousand pounds to watch this match. It sometimes makes me want to elute.
June 16th, 2014
Case: Smoking-Related CV Risk and the Need for Statin Therapy in a Former Smoker Who Quit Long Ago
Jay D Shah, MD, Neil J Stone, MD and James Fang, MD
A 66-year-old white woman without any significant medical history is seen for cardiovascular risk assessment. She has a blood pressure of 100/60 mm Hg, a total-cholesterol level of 210 mg/dL, and an HDL-cholesterol level of 40 mg/dL. She has no history of diabetes; her current fasting glucose is 87 mg/dL. She smoked one pack of cigarettes per day for 20 years, but she quit 15 years ago. Her father had a myocardial infarction at age 69.
She would like to know whether medical therapy is indicated to reduce her risk for atherosclerotic cardiovascular disease (ASCVD).
According to the Pooled Cohort Risk Equations calculator, her 10-year risk for ASCVD is 4.5% if she is considered a nonsmoker; however, when her smoking history is considered significant, the risk finding rises to 8.0%. (The distinction is important, as statin therapy is not recommended for the former group, but initiation of moderate-to-high intensity statin therapy [or at least a discussion of the possibility] is recommended for the latter.)
Questions:
1. How do you think this patient’s history of smoking affects her overall cardiovascular risk? How long after quitting does a longtime smoker’s smoking-related risk no longer contribute to his or her overall risk burden?
2. Would you check any other risk factors or other indicators to further evaluate this patient’s risk?
3. What else, if anything, would you do?
Response:
This instructive case illustrates the value of discussing risk with primary-prevention patients for whom quantitative risk determination is uncertain. The emphasis on this type of discussion is one of the new features of the 2013 prevention guidelinesthat primary care physicians tell me they especially appreciate.
This patient’s smoking history is of concern. Currently, female smokers are as likely as male smokers to die from the many diseases caused by smoking, including heart attack and stroke. The patient says she quit 15 years ago, yet her HDL-cholesterol level is 40 mg/dL, much lower than the average HDL-c level for women (55 mg/dL). One potential explanation for a lower HDL-c level is current cigarette smoking, raising the question of whether she has truly quit. Older studies employing biochemical verification of smoking status after myocardial infarction show substantial rates of ongoing tobacco exposure among people who indicated that they had quit. Thus, this patient should be asked how many cigarettes she has smoked in the past 30 days, not simply whether she has stopped smoking. An astute clinician might also ask her whether she lives with a smoker, given that evensecondhand smoke can increase the risk for smoking-related problems, including stroke and coronary artery calcification (CAC). If we assume that she has truly quit, we can consider the Framingham Heart Study’s finding, 40 years ago, of a drop in rates of coronary heart disease (CHD) and total mortality among men who quit smoking. The CDC also suggests that CHD risk declines within 1 to 2 years after quitting.
(This patient’s low HDL-c level could also, in theory, reflect genetics or the metabolic syndrome. Although we would need to know her waist circumference and triglyceride level to evaluate her for the metabolic syndrome, her low blood pressure and low-normal fasting glucose do not support this diagnosis.)
In the end, the new 2013 prevention guidelines would recommend a clinician–patient discussion in this case. The goal is to address all relevant risk factors, endorse optimal lifestyle changes, and (in selected patients) consider additional factors to determine whether the potential benefit from a statin outweighs the downsides of such therapy. These extra factors — family history of premature ASCVD, LDL-c ≥160 mg/dL, hs-CRP ≥2.0 mg/L, CAC ≥300 Agatston units (or 75th percentile based on age, race, and sex), ankle–brachial index (ABI) <0.9 — may be useful to assess in older individuals such as this patient. Finally, the discussion should ascertain the patient’s preference after she has been adequately informed of the risks and benefits. For example, she may prefer greater adherence to optimal lifestyle changes, including avoidance of tobacco exposure, in which case no further workup would be required.
