Web App Ups Lung Cancer Survival by 7 Months


A web-based application that prompts lung cancer patients to complete a symptom chart weekly on a smartphone, tablet, or computer improved overall survival by 7 months, compared with standard follow-up care, according to results from a prospective phase 3 trial from France.

The key to the intervention is that it allowed “earlier detection of relapse” and, thus, early supportive care in the study patients, 90% of whom had stage III or IV disease, and all of whom had received previous first-line chemotherapy, said Fabrice Denis, MD, PhD, from the Institut Inter-regional de Cancérologie Jean Bernard in Le Mans, France.

“Relapse does not occur during a planned visit,” Dr Denis pointed out.

He spoke during a press conference here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

Dr Denis explained that the technology automatically triggers an email alert to the physician (which leads to a clinic visit) upon the detection of any anomaly in the data stream from the patient.

This system a “tremendous advance,” said Patricia Ganz, MD, a medical oncologist at the University of California, Los Angeles, who moderated the press conference.

“If we had a drug that provided this level of survival benefit, wouldn’t we want to go out and use it?” she asked.

In a multi-institutional, randomized trial, 60 patients used the app, known as Moovcare (Sivan Innovation), and 61 patients — the control group — received standard care, which was clinical routine assessment with a CT scan every 3 to 6 months, or at the investigator’s discretion.

Median overall survival was better in the app group than in the control group (19 vs 12 months). This translated into a 67% reduction in the relative risk for death (hazard ratio, 0.33; P = .0025).

The rate of 1-year overall survival was also better in the app group than in the control group (75% vs 49%); the absolute benefit was 26%. This was achieved despite the fact that the study was stopped early — at the planned 9-month interim analysis — because of positive benefit, and the control patients crossed over into the app group.

But the results need to be taken with a grain of salt, said study discussant Egbert Smit, MD, PhD, from the Netherlands Cancer Institute in Amsterdam.

The overall survival benefit was through delivery of appropriate treatment.

“We have to remember that the overall survival benefit was through delivery of appropriate treatment,” Dr Smit explained.

At relapse, more patients in the app group than in the control group received optimal therapy (74% vs 33%; P < .001). The exact therapies used were not indicated in the study data, he noted.
The disparity in optimal therapy at time of relapse was a reflection of patients in the app group maintaining a better performance status, which, in turn, was a reflection of the efficiency of the app in expediting clinical care, Dr Denis explained.

Despite reservations, Dr Smit called the app a “simple and clever tool,” and observed that there is no standard follow-up care after first-line therapy for lung cancer. He called for a confirmatory study.

This kind of “real-time interaction is already implemented at major centers,” said David Carbone, MD, a lung cancer specialist at the Ohio State University Comprehensive Cancer Center–James Cancer Hospital in Columbus.

For example, at Ohio State, cancer patients can call a 24-hour-a-day hotline staffed by a triage nurse, who interviews the patient and decides whether or not to contact a physician. Dr Carbone said he believes that “talking to a person may be preferred.”

The app, or similar technology, might be best when used in under-resourced settings and smaller practices, he told Medscape Medical News.

But Dr Ganz suggested that, in general, waiting for cancer patients to be forthcoming with their problems is not optimal.

“Systematically asking about things with a patient and asking them to respond [as the app does] is different than asking them, ‘How are you today? Are you having any problems?’ They won’t volunteer it,” she said.

The app requires that patients assess themselves weekly on 12 different measures, including asthenia, cough, dyspnea, and anorexia. Patients can also send a note through a text window.

The fact that the app requires patients to actively report their symptoms or complications is important, said Gregory Masters, MD, a lung cancer specialist at Christiana Care’s Helen Graham Cancer Center in Newark, Delaware, who served as an expert commentator at ASCO.

Lung cancer patients are often reticent about contacting their healthcare providers, he explained.

“Many of these patients have a lot of guilt about their diagnosis; we see that more in lung cancer patients than in many other patients,” he said. “Some patients do not want to bother the doctor, the nurse, or the healthcare team with their symptoms, or they think they are not important.”

During the press conference, Dr Masters pointed out that engaging patients is key to the outcome in this study, but is not exclusive to this specific app. “This study doesn’t show it is the only way or the best way [to improve survival].”

Dr Denis did not take offense at the comment. “You will have the same results if you call patients every week by phone,” he said.

It is not possible to follow many patients simultaneously [with the phone].
But that is impractical, he pointed out. “It is not possible to follow many patients simultaneously [with the phone].”

With the app, a clinician can spend 15 minutes a week following 60 patients, Dr Smit reported.

The benefits of timely intervention with the app were multiple.

There was a 50% reduction in imaging tests per patient per year in the app group, compared with the control group. And quality-of-life scores were higher in the app group.

Relapse rates were about 50% in both groups.

The Moovcare app is the first web-application for follow-up and early detection of relapses and complications for patients with advanced lung cancer, according to the Sivan Innovation website. The technology has a patent in the United States and Europe, and is currently undergoing a CE marking procedure in Europe. The company is developing the app for 15 other indications in oncology, including lymphoma. The latter project is being conducted in partnership with Takeda France.

Dr Carbone should be pleased. He believes that technology is not fully tapped in terms of healthcare applications. “The more that these intelligent data captures become readily available, the more everyone benefits,” he said.

Schizophrenic Brain Tries to Heal Itself


The brains of patients with schizophrenia have the capacity to reorganize and perhaps counter the effects of the disease, a neuroimaging study suggests.

