April 3rd, 2014
Cardiovascular Disease Declines in Rich Countries but Grows Elsewhere
Larry Husten, PHD
A new Global Cardiovascular Disease (CVD) Atlas portrays a divided world where rich countries are gradually freeing themselves from the yoke of CVD but where many poor and middle-income countries are still struggling.
Ischemic heart disease and stroke were the two biggest contributors to the global burden of disease in 2010, accounting for 5.2% and 4.1%, respectively, of all disability adjusted life years (DALYs). From 1990 to 2010 the global age-standardized mortality rates of heart disease and stroke decreased, but the absolute number of deaths increased from 5,211,790 to 7,029,270 deaths for heart disease and from 4,660,450 to 5,874,180 deaths for stroke.
Diet, high blood pressure, and tobacco were the three leading risk factors worldwide. Tobacco’s role was much larger in East Asia and Southeast Asia than in Australasia, Western Europe, and North America, where efforts to curb smoking have been successful. Alcohol was the fifth most important risk factor in Eastern Europe, but ranked no higher than 10th in other regions. In East Asia air pollution was the fourth most important risk factor. High body mass index was the third most important risk factor in Australasia, North America, Europe, Central Asia, Latin American/Caribbean, North Africa, and the Middle East.
From 1990 to 2010 Norway, Ireland, the U.K., and Israel nearly cut in half the crude DALY burden per 100,000 people. “The reductions in CVD burden per capita in high income regions are impressive, and have occurred despite aging populations,” said Andrew Moran, the first author of a summary published in Global Heart. “Other studies of CVD trends suggest that CVD reductions in the high income world are due to a combination of reduced smoking, improved risk factor control, and improved treatments. Some changes in diet, lifestyle, and broader social and economic forces may play a role too, but are harder to measure.”
By contrast, the countries of the former Soviet Union had large increases of at least 30% in their DALY burden. Said Moran, “the big contributions of alcohol and tobacco points to underlying social and economic forces at work.”
Obesity, poor diet, and high blood pressure have caused increases in the burden of CVD in North Africa and the Middle East. In Kuwait the incidence of CVD DALYs increased by 28%.
In the U.S., per capita DALYs decreased by 33% between 1990 and 2010, but the overall crude DALY rate of 4485.86 per 100,000 people left it in the middle of the pack of high-income countries. In 2010, Brunei had the lowest rate in this group — 2321.97 per 100,000 — while Greece had the highest rate — 6455.03 per 100,000.
Moran said that the only way to lower the high burden of CVD in much of the world “will be to extend the CVD control successes of the high income world to low and middle income countries. In some cases this may mean adapting past successful programs; in other cases locally tailored and innovative approaches will be needed.”
March 31st, 2014
Novartis Trial Was Stopped Early Because of a Significant Drop in Cardiovascular Mortality
Larry Husten, PHD
The largest-ever trial in heart failure was stopped early because of a highly statistically significant reduction in cardiovascular mortality, according to one of the trial’s two primary investigators.
Earlier today I reported that the PARADIGM-HF trial testing LCZ696, a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor (ARNI), had been stopped early because the trial had demonstrated a significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization. This information was taken from a Novartis press release.
But it turns out that the press release wasn’t entirely accurate. For once, a company appears to have actually downplayed a positive finding in its trial. According to Milton Packer, the trial’s Co-Principal Investigator, the data are much more persuasive than might be gathered from the press release. (I spoke with Packer at the American College of Cardiology meeting in Washington, DC.)
In general, when a trial has a combined endpoint — for PARADIGM-HF it was the combination of cardiovascular death and heart failure hospitalization — the results are largely driven by the “softer” component of the endpoint (in this case, heart failure hospitalization and not the “harder” endpoint of cardiovascular death.) This often leads to criticism when a trial has been technically superior in reducing a combined endpoint but shows little or no effect on the harder, more important, endpoint.
