September 18th, 2014

Do Hemodynamic Endpoints Have Value in Patients Treated for Pulmonary Arterial Hypertension?

CardioExchange’s John Ryan interviews Corey E. Ventetuolo about her research group’s study of hemodynamic endpoints in clinical trials of patients with pulmonary arterial hypertension. The study is published in Circulation.

Ryan: Please summarize the main finding of your paper.

Ventetuolo: We conducted a large patient-level analysis of 1119 participants from four randomized clinical trials in pulmonary arterial hypertension (PAH). Our aim was to determine whether treatment-induced changes in hemodynamics are valid surrogate endpoints in this population. We found that although active therapy was associated with favorable hemodynamic changes and a reduction in clinical events (such as death, lung transplantation, hospitalization for worsening PAH and escalation in PAH therapy) at 12 weeks, these changes only partially affect the probability of short-term outcomes. At most, decreases in pulmonary vascular resistance explained about 14% of the treatment effect. The findings, which suggest that short-term changes in resting hemodynamics are not valid surrogate endpoints in clinical trials, challenge our understanding of how PAH therapies work.

Ryan: If the hemodynamic changes are not accounting for the changes in short-term outcomes, what do you think is the cause of the improvements in the outcomes?

Ventetuolo: We were surprised by the findings, since PAH is a hemodynamic disease by definition. Our therapies may be acting via alternative mechanisms not previously defined or studied, perhaps by exerting systemic effects or by changing right ventricular adaptation. Of course, because of the short-term design of traditional PAH trials, we cannot know whether hemodynamic changes with longer-term therapy would reliably predict clinical events beyond 12 weeks.

Ryan: After starting therapeutic agents for PAH, what is your practice for obtaining follow-up hemodynamic measures?

Ventetuolo: There are minimal data to guide practice in this area, and each patient needs to be considered individually. Generally if a patient is doing well on therapy by other noninvasive tests (making gains in their symptoms, functional class, 6-minute walk distance, and markers of right ventricular function), we try to repeat hemodynamic measurements annually. Patients with a robust response to therapy may have longer periods between testing. If a patient is doing poorly or certainly in patients treated with prostacyclins, we may repeat hemodynamic measurements more frequently, sometimes within weeks.

 Ryan: As you know, the trials and your results exclusively address resting hemodynamics. What role, if any, do you think exercise hemodynamics play in these patients?

Ventetuolo: This is a great point. We need to better understand hemodynamic changes with exercise in normal individuals (as they age or develop comorbid conditions), as well as in PAH, to better define cut-points and protocols that can be highly standardized. For these reasons, exercise-induced pulmonary hypertension is not included in current definitions of pulmonary vascular disease. In clinical practice, we sometimes use exercise hemodynamics to unmask diastolic abnormalities and distinguish pulmonary venous hypertension from PAH in patients who have risk factors for Group 2 disease but have low or high-normal left-heart filling pressures at rest. However, exercise measurements are not ready for prime time use in clinical trials.

Ryan: With the minimal impact of invasive hemodynamics on outcomes, do you think we should focus our efforts on no-invasive imaging in clinical trials (MRI, echo, etc.)?

Ventetuolo: Trials to-date have not incorporated endpoints that track changes in right ventricular performance in a large-scale fashion. A number of advanced or novel RV imaging techniques that may prove useful now exist, but it is important to validate potential noninvasive surrogates before using them in clinical trials. Alternatively, we could design trials that aim to improve the ultimate endpoints for our patients (survival, patient-reported outcomes, clinical events) with PAH therapies.


Share your perspective on Dr. Ventetuolo’s research findings.  

September 18th, 2014

FDA Approves New Once-Weekly GLP-1 Receptor Agonist for Type 2 Diabetes

The FDA said today that it had approved dulaglutide, Lilly’s once-weekly injection to control blood sugar in adults with type 2 diabetes. The drug will be marketed under the brand name of Trulicity.