Although schizophrenia is generally associated with a widespread reduction in brain tissue volume, the new study found a subtle increase in brain tissue in certain regions.

“This provides us hope to consider strategies that can harness brain’s plasticity in treating this illness and reversing some features that are, so far, considered irreversible with current medical and psychological treatments,” lead investigator Lena Palaniyappan, MBBS, PhD, of the Lawson Health Research Institute London, Ontario, Canada, told Medscape Medical News.

The study was published online May 26 in Psychological Medicine.

Noticeable Remodeling

It is now well established that MRI reveals reductions in the thickness of gray matter in patients with schizophrenia, indicating either a developmental or an acquired deficit in the amount of brain tissue, Dr Palaniyappan explained.

“These reductions are seen both in treated and untreated patients, suggesting that current treatments do not reverse the process of tissue loss. We wanted to study if subtle increase in brain tissue also accompanied this reduction.”
The researchers followed 98 treated, clinically stable patients with schizophrenia (80 males, 18 females) and compared them to 83 patients without schizophrenia. They used MRI and covariance analysis to measure changes in cortical thickness.

“We observed that across the group of 98 medicated patients, reduced thickness was consistently accompanied by subtle but nevertheless noticeable increases in thickness,” said Dr Palaniyappan. Of note, a pattern of cortical amelioration or normalization (assessed by reduced deviation from control patients) was observed with a longer duration of illness, particularly in the occipital cortex.

This suggests that a “compensatory remodeling process might contribute to the cortical thickness variations in different stages of schizophrenia,” the researchers write.

“The most important message is that in patients with schizophrenia, the brain changes are not simply a downhill one-way traffic lane. There is small but perhaps crucial ‘gain of structure’ that often goes unnoticed by the prevailing focus on ‘loss of structure.’ This may be a reminder for us to acknowledge the compensatory mechanisms that are in action alongside pathological processes that contribute to symptoms of schizophrenia,” said Dr Palaniyappan, medical director at the Prevention and Early Intervention Program for Psychoses at the London Health Sciences Centre (LHSC).

“These findings are important not only because of their novelty and the rigor of the study but because they point the way to the development of targeted treatments that potentially could better address some of the core pathology in schizophrenia,” Jeffrey Reiss, MD, LHSC site chief of psychiatry, said in a press statement. “Brain plasticity and the development of related therapies would contribute to a new optimism in an illness that was 100 years ago described as premature dementia for its seemingly progressive deterioration,” Dr Reiss added.

Dr Palaniyappan urged caution in interpreting the findings from this single cross-sectional study and said that several questions remain unanswered.

“It is not clear if the subtle increase is a compensatory effect or an additional pathological phenomenon. This needs to be clarified in future studies. Further, while clinicians do not often see a full reversal of the diagnostic features of schizophrenia in many patients, there exists a sizable subgroup of patients who recover completely and never come back to see a psychiatrist. We really need to understand the brain mechanisms that underlie such resilience. This, in my opinion, is the most important piece of puzzle on which, unfortunately, not enough effort has been spent to date,” Dr Palaniyappan told Medscape Medical News.

Intensive Glycemic Control May Harm Some Diabetes Patients


One in five elderly and “clinically complex” patients with type 2 diabetes may be receiving unnecessarily intensive glucose-lowering treatment, leading to a dramatically increased risk for severe hypoglycemia, a new study finds.

The findings were published online June 6 in JAMA Internal Medicine by Rozalina G McCoy, MD, assistant professor of medicine at the Mayo Clinic, Rochester, MN, and colleagues.

“It is time that we, as physicians and patients, recognize that high-quality diabetes care should emphasize not only avoiding hyperglycemia but also preventing hypoglycemia,” Dr McCoy told Medscape Medical News.

She added, “We should recognize the harms of intensive treatment and hypoglycemia, particularly when there is little likely benefit of keeping HbA1c low in the setting of limited life expectancy or multiple comorbidities.”

The retrospective database analysis included over 30,000 adults with type 2 diabetes who had HbA1c levels less than 7% without using insulin and had no episodes of severe hypoglycemia or hyperglycemia in the prior 12 months.

Nearly 4000 of the subjects were aged 75 years or older and/or had serious comorbidities. During the 2-year study period, 19% of that “high clinical complexity” group received intensive glucose-lowering therapy. And among those patients, the risk for severe hypoglycemia necessitating medical care was 3%, compared with just 1.7% for the high-complexity patients not receiving intensive treatment.

“Severe hypoglycemia is not rare, even among patients who are not treated with insulin and who have no prior history of severe hypoglycemia,” Dr McCoy commented.

More Research Needed on How to Deescalate Treatment

The findings highlight the lack of clinical guidance on when to stop or “deescalate” treatment in people with chronic conditions, and in fact clinicians are often incentivized not to, say Eve A Kerr, MD, of the Veterans Affairs Center for Clinical Management Research, University of Michigan Medical School, and Timothy P Hofer, MD, professor in the division of general medicine, University of Michigan, Ann Arbor, in an accompanying editorial.
“Balancing the medical profession’s focus on aggressively treating patients who are likely to benefit with an explicit consideration of when to deintensify treatments when they are no longer useful or are potentially harmful, and doing so in a manner that is respectful to the patient-physician relationship and promotes shared decision making, is the next frontier for improving care quality,” Drs Kerr and Hofer write.