We won’t know the full results of PARADIGM-HF until they are presented at a medical meeting, perhaps the European Society of Cardiology meeting in August in Barcelona. But according to Packer, the trial will definitely show a large and convincing reduction in the more important endpoint component, cardiovascular death.
Packer told me that the stopping rule for the trial was “the most conservative stopping rule in any clinical trial I have ever been involved with.” More importantly, he said, “The stopping rule was not on the primary endpoint, it was on cardiovascular death. It was a stopping rule that required a very high level of statistical significance for early termination.” And it was based on this stopping rule that “the Data and Monitoring Board decided that stopping the trial was appropriate.”
Packer said, “The press release implies that the trial was stopped for the primary endpoint but that was not the case, the trial was stopped for a persuasive effect on cardiovascular mortality alone, and my enthusiasm was based on that very persuasive effect.”
Packer also told me that the trial had been powered to detect a difference in cardiovascular mortality, so the finding may not be quite so unexpected. This also explains the trial’s large size.
To view all of our coverage from the ACC meeting, go to our ACC.14 Headquarters page.
March 31st, 2014
Master of All Trades
Saurav Chatterjee, MD
Several Cardiology fellows who are attending ACC.14 in Washington, D.C. are blogging for CardioExchange. The fellows include Kumar Dharmarajan, Seth Martin, and Saurav Chatterjee. For more of our ACC.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our ACC.14 Headquarters.
An intriguing and practical discussion with a nearly graduated fellow opened up new avenues for thought. In spite of general feelings on how mentorship may sometimes be lacking – especially in terms of quality – for those in academic cardiology, overall most fellows are fortunate enough to have at least one or more academic mentors who allow them to fine-tune their careers according to sage advice. However, those embarking on careers in private practice appear to have less available and structured guidance.
From my conversation with the aforementioned fellow, it appears as though many practices have now set the bar high in terms of clinical experience – in other words, they want applicants to have COCATS level IIs and IIIs in several (if not all) of the sub-specialties. The logical question, of course, is with other commitments to education and research, how realistic it is to expect one person to become proficient in several of these sub-specialties? In addition, there appears to be several boards for certifications like the “echo boards,” “Nuc boards” and the “Vascular boards.”
Another largely unanticipated issue is the fact that someone planning on taking one or more of these boards may incur significant additional expenses in the final year of fellowship. This may need to be budgeted for ahead of time – especially for those with families and children. In addition, the American Board of Internal Medicine has has implemented a “maintenance of MOC” program for board-certified physicians in various specialties that may potentially add to further expenses. These are surely things to ponder ahead of time.
March 31st, 2014
Early Success for Novel Novartis Heart Failure Drug
Larry Husten, PHD
A large clinical trial testing a novel compound from Novartis for chronic heart failure has been stopped early for efficacy. In a press release Novartis said the Data Monitoring Committee had recommended early closure of the PARADIGM-HF trial because the trial had demonstrated a significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization.
PARADIGM-HF randomized patients with heart failure and reduced left ventricular ejection fraction to either the ACE inhibitor enalapril or LCZ696, an Angiotensin Receptor Neprilysin Inhibitor (ARNI) that is the first in its class. Almost 8,500 patients were studied in the trial, which Novartis said made it the largest-ever trial in heart failure.
“The results of PARADIGM-HF are truly impressive” said heart failure expert Milton Packer, a Principal Investigator of the trial. “The finding that treatment with LCZ696 was superior to currently recommended doses of enalapril has profound implications for the care of patients with chronic heart failure. We now have compelling evidence that supports LCZ696 as a new cornerstone in the management of chronic heart failure.”
Novartis said the trial findings will be presented at a medical conference in the future and that the company will seek to gain approval for the drug with regulators.
The announcement follows by only a few days the rejection of a different Novartis heart failure compound, serelaxin, by an FDA advisory panel.
March 31st, 2014
Are We Equipped to Make a CHOICE Between TAVR Devices?