The FDA said that the safety and efficacy of dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, had been studied in  3,342 type 2 diabetics. The drug can be given as monotherapy or in combination with other diabetes drugs including metformin, sulfonylurea, thiazolidinediones, and prandial insulin. It is not indicated for use in type 1 diabetics, in people with diabetic ketoacidosis, or in people with severe intestinal problems. It should not be used as initial therapy in diabetics who cannot be managed with diet and exercise.

The drug label will contain a boxed warning that in rodents dulaglutide was linked to tumors of the thyroid gland (thyroid C-cell tumors). The FDA says that it is unknown whether the drug can cause these tumors in humans, including a type of thyroid cancer called medullary thyroid carcinoma (MTC). Dulaglutide should not be used in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2, which may predispose them to MTC.

The most common side effects found in people taking dulaglutide were nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.

The FDA said that it would require Lilly to perform a number of post-marketing studies, including a cardiovascular outcomes trial, a trial in pediatric patients, and a long-term (15-year) registry to identify any increase in the rate of MTC.

Lilly will also be required to implement a Risk Evaluation and Mitigation Strategy (REMS), in which the company will inform physicians and other healthcare professionals about the serious risks linked to the drug.



September 17th, 2014

Is It Safe to Offer PCI at VA Centers Without On-Site Cardiothoracic Surgery?

CardioExchange’s Harlan M. Krumholz interviews Thomas M. Maddox about his research group’s study of post-PCI outcomes at VA centers with or without on-site cardiothoracic surgery. The article is published in Circulation.

Krumholz: Please summarize the main findings of your paper.

Maddox: We explored whether the VA’s policy of offering PCI at centers without on-site cardiothoracic (CT) surgery is safe and improves veterans’ access to PCI. From October 2007 through September 2010, PCI was conducted in 24,387 patients at 59 VA centers; 6616 of these patients underwent PCI at 18 facilities without on-site CT surgery. We found no significant differences in peri-PCI adverse outcomes, 1-year all-cause mortality, and rehospitalization for MI between centers with versus without on-site CT surgery. The availability of the 18 non-CT surgery PCI centers allowed patients to be a median of 91 minutes closer to a PCI center than they otherwise would have been. Therefore, the findings suggest that the VA policy for PCI is safe and improves access to PCI.

Krumholz: You found no difference between facilities with versus without CT surgery capabilities, but you cannot exclude a hazard as large as 20%. And you did find that revascularization rates in follow-up were higher for the patients who underwent PCI at centers without on-site surgery. How do you then respond to people who question the claim that outcomes are the same?

Maddox: It’s equally likely that centers without CT surgery had 13% lower rates of adverse outcomes. It is also comforting that the point estimate of the adverse outcome ratio was 1.02, suggesting nearly equivalent absolute rates of events between the two types of centers. With respect to the most important complication — peri-PCI need for emergent CABG — the rates at both types of centers were extremely low and, indeed, occurred less frequently at centers without on-site CT surgery. Therefore, VA interventional cardiologists seem to be selecting their patients carefully and performing PCI in a safe manner. Nevertheless, it will be important to follow annual outcomes for these patients, which is easy to do under the VA’s national Clinical Assessment, Reporting, and Tracking (CART) quality-oversight program for PCI. This periodic surveillance will allow us to detect and address any issues quickly.

The higher revascularization rates at centers without on-site surgery were confined only to elective cases — they were not the result of higher rates of MI. As we discuss in our article, this may be explained by interventional cardiologists’ more conservative approach to initial revascularization strategies, although similar rates of successful PCI and higher rates of complex PCI were noted in centers without on-site CT surgery. Another potential explanation is that centers without on-site CT surgery are more likely to take an ischemia-guided PCI approach to managing coronary disease, given that the logistics of getting patients to a CABG-capable center are more difficult or may not be in line with the patient’s preference. Regardless of the explanation, we were encouraged to see that the higher rates of revascularization were not associated with a signal of harm.

Krumholz: Do you think that patient consent protocols at facilities without CABG should mention the potential for increased risk?