Dr McCoy agrees. “The culture of healthcare has been that ‘more is better,’ and doing less is automatically an indicator of low-quality care. We need studies looking at how and when treatment should be deescalated…without causing patient harm.”

Also in the same issue of JAMA Internal Medicine is a short research letter describing a small study by Medha N Munshi, MD, of Joslin Diabetes Center, Boston, Massachusetts and colleagues, in which the insulin regimen in older adults with type 2 diabetes was simplified. This was achieved by switching multiple daily premeal dosing of insulin to once-daily insulin glargine, resulting in decreased hypoglycemia and disease-related distress without compromising glycemic control.

Dr McCoy commented, “It was reassuring to see that their HbA1c did not rise, which I think is a common fear of physicians and patients when faced with the prospect of deintensifying glucose-lowering therapy.”

Clinical Complexity and Hypoglycemia

In Dr McCoy et al’s study, the researchers obtained 2001–2011 figures for adults with diabetes who had HbA1c levels below 7% over 2 years from an administrative claims database of more than 100 million individuals enrolled in private and Medicare Advantage plans across the United States.

After exclusion of patients with severe hypoglycemia in the prior 12 months, those prescribed insulin in the prior 120 days, and those with type 1 or gestational diabetes or missing data, a total of 31,542 patients were included.

High clinical complexity, defined as a composite of age 75 years or older or high comorbidity burden defined by the presence of end-stage renal disease, dementia, or three or more serious chronic conditions, was identified in 12.4% of the total (3910 patients).

“Intensive” treatment was defined by the addition of any medication in those with baseline HbA1c levels of 5.6% or below, the use of two or more drugs at baseline or the addition of one more over the study period in those with initial HbA1c 5.7% to 6.4%, or the addition of two or more drugs or insulin in those with baseline HbA1c 6.5% to 6.9%.

Regimens that did not meet intensive-treatment criteria were considered standard treatment.

In all, 8048 patients (25.5%) were treated intensively, including 7317 (26.5%) with low clinical complexity and 731 (18.7%) with high clinical complexity.

Of note, 76% of the intensively treated patients did not have their treatment deescalated after the low HbA1c test result was obtained. Approximately three-quarters of both the low and high clinical complexity groups continued with their baseline intensive regimen.

The risk-adjusted probability of intensive treatment was 25.7% for patients with low clinical complexity and 20.8% for those with high clinical complexity (P < .001 for the absolute difference).

Patients with high clinical complexity were significantly less likely to be treated intensively than patients with low clinical complexity (odds ratio [OR], 0.76).

The overall unadjusted 2-year incidence of severe hypoglycemia — defined as episodes necessitating an outpatient, inpatient, or emergency visit — was 1.4%.

Severe hypoglycemia was significantly more frequent among patients with high vs low complexity (2.9% vs 1.2%, P < .001).

Among patients with low clinical complexity, the risk-adjusted probability of severe hypoglycemia did not increase with intensive treatment (1.02% with standard treatment vs 1.30% with intensive treatment).

In contrast, among patients with high clinical complexity, the risk-adjusted probability of severe hypoglycemia increased significantly from 1.74% with standard treatment to 3.04% with intensive treatment.

Sulfonylurea and glinide therapy significantly raised the risk of severe hypoglycemia (OR, 2.19). However, the overall results remained consistent in a sensitivity analysis even after researchers excluded patients using these agents, although the numbers were small.

Dr McCoy noted that newer diabetes drugs are “thought not to cause hypoglycemia and therefore used with less caution…yet we now see that these medications too can cause hypoglycemia among clinically complex patients…I think that physicians need to ask all patients receiving pharmacotherapy for diabetes about hypoglycemia, not just if they receive insulin or sulfonylureas.”

 Also of note, patients treated by endocrinologists had significantly higher risk of hypoglycemia (OR, 1.65), even after adjustment for the HbA1c level and medications used.

Reasons for Not Deescalating

In their editorial, Drs Kerr and Hofer summarize four main reasons that treatment deintensification is rare even when clearly indicated.

First, the question is rarely examined in clinical trials, so data are lacking about when to stop most medical services.

Second, physicians and patients may suspect that cost saving is behind recommendations to stop treatments. Third and, “less nobly, physicians may be concerned about their own performance on report cards.”

Finally, the editorialists suggest, lack of time and effective decision-support tools may hinder discussion about stopping or scaling back on established treatments and services.

“When guidelines are silent on the limits of generalization, the default in clinical practice and pharmaceutical marketing is often to generalize to the entire population all treatment benefits in the absence of definitive proof of harm,” they write.

Dr McCoy added another possible factor: “I think we also need to recognize the discomfort that physicians may feel in telling patients that they may not benefit from intensive treatment. I think that we, as physicians, may worry that this comes across as us saying that patients don’t have long to live or do not ‘deserve’ high-quality care.”

And regulatory bodies should not necessarily always equate low HbA1c with high-quality care, she said, adding, “High-quality care is care that is efficient and safe, so quality metrics should incorporate indices of overtreatment and hypoglycemia in them.”

“If physicians are ‘graded’ and reimbursed on the basis of how low their patients’ HbA1c is, there is inevitable potential for seeking lower HbA1c at the expense of potential patient harm.”

One Way to Simplify

The single-arm intervention study by Dr Munshi and colleagues recruited 65 adults with type 2 diabetes who were 65 years or older and had a mean HbA1c of 7.7%, taking two or more insulin injections a day (mean 3.7) and who had had hypoglycemia in the past 5 days detected by continuous glucose monitoring.