Of course, the patient may have additional concerns. Although the guidelines list a family history of premature ASCVD as a factor that can alter the risk decision, her father’s MI in his late sixties would not be considered premature. Again, asking her whether her father had positive stress tests or angina in his fifties, and whether he had siblings with premature CHD, could affect how family history influences the decision.
Overall, in a case like this (when a risk decision is uncertain), the 2013 guidelines would recommend considering three factors to inform the risk decision:
a. CAC score: The clinician and this 66-year-old patient might decide that, if she truly has not smoked since 15 years ago, the radiation risk to see if the CAC score is zero would be acceptable — and that statin therapy is not needed;
b. ABI, which may be useful in detecting peripheral vascular disease in a former smoker;
c. Determining whether hs-CRP is ≥2.0 mg/L: The JUPITER trial enrolled women 60 years or older, with elevated hs-CRP is elevated and LDL-c is <130 mg/dL. JUPITER showed a benefit of rosuvastatin in men and women without diabetes or atherosclerotic cardiovascular disease at entry.
The clinician–patient discussion, as outlined above, can synthesize the best current evidence, the clinician’s judgment, and the principle of shared decision making with the patient.
Response:
How do you think this patient’s history of smoking affects her overall cardiovascular risk? How long after quitting does a former smoker’s smoking-related risk no longer contribute to her overall risk burden?
A history of smoking affects CV risk, but the effect is not as great as current smoking. Moreover, that risk declines with time, and endothelial function does improve with smoking cessation when assessed a year later. How long does it take to no longer contribute to overall risk burden? That question is difficult to pin down; 3 years after an MI, the risk for recurrent MI falls to a nonsmoker’s risk with smoking cessation. Some people note that CV risk drops by 50% after a year. It is probably more relevant to ask whether or not the patient has atherosclerosis precipitated by past smoking, as I discuss below.
Would you check any other risk factors or other indicators to further evaluate her risk?
I would consider other surrogates for evidence of atherosclerosis (e.g., ABI, hs-CRP, CAC). If atherosclerosis is present, the threshold to consider statin therapy would be lower and may also prove to motivate the patient for lifestyle changes and statin therapy.
What else, if anything, would you do?
Continued emphasis on smoking abstinence and lifestyle changes should be part of the patient’s regular follow-up.
Follow-Up:
July 3, 2014
In the end, the decision was made to further risk-stratify the patient by ascertaining her high-sensitivity CRP level, which turned out to be 2.2 mg/L. Rosuvastatin, 20 mg daily, was initiated. Approximately one week after starting statin therapy, the patient developed severe, diffuse myalgias, and the statin was discontinued. For now, the patient will forgo statin therapy and focus on lifestyle modification (exercise and weight loss).
June 16th, 2014
European Regulators Investigate Cardiovascular Safety of Ibuprofen
Larry Husten, PHD
The European Medicines Agency announced on Friday that it had initiated a review of the cardiovascular safety of ibuprofen when taken in high doses over an extended period of time. The review will be performed by the Pharmacovigilance Risk Assessment Committee (PRAC).
The EMA said that people taking ibuprofen should continue to take it as long as they follow the package label or the instructions of their physician or pharmacist.
The cardiovascular risk of all non-steroidal anti-inflammatory drugs (NSAIDs) has been under close scrutiny for a number of years. The increased risk associated with one group of NSAIDs, the COX-2 inhibitors, has been known for more than a decade. Researchers have also found evidence for cardiovascular problems with the NSAID diclofenac.
The EMA said it had found no evidence for a problem in people taking doses less than 2400 mg/day or for short periods of time. “Ibuprofen is one of the most widely used medicines for pain and inflammation and has a well-known safety profile, particularly at usual doses,” the agency said.
June 16th, 2014
Positive Results for New Oral Pulmonary Arterial Hypertension Drug
Larry Husten, PHD
Actelion has announced positive top-line results for a phase III trial of a new oral drug for the treatment of pulmonary arterial hypertension (PAH). The drug, selexipag, is a first-in-class orally available selective prostacyclin IP receptor agonist.