Maddox: Given that we found no evidence of increased risk for peri-PCI or longer-term adverse outcomes at centers without on-site surgery, there is no rationale for different consent processes. Rather, we would suggest that, when discussing PCI with prospective patients, all centers describe the risks inherent to the procedure, as well as their local processes for handling complications. For centers without on-site CT surgery, their plans for patient stabilization and transfer to a CT surgery-capable center should be part of this discussion.


Offer your thoughts on Dr. Maddox’s analysis of findings from the VA CART program.

September 15th, 2014

Cheaper Generic Statins Beat Brand-Name Statins in Adherence and Outcomes

A large observational study finds that people who received a prescription for a generic statin were more likely to take their pills than people who received a prescription for a brand-name statin. This increased adherence appeared to lead to a small but significant improvement in outcomes.

In a paper published in Annals of Internal Medicine, Joshua Gagne and colleagues at the Brigham and Women’s Hospital and CVS Caremark (the study was funded by generic manufacturer Teva Pharmaceuticals) compared data from 83,731 people who started a prescription for a generic statin with 6,380 people who started a prescription for a brand-name drug. They found that adherence,  as measured by the proportion of days covered (PDC) up to one year, was significantly higher in the generic group than in the brand-name group (average PDC: 77% versus 71%, p<0.001). The patients in the generic statin group also had a corresponding 8% reduction in the incidence of death and hospitalization for an acute coronary syndrome, which the authors calculated led to a reduction of 1.53 events per 100 person-years.

The mean copayment for the prescriptions was $10 in the generic group and $48 in the brand-name group. “Our finding that adherence is greater with generic statins than with brand-name statins is therefore not surprising and is consistent with other studies that have shown a direct relation between higher copayments and lower adherence.”

In an accompanying editorial, Walter Cullen and Patrick Murray write that the authors “make the distinction between generic and brand-name drugs, but the operating factor for patients is affordability.”



September 15th, 2014

Selections from Richard Lehman’s Literature Review: September 15th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM 11 September 2014 Vol 371

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction (pg. 1016): Ticagrelor has had mixed fortunes since it was introduced as a new thienopyridine platelet aggregation inhibitor a few years ago. The PLATO trial left lingering doubts whether it is better than the much cheaper clopidogrel when used in acute coronary syndromes. Rather than attempting to resolve these, the latest trial (ATLANTIC) compares prehospital administration of ticagrelor with in-hospital administration in patients undergoing immediate percutaneous coronary intervention for ST-elevation myocardial infarction. There is no difference. The name ticagrelor keeps reminding me of Excelsior, in Henry Wadsworth Longfellow’s poem of that name:

THE SHADES of night were falling fast,
As through an Alpine village passed
A youth, who bore, ‘mid snow and ice,
A banner with the strange device,

but alas, several stanzas later:

A traveller, by the faithful hound,
Half-buried in the snow was found,
Still grasping in his hand of ice
That banner with the strange device,

His name was Herbert Seneca,
He worked for Astra Zeneca,
And ere he died he thought it nice
To use with every stent device

There, in the twilight cold and gray,
Lifeless, but beautiful, he lay,
And from the sky, serene and far,
A voice fell, like a falling star,

Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure (OL): Ah, there is much poetry in cardiology, although sometimes it can be hard to appreciate. A negative trial of Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure will not fill the hearts of most doctors with song. Many indeed may never have heard of ivadabrine, let alone used it, although it has been around for nearly 10 years. Its unique virtue is that it acts by reducing the heart rate via specific inhibition of the funny channel. Now funny channel inhibition has to be poetic. Only it’s a shame that it doesn’t seem to do anything.