Mealtime insulin was stopped, and all were switched to once-daily insulin glargine, with or without noninsulin agents as needed, over 5 months. Hypoglycemia duration decreased at 5 and 8 months (P < .001) without any change in HbA1c levels after simplification.

Improvements in HbA1c occurred in patients with baseline HbA1c levels 8% to 9% (P < .001) and above 9% (P = .03), whereas there was a small worsening in those with baseline HbA1c levels below 7% (P = .03), and no change in those with HbA1c levels between 7% and 8% (P = .80).

Diabetes-related distress scores improved at 5 months and remained low at 8 months (P < .001).

In a short note, journal editor Deborah Grady, MD, of the Veterans Affairs Medical Center, San Francisco, California, points out that the study by Dr Munshi and colleagues is small and uncontrolled and therefore should be considered preliminary.

However, she wrote, “we decided to publish the study because we believe it should inspire larger trials to investigate optimum insulin regimens that minimize hypoglycemia and patient burden.”

‘New Era’ of Type 2 Diabetes Treatment as LEADER Unveiled?


Details of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial of the glucose-lowering drug liraglutide (Victoza, Novo Nordisk), showing that it significantly reduced the rates of major adverse cardiovascular events in type 2 diabetes patients at elevated cardiovascular risk, were reported today.

The study is the second such mandated FDA cardiovascular safety study for a diabetes drug to show cardiovascular benefit, rather than just lack of harm, on top of standard therapy in type 2 diabetes patients at high cardiovascular risk after the EMPA-REG trial, and the first with an agent from the glucagonlike peptide 1 (GLP-1) receptor agonist class. Results of a previous trial with another GLP-1 agonist, ELIXA, were neutral.

Experts here said that LEADER and EMPA-REG may now begin to change the landscape of diabetes therapy, giving doctors a somewhat clearer choice when deciding which drug to use second line after metformin in type 2 diabetes.

The results from the multicenter, international study were presented June 13, 2016 here at the American Diabetes Association (ADA) 2016 Scientific Sessions and were published online simultaneously in the New England Journal of Medicine, by Steven P Marso, MD, of University of Texas Southwestern Medical Center, Dallas, and colleagues.

LEADER began in 2010 and followed 9340 high-risk adults with type 2 diabetes for 3.5 to 5 years, who were randomly assigned to receive either a subcutaneous injection of liraglutide 1.8 mg once daily (or the maximum tolerated dose) or placebo along with standard treatment.

The primary end point was the first occurrence of the three-point major adverse cardiac event (MACE) components: cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke.

The degree of risk reduction for MACE was 13% (occurring in 608 of 4668 patients taking liraglutide) vs 14.9% (in 694 of 4672 taking placebo) (P = .01 for superiority), including a 22% lower rate of cardiovascular death (4.7 vs 6.0%, P = .007), Dr Marso reported in a press briefing held at the ADA meeting in advance of a special 2-hour symposium devoted to the findings.

The number of patients who would be needed to treat to prevent one event in 3 years was 66 for the MACE composite and 98 for death from any cause.

Liraglutide also reduced HbA1c, body weight, and hypoglycemia, and its safety profile was similar to what has been seen in previous trials, with gastrointestinal adverse events and increases in heart rate being the most common.

New Trials Inform Clinical Choice of Second Drug for Type 2 Diabetes

Coming on the heels of the cardiovascular benefit seen for the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in the EMPA-REG trial, the LEADER findings have experts talking about a “new era” in the management of type 2 diabetes.
While most agree that metformin remains the first-line drug of choice, these new landmark study data are starting to better inform the clinical choice of second drug based on characteristics beyond their glucose-lowering capacity, speakers said during the press briefing.

“In type 2 diabetes, most of us agree that under most circumstances metformin is the drug of choice,” briefing moderator Robert H Eckel, MD, of the University of Colorado, Denver, said, noting that additional potential cardiovascular and also anticancer benefits have been seen with that drug as well.

However, he said, “It’s interesting, with LEADER the benefit for cardiovascular death is very similar to what statins do. I think with validation, it could potentially change practice….I’d like to see second and third trials for both [liraglutide and empagliflozin]. Keep in mind there are 25 or 30 trials for statins showing benefit,” said Dr Eckel, who was not involved in LEADER or EMPA-REG.

Senior investigator of LEADER, John Buse, MD, of the University of North Carolina, Chapel Hill, added: “I think this changes the conversation with patients. Now, instead of just saying we’re giving you this drug to manage your hyperglycemia in diabetes, [we can say] this drug also has the potential to modify your risk for cardiovascular disease and death.

“It was beyond our expectations that we would be able to demonstrate cardiovascular efficacy,” he told the press briefing.

Asked to comment, Simon Heller, MD, professor of clinical diabetes, University of Sheffield, United Kingdom, toldMedscape Medical News, “I think we are in a different era now. People die from hypoglycemia, whether by insulin or sulfonylureas. We shouldn’t forget that.

“These drugs [liraglutide and empagliflozin] don’t cause hypoglycemia and have other effects that may be beneficial. I agree absolutely we need to confirm with other studies, but I think we’re definitely going to see a shift toward modern therapies.”

Benefits Seen for Multiple Cardiovascular End Points

The LEADER trial included patients with type 2 diabetes who had HbA1c levels of 7.0% or higher. Entry criteria were either age 50 and above with established cardiovascular disease or chronic renal failure or age 60 and older with CVD risk factors.