The pivotal, double-blind GRIPHON study was the largest outcome trial ever performed in PAH. A total of 1,156 PAH patients were randomized to selexipag or placebo. The company said that trial had “met its primary efficacy endpoint with high statistical significance.” After followup of up to 4.3 years, selexipag reduced the risk of a morbidity or mortality event by 39% (p<0.0001). The results were consistent across the key subgroups of age, gender, WHO functional class, PAH etiology, and background therapy. Endpoint events were adjudicated by a blinded independent committee.
Actelion reported that 14% of patients in the selexipag group and 7% of patients in the placebo group discontinued treatment due to adverse events. The most common adverse events associated with selexapig were similar to those seen with previous prostacyclin therapies, including headache, diarrhea, nausea, jaw pain, vomiting, pain in extremity, myalgia, nasopharyngitis, and flushing.
Most patients in the study were taking other oral PAH drugs at the start of the study.
“I have been prescribing intravenous prostacyclin therapies in PAH patients for almost twenty years. Today’s GRIPHON results represent a major step forward. For the first time, with selexipag, we have an oral compound acting on the prostacyclin pathway showing a significant risk reduction on a highly clinically relevant endpoint,” said Gérald Simonneau, a member of the trial’s steering committee, in the Actelion press release.
John Ryan, an expert on PAH at the University of Utah, expressed enthusiasm for the news:
This is an exciting trial and an intriguing result, especially when considering the size of the study, the prolonged follow-up, and the high percentage of patients already on background therapy. Having an oral agent in PAH that significantly impacted mortality/morbidity represents a major step forward and could be a real game changer in this aggressive and fatal disease.”
June 16th, 2014
European Medicines Agency Initiates Review of Ivabradine
Larry Husten, PHD
There may be trouble on the horizon for ivabradine, a heart drug marketed by Servier under the brand names of Corlentor and Procoralan. The drug is widely available in Europe and elsewhere, though it is not available in the U.S., where it is under development by Amgen. Although it hasn’t been widely reported, the European Medicines Agency said last month that it has started a review of the drug based on troubling findings from the SIGNIFY study. (Ivabradine is used to treat patients with long-term stable angina and long-term heart failure.)
The main results of SIGNIFY are scheduled to be presented on August 31 at the European Society of Cardiology meeting in Barcelona. However, on May 8, the European Medicines Agency announced that it had initiated a review of ivabradine based on preliminary results:
The review follows preliminary results from the SIGNIFY study, which was evaluating whether treatment with Corlentor/Procoralan in patients with coronary heart disease reduces the rate of cardiovascular events (such as heart attack) when compared with placebo (a dummy treatment). Patients in the study received up to 10 mg twice daily, which is higher than the currently authorised maximum daily dose (7.5 mg twice daily), and the results showed a small but significant increase in the combined risk of cardiovascular death or non-fatal heart attack with the medicine in a subgroup of patients who had symptomatic angina (Canadian Cardiovascular Society class II – IV).
The European Medicines Agency will now evaluate the impact of the data from the SIGNIFY study on the balance of benefits and risks of Corlentor/Procoralan and issue an opinion on whether the marketing authorisation should be maintained, varied, suspended or withdrawn across the EU.”
Ivabradine slows the rate of the heart by inhibiting the so-called “funny” current within the heart’s natural pacemaker, the sinoatrial node.
It should be noted that Amgen recently announced that the FDA had granted fast track status to the drug. But it should also be noted that every FDA expert with whom I’ve spoken has said that the fast track designation means absolutely nothing (though in my experience it’s nearly always a good excuse for a company to issue a press release). In a statement Amgen said that it planned to submit the FDA filing for ivabradine for patients with chronic heart failure. The SIGNIFY trial included patients with chronic stable coronary artery disease without heart failure.
NEJM Journal Watch — Recent Cardiology Articles- Major and Intracranial Hemorrhage Risk with Direct Oral Anticoagulants vs. Aspirin
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