E Murat Tuzcu, MD
CardioExchange’s Rick Lange and David Hillis ask E. Murat Tuzcu for his perspective on the CHOICE trial comparing the CoreValve and Edwards Sapien XT devices for transcatheter aortic valve replacement (TAVR). Dr. Tuzcu is a coauthor of the JAMA editorial on CHOICE. For CardioExchange’s news coverage of CHOICE, click here.
THE STUDY
The Comparison of Transcatheter Heart Valves in High-Risk Patients With Severe Aortic Stenosis: Medtronic CoreValve vs Edwards SAPIEN XT (CHOICE) study is the first randomized clinical trial to compare two different TAVR heart-valve technologies. The participants were 241 high-risk patients with severe aortic stenosis in Germany.
The rate of “device success,” the primary endpoint, was significantly higher with the balloon-expandable Sapien XT device than the self-expandable CoreValve (95.9% vs. 77.5%). That finding was attributable to a significantly lower frequency of more-than-mild paravalvular aortic regurgitation with the Sapien XT device (4.1% vs. 18.3%) and the Sapien group’s significantly lower rate of need for implanting 2 devices to achieve an acceptable hemodynamic outcome (0.8% vs. 5.8%).
Major adverse cardiovascular and cerebrovascular events at 30 days were numerically, but not statistically, higher in the Sapien group (6.6% vs. 3.4%; RR, 1.93; 95% CI, 0.60–6.25; P=0.38). The cardiovascular mortality rate at 30 days was similar in the two groups (4.1% and 4.3%, respectively).
THE INTERVIEW
Lange and Hillis: This relatively small study revealed no difference between the devices in 30-day cardiovascular mortality. Are the primary-endpoint differences clinically meaningful?
Tuzcu: Previous studies have shown a positive correlation between moderate and severe aortic regurgitation (AR) and mid-term mortality. In the PARTNER trial, even mild AR correlated with 1-year mortality. Thus, the differences in the primary endpoint in the CHOICE trial should not be taken lightly. We published a meta-analysis (of 45 studies) that also showed a higher rate of post-TAVR AR with the self-expanding (SE) CoreValve than with the balloon-expandable (BE) Edwards valve. In the search for an ideal transcatheter valve, elimination of post-TAVR AR is a critical step that cannot be ignored.
Another important contributor to the device success, as reflected in the CHOICE trial’s primary endpoint, was the implantation of a second valve during the index procedure. Analyzing the relevant PARTNER trial data, Makkar et al. concluded that valve in valve implantation to treat acute aortic regurgitation predicts 1-year mortality. In summary, the primary-endpoint differences are clinically meaningful.
Lange and Hillis: Is the nonsignificant difference between the devices in the rate of major adverse cardiovascular and cerebrovascular events real? How do you weigh this against reduced incidences of paravalvular aortic regurgitation and need for a second valve with the balloon-expandable device?
Tuzcu: Major adverse cardiovascular and cerebrovascular events were 6.6% and 3.4% with the BE and SE valves, respectively, predominantly due to the statistically nonsignificant (P=0.33) difference between the stroke rates. We learned from presentation of the CHOICE trial at ACC.14 that there were 4 minor strokes in the BE group but none in the SE group. The major stroke rates were essentially same in the 2 groups.
This month we published a meta-analysis in JACC focusing on the post-TAVR stroke issue in 23 multicenter and 33 single-center studies. The stroke rate did not differ between the BE and SE valves. Data suggest that the stroke rate after TAVR decreased over time. This is likely due to better patient selection, improved technology, and enhanced experience.
Although I don’t see a cause for alarm in the stroke data from CHOICE and other studies, I think we should be vigilant for possible differences not only between the two valves tested in this trail, but also among the new-generation valves entering clinical use (because it is the most consequential complication of the TAVR procedure).
Lange and Hillis: If you needed to undergo TAVR today, do you have enough information to decide between the two devices?