Dr Robert H Eckel on podium; left to right, Drs Simon Heller, John Buse, Steven P Marso, and Bernard Zinman

Patients could be drug-naive or taking oral agents or basal insulin but not other GLP-1 agonists or DPP-4 inhibitors, pramlintide, or rapid-acting insulin. In both treatment and placebo groups, current standards of care were targeted for HbA1c, blood pressure, lipids, and antiplatelet therapy.

Subjects had a mean baseline age of 64 years, diabetes duration 13 years, and HbA1c 8.7%.

At 36 months’ postrandomization, HbA1c levels were 0.40 percentage points lower in the liraglutide group, a significant difference (P < .001). Body weight also dropped significantly, by 2.3 kg (P < .001).

Overall, results for each of the components of the composite primary MACE outcome were in favor of liraglutide, with a 22% reduction in cardiovascular death (4.7% vs 6.0%, P = .007), which was significant, and a nonsignificant 12% reduction in nonfatal MI (6.0% vs 6.8%, P = .11) and an 11% lower rate of nonfatal stroke (3.4% vs 3.8%, P = .30).

Also significant were a 15% reduction in all-cause death (8.2% vs 9.6%, P = .02) and an expanded composite CV outcome that included coronary revascularization, unstable angina, or hospitalization for heart failure (20.3% vs 22.7%, P = .005).

Hospitalization for heart failure itself was 13% less frequent in the liraglutide group (4.7% vs 5.3%, P = .14). Although not statistically significant in terms of benefit, the lack of any signal for concern with regard to heart failure is noteworthy, Dr Marso said. “There has been a lot of discussion in the incretin space about whether agents such as SGLT2 inhibitors, DPP-4 inhibitors, or GLP-1 receptor agonists are neutral, hazardous, or beneficial for heart failure.”

He added: “What’s striking is the consistency in the relative risk reduction in all of the major cardiovascular end points that we measured in LEADER.”

The prespecified primary microvascular outcome in LEADER was a composite of nephropathy and retinopathy outcomes, and there was a benefit with liraglutide over placebo: time to first renal event was 22% longer with liraglutide, a significant difference. However, this latter effect drove the benefit, as there was no significant difference in retinopathy events between the two groups.

Safety Profile Shows No Signals

Overall adverse events occurred in two-thirds of both treatment groups and were not significantly different (= .12). Serious adverse events occurred in 50% of both groups and severe events in a third of both (P = .51).

Adjudicated cases of acute pancreatitis occurred in 0.4% of patients taking liraglutide compared with 0.5% on placebo (P = .44). There were two cases of chronic pancreatitis, both in the placebo group.

However, acute gallstone disease was more common with liraglutide, 3.1% vs 1.9% (P < .001).

Hypoglycemia was more common in the placebo group, both with overall confirmed cases of blood glucose levels below 56 mg/dL (43.7% with liraglutide vs 45.6% with placebo, P < .001) and in severe hypoglycemia requiring assistance (2.4% vs 3.3%, P = .016). The likely reason for this, Dr Eckel noted, is that the placebo patients may have been treated more intensively with insulin in attempt to achieve HbA1c targets.

Neoplasms were not different between the groups except for a 46% reduction in prostate cancer (0.9% vs 1.6%) and a lower rate of leukemias (0.1% vs 0.3%) in the liraglutide group.

There was a numeric increase in the number of pancreatic-cancer cases with liraglutide (13 vs five) for a higher rate of pancreatic cancer in the liraglutide group (0.3% vs 0.1%), but four more cases were identified on imaging in the placebo group that did not have pathology to establish the diagnosis, so the two groups were not significantly different, Dr Buse noted.

Everything Changing Modestly, but in the Right Direction

Dr Eckel said that the results of LEADER follow in the same vein as those of EMPA-REG.

“In EMPA-REG, many things related to CVD risk were modified in a modest but favorable way. LEADER gives a hint of the same kind of modification.…Everything is kind of changing modestly in the right direction.”

But the LEADER investigators note some differences in how the drugs may be working.

“The pattern of cardiovascular benefits that were associated with liraglutide in our trial appears to differ from that with the SGLT-2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial.”

The time to benefit emerged earlier in EMPA-REG than in LEADER, they note, and the variability of the direction and magnitude of the effects on the components of the composite primary outcome in that trial “contrasts with the consistency of effect in the present trial.”

The observed benefits in EMPA-REG “may be more closely linked to hemodynamic changes, whereas in the present trial, the observed benefits are perhaps related to the modified progression of atherosclerotic vascular disease,” they conclude.

FIRE and ICE: Analysis Strengthens Case for Cryoballoon Over RF Ablation in Paroxysmal AF


Prespecified secondary analyses from the FIRE and ICE trial show significantly fewer rehospitalizations and repeat ablations for patients with paroxysmal atrial fibrillation (PAF) treated with cryoballoon ablation rather than the gold standard of radiofrequency ablation[1].

“I do believe that 5 years from now there will be no more point-to-point ablation to isolate the pulmonary veins; everything will be done with this balloon technology,” lead author Dr Karl-Heinz Kuck (Asklepios Klinik St Georg, Hamburg, Germany) said to an audible gasp here at the European Heart Rhythm Association (EHRA) EUROPACE-CARDIOSTIM 2016 meeting.

Dr Jonathan Kalman (Royal Melbourne Hospital, Australia) told heartwire from Medscape, “It is a bold statement, but I would make the observation that the differences were small, that the curves diverged late, and a 50% relative reduction is a 3% absolute reduction in cardioversions.”