Fractional Flow Reserve–Guided PCI for Stable Coronary Artery Disease (OL): Since the COURAGE trial showed that most patients with stable coronary artery disease are as well off on medical treatment as with revascularization procedures, interventional cardiologists have fought back with attempts to find subgroups who might still benefit from their expensive ministrations. The diagnostic test that they favour is fractional flow reserve. To a mere outsider like myself that seems puzzling, since what matters is plaque stability, not some one time measure of perfusion, but I must not doubt the importance of FFR since it was the determinant in the FAME-2 trial. And in this trial, “In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone.” So what was the outcome? It’s not entirely clear from the abstract, where the naughty NEJM proofreaders have let through something called “myocardial infection.” And the full text also has some seemingly conflicting statements. The trial was not blinded and was stopped prematurely due to an excess of revascularization procedures in the medical therapy group. I will leave you to pore over the details of this trial, funded by the stent manufacturer St Jude. As for the poetry, that’s easy: every civilized person should know the lines from Milton’s Lycidas about FAME as the result of honest endeavour:

Fame is the spur that the clear spirit doth raise
(That last infirmity of Noble mind)
To scorn delights, and live laborious dayes.
(English Poems, 1645)

JAMA 10 September 2014 Vol 312

Open Access to Clinical Trials Data (pg. 1002): There is more rather unpoetical cardiology in this week’s JAMA, but first read some masterly prose: Open Access to Clinical Trials Data by Harlan Krumholz and Eric Peterson. Go on, click the link: it’s free and will take you just a couple of minutes to read. It’s a perfectly stated argument for data openness. My only worry is that when data do become freely available, too few people will have the time, resources, and tenacity to dig deep into them.

Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome: The SOLID-TIMI 52 Randomized Clinical Trial“ (pg. 1006:) — see what I mean about unpoetical? I defy anyone to find a convincing rhyme for darapladib. Or indeed for lipoprotein associated phospholipase A2, which it inhibits. This is supposed to interfere with plaque formation and inflammation.

So said Glaxo Smith & Kline
While working out their trial design:
Countless billions might accrue.
But given after ACS
Its effect was nil or less.
Alas, alas for darapladib:
Another hopeful drug has had it.

Lancet 13 September 2014 Vol 384

Glucagon-like Peptide-1 Receptor Agonist and Basal Insulin Combination Treatment for the Management of Type 2 Diabetes (OL): In the catastrophizing parlance of the Lancet, type 2 diabetes is sometimes described as a “public health emergency.” If people must use this kind of language, they should really be more careful to distinguish between a challenge, a problem, a disaster, and an emergency. Describing the rise in type 2 diabetes as an emergency suits pharmaceutical companies because they want to sell drugs for diabetes without waiting for substantive proof of long term benefit. I have made this point so often that I will let you off for yawning. But what have we here? A systematic review of glucagon like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes, which reads more like an advertising hoarding than a scientific paper. “GLP-1 agonist and basal insulin combination treatment can enable achievement of the ideal trifecta in diabetic treatment: robust glycaemic control with no increased hypoglycaemia or weight gain. This combination is thus a potential therapeutic strategy that could improve the management of patients with type 2 diabetes.” It’s so wonderful that they’ve even had to make up a new word to describe it. I think “trifecta” means something that has three effects, but there’s one fecta that counts above all in type 2 diabetes: reduction of vascular end points. And I excuse you a second yawn, but I just have to keep saying this as long as papers of this sort find their way into high impact journals.

September 15th, 2014

No Endorsement for Routine ECG Screening of Young People

In a new scientific statement the American Heart Association and the American College of Cardiology do not recommend the routine initial use of ECGs to screen young people for underlying congenital or genetic heart disease.

More aggressive screening for heart disease in young people is often advocated in response to pressure resulting from the rare but tragic cases of sudden death in young people. But a detailed examination of the evidence led the AHA/ACC group to conclude that routine initial ECG screening “in healthy people 12-25 years old without positive findings on the history and physical examination has not been shown to save lives.”

The expert committee recommends that healthcare providers screen young people using a 14-point checklist that contains  information taken from the personal history, family history, and physical examination of people aged 12 to 25.  A positive finding on any of the 14 points means that further testing, including a 12-lead ECG, may be indicated.

“Although sudden death among young people is rare, it is always a tragedy, and the infrequency of these events in no way mitigates their importance or impact on families and the community. However, the media coverage of sudden cardiac arrests in athletes may have created the exaggerated impression that these tragic events are far more common than they actually are, or that they are limited to athletes,” said Barry Maron, a co-chair of the writing panel, in a press release.