Tuzcu: This is not an easy question to answer. I would acknowledge that I do not have conclusive information. But if I had to make a decision with the totality of information we have today, I would probably look at anatomical characteristics. If I had a small, heavily calcified annulus and LVOT, short distance between annulus and coronary ostia, I might choose an SE valve. This would minimize my risk for annular rupture and coronary obstruction, both of which are infrequent but potentially lethal complications. Although we don’t have a lot of data, if I had predominantly regurgitant and minimally calcified aortic valve disease, I would ask for an SE device. Lacking those characteristics, I would choose the BE valve, thinking that I would have a lower risk of needing a pacemaker, a greater chance of device success, and maybe less risk for rehospitalization.
JOIN THE DISCUSSION
Share your thoughts on Dr. Tuczu’s analysis of the findings from CHOICE.
To view all of our coverage from the ACC meeting, go to our ACC.14 Headquarters page.
March 31st, 2014
Aspirin and Clonidine Fail to Help Surgery Patients
Larry Husten, PHD
Myocardial infarction (MI) is among the most common and serious side effects of noncardiac surgery. An effective regimen to minimize this risk has been the subject of considerable debate in recent years. The controversy was recently exacerbated because the recommendation to use beta-blockers in this setting was based on research which has now been discredited. Substantial evidence against the use of perioperative beta blockers came from the original POISE trial.
Now a second POISE trial, the Perioperative Ischemic Evaluation 2 (POISE-2) trial, casts doubt on the value of two other proposed strategies to reduce death and MI in patients undergoing noncardiac surgery. Results of POISE-2 were presented at the American College of Cardiology meeting in Washington, DC and published simultaneously in two papers in the New England Journal of Medicine.
Just over 10,000 patients were randomized, in a two by two factorial design, to either low-dose aspirin or placebo and to either low-dose clonidine or placebo. There was no benefit associated with either aspirin or clonidine, but there were significant disadvantages to each.
The primary endpoint of the study, death or nonfatal MI at 30 days, was not significantly changed by either treatment:
- 7% in the aspirin group versus 7.1% in the placebo group (HR 0.99, CI 0.86-1.15, p=0.92)
- 7.3% in the clonidine group versus 6.8% in the placebo group (HR 1.08, CI 0.93-1.26, p=0.29)
In the aspirin randomization, bleeding was more common in the aspirin group: 4.6% versus 3.7% (HR 1.23, CI 1.01-1.49, p=0.04)
In the clonidine randomization, hypotension occurred more often in the clonidine group than in the placebo group (47.6% versus 37.1%, HR 1.32, CI 1.24-1.40, p<0.001). There were also more nonfatal cardiac arrests in the clonidine group (0.3% versus 0.1%, HR 3.20, CI 1.17-9.73, p=0.22).
In their discussion the authors offered their advice about what to do with patients already taking aspirin: “For patients on a long-term aspirin regimen, the most effective time to restart aspirin would be 8 to 10 days after surgery, when the bleeding risk has diminished considerably. If physicians consider starting aspirin after surgery to treat a thrombotic event (e.g., stroke or myocardial infarction), they can expect an absolute increase of 1.0 to 1.3 percentage points in the risk of life-threatening or major bleeding if aspirin is administered within the first 2 days after surgery. Physicians and their patients will have to weigh this risk against the high risk of death from the thrombotic event and the potential benefits of aspirin.”
In the wake of the failure of beta-blockers, aspirin, and cloinidine in the perioperative setting, the authors state the obvious: “New strategies are needed to address the problem of major vascular complications after non cardiac surgery.”
To view all of our coverage from the ACC meeting, go to our ACC.14 Headquarters page.