He added, “Radiofrequency technology continues to evolve. So I think it remains to be seen, but there’s no question that for people doing RF ablation that these data represent a challenge.”

As reported this spring by heartwire , treatment with the cryoballoon (Arctic Front, Medtronic) ablation demonstrated noninferiority—but not superiority—compared with a radiofrequency catheter (ThermoCool, Biosense Webster) ablation for the primary efficacy end point of time to first recurrence of atrial fibrillation (AF) >30 s, atrial flutter, or atrial tachycardia, use of antiarrhythmic drugs, or reablation.

In the secondary analyses, patients treated with cryoballoon ablation compared with radiofrequency ablation had significantly fewer all-cause rehospitalizations (32.6% vs 41.5%: P=0.01) and cardiovascular rehospitalizations (23.8% vs 35.9%; P<0.01), including AF hospitalizations, Kuck reported during the late-breaking session.

There were 49 repeat ablations in 44 patients treated with cryoballoon ablation and 70 repeat ablations in 66 patients treated with radiofrequency ablation (11.8% vs 17.6%; P=0.03).
There were 13 direct-current cardioversions in 12 patients in the cryoballoon arm and 28 events in 24 patients in the radiofrequency ablation arm (3.2% vs 6.4%; P=0.04).

In a subgroup analysis of patients with a prior cardioversion at baseline, 20.9% treated with cryoballoon and 48.9% treated with radiofrequency ablation had a CV rehospitalization (P=0.05), Kuck reported.

Mental and physical quality of life, assessed at baseline and every 6 months after ablation, improved in both groups at 6 months and was maintained throughout 30 months of follow-up.

Session cochair Dr Helmut Puererfellner (Elisabethinen Hospital, Linz, Austria) told heartwire the preplanned secondary analyses are a “mind-changer” that will clearly spark debate.

“It simply shows that the lesions might hold longer, and this seems to lead to fewer events in the phase after ablation and in the first year and even longer, and this is something we have to discuss.”

He added, “It does not give a definite answer whether cryo is better because the primary result still remains the primary result; that it was noninferior.”

Both Kalman and Puererfellner said it remains to be determined which patients are best served by cryoballoon ablation and that most labs will likely offer both procedures.

Based on the primary initial results of FIRE and ICE, Puererfellner said they’ve introduced cryoballoon ablation in his lab and that he will use both techniques going forward, initially favoring cryoablation for patients with a normal set of veins.

During the discussion following presentation of the data, Kuck said if there was a bias in FIRE and ICE it was in favor of point-to-point radiofrequency ablation because it was performed by extremely well-trained individuals. “At this point in time, doing a multicenter radiofrequency-based trial, you can’t do better than what was done.”

Kuck told heartwire that while there are strict rules on who can perform balloon-based procedures in the US, the data are likely to push wider application of the technology elsewhere. “There will be people, interventionalists, who will start to do balloon-based ablation procedures. I do see this, and our regulation at this point in time doesn’t prevent them from doing it.”

This shift will require some sort of global training and demonstration of competence to ensure that complications can be addressed should they arise during the procedure.

Still, he added, “The PVI-balloon–based procedure is such a safe procedure that I do believe that a very experienced interventional guy that is well trained in an [electrophysiology] EP lab can do it.”

While the abstract drew a strong round of applause, Kuck has recently been in a far less desirable spotlight. Earlier this week he withdrew his candidacy for president of the European Society of Cardiology following an out-of-court settlement in Germany last week, according to a statement by the ESC.

According to Die Welt , he was reportedly found guilty of treating patients he did not see and received a €100,000 fine and 1-year prison sentence that was suspended if he commits no further fraud.

Kuck, a former president of the European Heart Rhythm Association, also stepped down from the board of this ESC subspecialty association, “in order to protect the reputation of the ESC,” the statement noted, adding, “We wish to thank him for more than a decade of loyal service and his many contributions.”

Air-Pollutant Exposure Associated With Coronary Calcium Buildup


Long-term exposure to commonly encountered concentrations of ambient air pollutants, such as particulate matter less than 2.5 µm (PM2.5) and traffic-related pollution, may increase coronary artery calcium (CAC), new research suggests[1].

Ten-year analysis of almost 6800 participants in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) showed that “for each 5-µg PM2.5/m3 increase, coronary calcium progressed by 4.1 Agatston units per year (95% CI 1.4–6.8),” report the investigators, led by Dr Joel D Kaufman (University of Washington, Seattle).

In addition, CAC increased by 4.8 Agatston units per year (95% CI 0.9–8.7) for each 40-ppb increase in nitrogen oxides.

Although there was no association between change in carotid intima-media thickness and exposure to any of the pollutants examined, the overall findings “support the case for global efforts of pollution reduction in prevention of cardiovascular diseases,” write the researchers.

The findings were published online May 24, 2016 in the Lancet.

Calling this “the largest study of its kind,” Dr Bert Brunekreef (Utrecht University, Netherlands) and Dr Barbara Hoffman (Heinrich-Heine-University of Düsseldorf, Germany) note in an accompanying editorial[2] that the findings suggest that changing addresses from one with 11-µg-PM2.5/m3 annual average exposure to one with 22-µg-PM2.5/m3 concentrations “would result in about 38% faster annual progression of atherosclerosis.”

They write that the finding about nitrogen oxides was also striking, and the overall results “suggest to us that both locally generated and secondary pollutants are important.”