The panel also stated that it found no evidence that sudden cardiac arrest was more likely to occur in young athletes than in the general population of young people. Because there are many more non-athletes than athletes, most deaths occur in young people taking part in recreational sports or everyday activities.

One important point, often unappreciated, is that ECGs are far from perfect and can result in both false-negative and false-positive results. These can lead to a mistaken reassurance of low risk or an excessive concern, perhaps leading to non-participation in sports in otherwise healthy young people. The panel estimated that routine ECG screening among only the 10 million young athletes in the U.S. (not the much larger general population) would result in 500,000 false-positive cases who would then undergo unnecessary additional testing.

The writing panel also noted that the overall cost of a mandatory screening program would be at least $2 billion a year initially and would require the development of a complex infrastructure. “Many individuals at high risk for sudden cardiac death could be found by more uniform application of careful history taking and a detailed physical examination (without an ECG) utilized in all,” they said.


September 15th, 2014

New Observations on Saxagliptin

CardioExchange’s Harlan M. Krumholz interviews Benjamin M. Scirica about his study group’s analysis of data from the SAVOR-TIMI 53 randomized, placebo-controlled trial of saxagliptin in patients with type 2 diabetes. The new observations are published in Circulation.

Krumholz: Please describe your major findings how they add to those from the main trial.

Scirica: This analysis provides more detail on the initial finding of an increased risk of hospitalization for heart failure among patients treated with saxagliptin in the SAVOR-TIMI 53 trial that we reported last year in NEJM. Here are our major observations:

  • Treatment with saxagliptin increased the risk of hospitalization for heart failure from 2.8% to 3.5% over two years, a relative 27% increased risk in the 16,492 patients randomized to the trial.
  • The greatest risk of hospitalization for heart failure appeared to occur within the first 12 months after treatment initiation.
  • Although the relative risk of heart failure was not greatest in any subgroup, the absolute greatest excess in hospitalizations for heart failure occurred in patients who had the overall highest risk for heart failure (those with chronic kidney disease, prior heart failure, or elevated levels of natriuretic peptide).

Krumholz: In your discussion, you argue that this risk is likely to be real in part because it was prespecified. Why did you design the study to assess hospitalization for heart failure? Were you anticipating a problem, or did you expect a benefit?

Scirica: We prespecified hospitalization for heart failure as a component of the secondary endpoint for several reasons. First, diabetic heart failure is a growing, yet poorly understood disease, so we felt it was an important clinical endpoint to adjudicate. Moreover, heart failure is a challenging event to capture appropriately, and adjudication was the only way to ensure we were identifying true episodes of heart failure. Second, preclinical studies and some small human studies actually suggested potential benefit from incretin-based therapy, so we felt this was an important setting in which to test that hypothesis.

Krumholz: Do you think that this increased risk is a class effect, given what you know from the literature?

Scirica: It is too early to tell. There was a consistent, albeit not statistically significant, signal with alogliptin in the EXAMINE study. I think the results of the large, ongoing TECOS study of sitagliptin are likely to tell us whether this is a class effect. Literally tens of thousands of patients have completed or are participating in cardiovascular outcome studies of DPP-4 inhibitors and GLP1 agonists. These trials will provide an enormous amount of safety and efficacy data on hyperglycemic agents and will hopefully guide diabetes therapy with much greater certainty.

Krumholz: What do you say to your patients who are taking saxagliptin?

Scirica: Our finding in SAVOR-TIMI 53 was that for the great majority of patients, saxagliptin was safe from a cardiovascular standpoint and therefore provides a valuable option for improving glycemic control. For a small proportion of users of this drug, the risk for heart failure is high. In those patients, if needed, I would use DPP-4 inhibitors cautiously and closely monitor symptoms, in particular during the initial months of therapy.


Share your thoughts on Dr. Scirica’s new analysis of data from SAVOR-TIMI 53.

September 15th, 2014

How to Ace Your Fellowship Interview

The following compilation of fellowship interview tips was originally published on Twitter between August 15th and 18th by Ethan Weiss, a cardiologist with 13 years of experience interviewing fellowship applicants. Matthew Pirotte also supplied this helpful graph categorizing potential applicants.