March 30th, 2014
High-Sensitivity Troponin Test Could Identify Low-Risk Chest Pain Patients in the ED
Larry Husten, PHD
Approximately 15-20 million people in Europe and the United States go to the emergency department every year with chest pain. Many can be discharged early if they are not having an acute coronary syndrome. A large, new, single-center observational study, presented at the American College of Cardiology meeting in Washington, DC and published simultaneously in the Journal of the American College of Cardiology, provides fresh evidence that high-sensitivity cardiac troponin T (hs-cTnT) may be useful in helping identify chest pain patients in the emergency department who do not need to be admitted to the hospital.
Nadia Bandstein reported on 14,636 patients who presented to the emergency department at a Swedish hospital and had a hs-cTnT test. Of these, 61% (8,907) had a hs-cTnT below 5 ng/l. At 30 days, only 0.44% (39) of these patients had an MI. None of the patients in this group died. A total of 15 had MIs with no ischemic ECG changes. The authors calculated a negative predictive value of 99.8%.
The rapid and accurate diagnosis of MI in chest pain patients has been long sought and elusive. Bandstein said that in her hospital chest pain is “the second most common symptom reported in the emergency department. Since there are no established ways to quickly rule out heart attack, many patients are admitted to the hospital unnecessarily, at a large cost to the patient and to society.”
“Despite our observations before the study, we were still surprised by the strength of our findings,” Bandstein said in a press release. “Using this blood test along with an ECG, we will save about 500 to 1,000 admissions per year in our hospital alone, allowing us to use the beds for sicker patients.”
To view all of our coverage from the ACC meeting, go to our ACC.14 Headquarters page.
March 30th, 2014
Stage Set for Phase IV Trials of PCSK9 Inhibition
Seth Shay Martin, MD
Several Cardiology fellows who are attending ACC.14 in Washington, D.C. this week are blogging for CardioExchange. The fellows include Kumar Dharmarajan, Seth Martin, and Saurav Chatterjee. For more of our ACC.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our ACC.14 Headquarters.
Surrounded by tall glowing curtains colored in purple, blue, orange, red, and hot pink, I’m sitting here in the main tent at the Sunday morning LBCT session feeling the enthusiasm build for PCSK9 inhibitors. I’m typing as the presentation of GAUSS-2 by Dr. Stroes completes a series of five phase III evolocumab (AMG 145) presentations here at ACC.14.
Yesterday, MENDEL-2 confirmed efficacy as monotherapy, DESCARTES showed durability out to 52 weeks, and RUTHERFORD-2 addressed the heterozygous FH population. Now I’ve just I watched Dr. Robinson present LAPLACE-2, showing that evolocumab significantly lowered LDL-C over the course of a few months in patients with hypercholesterolemia on background statin therapy. And now GAUSS-2 is showing efficacy and safety in a well-defined statin-intolerant population. Overall, the results are complementary, consistent, and favorable.
We are seeing that LDL-C consistently gets cut in half or more, but what’s also very cool here is that Lp(a) is going down by about 25-30%. To date, we haven’t had a good armamentarium against Lp(a), with niacin being the main option. Another potential tool for this predominantly genetic disorder, which predisposes families to premature cardiovascular disease, is warmly welcomed.
The stage is set for the phase IV trials of ASCVD outcomes. As Dr. Robinson mentioned, FOURIER is underway, using evolocumab on top of statin therapy in 22,500 patients with clinical ASCVD.
Will I be shocked if the phase IV trials don’t work? You better believe it. The biology makes sense. The epidemiology was consistent. The phase III trials look great. Are you also feeling the enthusiasm build? Do you agree that PCSK9 inhibitors are a likely game changer? Assuming the phase IV trials pan out, can you think of patients in your practice who will find this to be a useful option?
Regarding safety, we’re not seeing a signal for adverse effects in the realm of neurocognitive effects in the overall evolocumab program. However, the FDA has asked for neurocognitive sub-studies in the phase IV trials. Anyone out there have more insight into this? Is this really a good use of resources? Another approach: support n-of-1 trials in patients in whom a cognitive concern arises.