Underlying Disease Process

The investigators note that although past research has shown a link between CV risk and long-term exposure to traffic-related pollutants, “the disease process underlying these associations remains uncertain.”

For the current study, they sought to examine effects of air-pollution exposure on CAC as well as on intima-media thickness.

MESA Air is a 10-year cohort study that enrolled 6795 US participants between the ages of 45 and 84 years (53% women; mean age 62 years). All underwent CT scans at baseline, as well as repeated scans at time points to 2012. CAC, as measured by CT, “is a surrogate of atherosclerosis extent,” note the researchers.
Ultrasound was used to measure baseline intima-media thickness and was repeated between 2010 and 2012 for 3459 of the study participants. Estimated concentrations of PM2.5 and nitrogen oxides from 1999 to 2012 were also collected.

Before risk-factor adjustments, CAC increased by a mean of 24 Agatston units/year for the entire study population, and intima-media thickness increased by 12 µm/year. PM2.5 levels for the participants during the years 2000 to 2010 ranged between 9.2 and 22.6 µg/m3 (mean 14.2).

“Exposures assessed in this study are low and relevant for understanding the health effects of ambient environments occurring nowadays in high-income, low-income, and rapidly industrializing countries,” the investigators write.

They note that the average concentration allowed by the US National Ambient Air Quality standards is 12 µg/m3 of PM2.5 annually, whereas the European Union Air Quality standards allow annual average concentrations of 25 µg/m3.

Of the six study sites, the highest levels of PM2.5 were in Los Angeles County, CA (17.7 µg/m3) and the lowest levels were in St Paul, MN (10.6 µg/m3). Nitrogen-oxide levels were highest in New York City and lowest in Winston-Salem, NC. The other two sites assessed were Chicago, IL and Baltimore, MD.

Decisive Action Needed

Overall, “the results provide important evidence that long-term exposure to these ambient air pollutants is associated with atherosclerosis progression in the coronary arteries and can explain previous findings that pollutants are associated with cardiovascular events and mortality,” write the researchers.

The editorialists note that the study “is exemplary in its prospective design, detailed air-pollution–exposure assessment, meticulous measurements of CAC progression, and its comprehensive approach to analysis.”

They note that while the WHO Air Quality Guideline has a standard for PM2.5 of 10 µg/m3, that number is expected to go down further in the next set of revisions, due to be released in a few years, based on increasing evidence of an association between PM2.5 and CV events.

“Yet European policy makers seem to be dragging their feet when it comes to taking decisive action against one of the biggest environmental health threats we face today,” write Brunekreef and Hoffman.

“How much more evidence do they need before coming up with a serious remedy?”

CV Event Risk Climbs in Women With Migraine


A large Nurses’ Health Study II cohort analysis shows migraine is a risk marker for coronary events and cardiovascular death[1].

Women with migraine compared with those without it had a 50% higher risk for developing major cardiovascular disease after multivariable adjustment (hazard ratio [HR] 1.50; P<0.01).

Specifically, risk was elevated for angina/coronary revascularizations (HR 1.73; P<0.01), stroke (HR 1.62;P<0.01), MI (HR 1.39; P<0.01), and CV mortality (HR 1.37;P=0.04), according to a recent online report in the BMJ.

“This is something that substantially adds to the story because it is such a large study, it’s a different age group, and the findings are quite robust,” lead author Dr Tobias Kurth (Charité–Universitätsmedizin, Berlin, Germany) told heartwire from Medscape.

Though the link between migraine and stroke is well established, prior studies have shown conflicting results regarding the association between migraine and other vascular outcomes.

The researchers previously reported[2] an increased risk for major CVD events and CV death with migraine in an older cohort of women, aged at least 45 years at enrollment in the Women’s Health Study, but the risk was present only in those with aura, a subgroup that represents about 30% of people with migraine.

Making the CVD Risk List

The present analysis involved 115,541 women aged 25 to 42 years at enrollment in the Nurses’ Health Study II, of whom 17,531 had migraine at baseline and another 6389 who were diagnosed during follow-up from 1989 through June 2011.

Women with migraine were more likely to have hypertension, elevated cholesterol, family history of MI before age 60, and body-mass index of >30 kg/m2—all factors adjusted for in the multivariable analysis. The model also adjusted for age, use of aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, and postmenopausal hormone-replacement therapy, as well as oral contraceptives and current smoking—two risk factors known to dramatically increase stroke risk in women with migraine.

In an accompanying editorial[2], Dr Rebecca Burch (Harvard Medical School, Boston, MA) and Dr Melissa Rayhill (State University of New York at Buffalo, NY) write, “It is time to add migraine to the list of early life medical conditions that are markers for later life cardiovascular risk.”

Although the magnitude of the risk is small at the individual patient level, it is still important at a population level because migraine is so prevalent, especially in certain US minorities and lower socioeconomic groups, which commonly have more cardiovascular risk factors.

Because all participants were female and information was not collected on migraine with aura, the study cannot answer whether CVD risk is elevated in men or whether, as with stroke, this risk is confined to the subgroup with aura, although “both things seem likely,” they note.

Kurth agreed the lack of information on aura is a clear limitation of the study but added, “For us it was still amazing to see that we see the flag for any migraine. If it’s true that it’s driven by migraine with aura, of course the estimates are higher for this group and less for migraine without aura.”

Driving forces

Several biological mechanisms linked to migraine have also been linked to higher CVD risk such as increased thrombogenic susceptibility, shared genetic markers, and systemic inflammation. Kurth said there’s likely not one mechanism but a combination of a genetic disposition plus other factors that need to be present before these events actually occur.