1. Prepare like you are interviewing for a job. You are. Know who you are meeting and who you want to meet with.

2. Learn the strengths and weaknesses of the institution you are visiting and use the information to help you.

3. Your choice of a research mentor is the most important decision you will make. Be ready to discuss who and why.

4. Do not overvalue opinions of first-year fellows in the first 3 months of training. Seek senior fellows or junior faculty.

5. Address any issues, problems, and obvious questions in your application head-on.

6. You do not need to know what you will do for your career, but you need to explain how you will figure it out.

7. You can be bold and dream, but be realistic about what you are likely to accomplish in fellowship.

8. Be prepared to discuss the things you think are important in healthcare, cardiovascular medicine, and science.

9. Even though it is a “seller’s market”, you are the consumer and should think about which program is best for you.

10. If you are interested in a program, demonstrate that meaningfully.

11. Do not tell multiple programs they are your first choice.

12. Be nice to other applicants and to program administrators. Programs pay attention to these things.

September 11th, 2014

Race and Ethnicity Do Not Affect the Benefits of Device Therapy in Heart Failure

CardioExchange’s Harlan M. Krumholz interviews Boback Ziaeian, lead author of an observational study exploring the benefits of guideline-recommended cardiac resynchronization therapy and ICD therapy in heart failure patients, according to race and ethnicity. The study is published in JACC.

Krumholz: Please briefly describe your study and its main findings.

Ziaeian: We used the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE-HF) to analyze the 2-year survival benefits of an implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) in select racial and ethnic groups. In a real-world outpatient population, we found no evidence that patients’ race or ethnicity affects their response to device therapy. Estimates of the degree of benefit were consistent among racial and ethnic subgroups and across prior randomized trials.

Krumholz: Why do you think the benefit of these devices in racial and ethnic minority groups have been questioned?

Ziaeian: The under-representation of women and minority groups in large randomized controlled trials is often highlighted as a criticism of the external validity of published trials. Clinical trials have historically over-represented white men at the expense of other groups. Despite the lack of a physiologic or well-grounded theory for why minorities may not derive a benefit similar to the one for white patients, these ideas persist. Furthermore, physicians and researchers often misinterpret subgroup analyses by focusing on the p-values for each subgroup rather than statistical tests for interactions.

Krumholz: What is it like for a fellow to be participating in research? Getting an article published in JACC is great.

Ziaeian: As a cardiology fellow in UCLA’s Specialty Training and Advanced Research (STAR) Program, it is an honor to publish my first JACC article on an important clinical issue for heart failure patients. Cardiovascular outcomes research is central to illuminating the gaps in our knowledge and provides clarity or, in some situations, further doubt on recommended clinical practices.

The STAR Program provides me with the educational foundation (through doctoral training at UCLA Fielding School of Public Health) and time to participate in research activities, as well as invaluable mentorship from Dr. Gregg Fonarow. This particular paper had 3 rounds of “revise and resubmit” during a 6-month period before final acceptance. Young investigators must appreciate the importance of addressing reviewers’ concerns, providing additional analyses, and rewriting the initial manuscript. Perseverance and acceptance of criticism are essential to the peer-review process.


Share your thoughts on Dr. Ziaeian’s research findings.

September 11th, 2014

Is This Trial Ethical?

Last month, an article appeared in The Telegraph (U.K.) describing a randomized trial in which cardiac arrest patients will be assigned to receive epinephrine or placebo during resuscitation.

Current ALCS guidelines contain a Class IIb, level A recommendation for administration of epinephrine for sustained VF and PEA/asystole but acknowledge that although epinephrine treatment has been demonstrated to increase rates of return of spontaneous circulation, it has not been shown to improve long-term survival.

This is not the first time epinephrine and placebo have been compared in a randomized trial; results of such a trial appeared in Resuscitation in 2011. Nonetheless, the new trial appears to have sparked ethical concerns about its delayed-consent procedure.

What do you think? Would you support such a trial in your EMS system?