March 30th, 2014
Taking Patient-Centeredness to the Next Level at ACC.14
Kumar Dharmarajan, MD MBA
Several Cardiology fellows who are attending ACC.14 in Washington, D.C. this week are blogging for CardioExchange. The fellows include Kumar Dharmarajan, Seth Martin, and Saurav Chatterjee. For more of our ACC.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our ACC.14 Headquarters.
A novel idea: a “patient” told his own story at the PM clinical focus session “Championing Care for Patients with Aortic Stenosis.” I use quotation marks because he really wasn’t a patient – he was a professional actor. Yet despite the tired eyes in the audience, he was able to connect sufficiently to make the case for shared decision-making when considering valve replacement.
My question: why don’t we do this more often at large conferences, especially when we operate in huge rooms with large physical distances to the speakers? As health providers, we’re already primed to connect with patients and their stories, more so I believe than to the usual behind-the-podium lecturers.
March 30th, 2014
Are Digital Conferences the Way of the Future?
Saurav Chatterjee, MD
Several Cardiology fellows who are attending ACC.14 in Washington, D.C. this week are blogging for CardioExchange. The fellows include Kumar Dharmarajan, Seth Martin, and Saurav Chatterjee. For more of our ACC.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our ACC.14 Headquarters.
The weather gods were acting like a spoilsport again while cutting-edge research was being presented on the inaugural day of the ACC 2014 Annual Scientific Sessions. As I rushed to D.C. after being on overnight call in order to present my poster on time, the overcast skies reflected my mood while I seethed at the occasional rain-induced traffic snarl. Reflecting back to another recent meeting in Florida, where a mid-January snowstorm in the northeast had upset travel plans, I remembered how my Chief of Cardiology had used a Skype video call to make his presentation – and with great effect.
This got me thinking if that was indeed how meetings of the future may be conducted – transcending all time and space barriers, allowing one to participate in presentations from the comfort of his or her own study! In this era of cost-consciousness and cost-benefit analyses, it’s only a matter of time before someone shows that to be a viable, even preferable option, even if it purely comes from an economic standpoint.
Even today the ACC offers “iScience meeting on demand” to help one catch up with the different concurrent sessions that would otherwise have to be foregone. Starting this year the ACC has also introduced options for streaming live sessions on CardioSource for its members, as well as the opportunity to transmit live tweets from selected sessions. So it may not be long before the long waits at bus stations, train stations, and airports, the discomfiture of travel, the need for re-arranging of schedules, and the obvious expenses associated with travel becomes a thing the past.
Then, as I reached the convention center, I met an ex-graduate from my fellowship program who greeted me with a warm handshake, and we chatted about our common friends and who among them were attending the conference. Soon thereafter, I attended a media session where one of my research posters was discussed, and I received extremely valuable advice from a stellar panel of discussants on ways to improve my paper for submission to an impactful journal. This was followed by one-on-one sessions with Dr. Franz Messerli (who has co-authored the editorial for the SYMPLICITY HTN-3 trial in the NEJM) in order to hear his take on renal denervation and its future; mentors who dispensed advice on initiation, tribulations and tips for success in academic cardiology; strategies to respond to reviewers for a recent journal submission involving authors from multiple centers; and finally, a nice dinner with friends and mentors.
Can this experience be matched with structured webinars? Maybe the future, in my humble opinion, is not ready for prime time just yet.
NEJM Journal Watch — Recent Cardiology Articles- Major and Intracranial Hemorrhage Risk with Direct Oral Anticoagulants vs. Aspirin
- Chlorthalidone vs. Hydrochlorothiazide for Hypertension: Renal Outcomes
- Estimating Heart Failure Risk in the U.S. Population with the PREVENT Calculator
- Atrial Fibrillation and Stable Coronary Artery Disease — What Is the Optimal Anticoagulation–Antiplatelet Regimen?
- β-Blockers After Myocardial Infarction