There is evidence, however, that the risk increase for stroke is different from that for CVD. In 2008, the researchers reported[4]that for stroke women with migraine and aura had a fairly healthy CV risk profile, but for MI the opposite was true and they had an unhealthy CV risk profile. “But the numbers we are playing with are fairly low, so I have to be careful in making causal implications.”

Burch and Rayhill write that it is important to understand how the vascular risk attributable to migraine interacts with other risk factors. “A special worry is whether the combined effects of two risk factors may result in multiplicative, rather than additive, risks.”

This is particularly relevant for phase 3 migraine trials under way examining antibodies to calcitonin-gene–related peptide (CGRP) or its receptors, as animal studies suggest the risk of vascular events increases during long-term CGRP blockade.

To Treat or Not

The editorialists write that the results raise many questions regarding treatment: “Do treatments that decrease the frequency or severity of aura or headache reduce later-life vascular risks? Should patients with migraine be treated with statins or aspirin?”

Despite “their intuitive appeal,” however, they urge caution in assuming that these interventions will benefit patients with migraine. An exploratory analysis from the Women’s Health Initiative, for example, showed that women with migraine with aura who took aspirin actually had an increased risk of MI.

“At present, migraine is probably best thought of as a situation in which the medical urge to ‘do something’ (beyond currently recommended assessments for cardiac risk and advocating a healthy lifestyle) should be resisted.”

Kurth said none of the studies they’ve published would indicate that treating migraine would reduce the risk of CV events but that there is a paucity of evidence in this area and in migraine research in general.

For now, women with migraine can talk with their clinicians about how to modify or treat CVD risk factors such as hypertension. They can also demand more research.

“We cannot leave millions of women with migraine and by the way, also men, alone and say, ‘We have this increased risk, but sorry we cannot give you any answers because we have no data.’ This is unacceptable.”

Childhood appendicitis halves the risk of ankylosing spondylitis


childhood appendicitis and respiratory tract infection on ankylosing spondylitis risk

Appendicitis during childhood reduced the risk of developing ankylosing spondylitis (AS) later in life by almost half, while hospitalization with childhood respiratory tract infection (RTI) increased the risk, according to a study presented at the recent European League Against Rheumatism Annual Congress (EULAR 2016) held in London, UK.

The study analysed data from 2643 AS cases and 11,064 matched controls based on the Sweden national health care register from 1964 to 2009. Each indexed case was matched to five controls by age, sex, and county from the population register. [EULAR 2016, abstract OP0082]

Individuals hospitalized with either gastrointestinal, urogenital, appendicitis or respiratory tract infections before their 17th birthday were included, while those diagnosed with inflammatory bowel disease (IBD), rheumatic disease, iridocyclitis or psoriasis before age 17 were excluded.

Individuals with appendicitis during childhood were 40 percent less likely to be diagnosed with AS later in life (odds ratio [OR], 0.59, 95 percent confidence interval [CI], 0.42-0.82), while those who had been hospitalized with RTI during childhood were 20 percent more likely to develop AS (OR, 1.18, 95 percent CI, 1.01-1.39).

These relationships remained significant even after excluding all individuals diagnosed with IBD up to 2 years after the index case was first diagnosed with AS.

“These findings suggest the way the immune system responds during childhood, either by influencing the risk of a severe childhood infection or [through infection-induced changes in immunological response], may explain how AS develops,” said lead author Ulf Lindström from the Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg in Gothenburg, Sweden.

Inflammatory responses triggered by childhood appendicitis could have immunologically modified the colonic mucosa, which protected these individuals from developing AS, he proposed.

In contrast, hospitalization for gastrointestinal tract or urogenital infections during childhood was not predictive of an AS diagnosis later in life.

Previous studies have implicated microbes exposure, in the form of gut flora or infection, in the development of several AS-related conditions including reactive arthritis and IBD. [Best Pract Res Clin Rheumatol 2014;28:687-702]

“Despite decades of effort to understand its aetiology, the causes of AS remain poorly characterised, so this is a significant development in helping us better understand this debilitating disease,” said Lindström.

Tofacitinib may be a promising therapeutic option for AS


The oral Janus kinase (JAK) inhibitor tofacitinib may be a promising therapeutic option for patients with ankylosing spondylitis (AS), according to an expert who presented results from a phase II study that was touted as the first to demonstrate the efficacy of a JAK inhibitor in AS.

Tofacitinib demonstrated greater clinical and imaging efficacy vs placebo in reducing the signs and symptoms of AS, said lead investigator Professor Désirée van der Heijde from the Leiden University Medical Centre in Leiden, The Netherlands. “Our data are quite consistent if you look at objective measures of response. There was a clear dose-response [relationship] in all clinical imaging outcome measures at week 12.”In the Bayesian Emax model analysis, patients taking tofacitinib 5 and 10 mg twice daily had a predicted 22.9 and 27.3 percent higher response in ASAS20 (improvement of at least 20 percent in the Assessment in Ankylosing Spondylitis Response Criteria at week 12) versus placebo. Those taking tofacitinib 2 mg twice daily had a 15.8 percent higher response in the ASAS20. [EULAR Congress 2016, abstract OP0002]

In addition, there was an improvement in MRI SPARCC (Spondyloarthritis Research Consortium of Canada) scores with tofacitinib, particularly in the 5 mg and 10 mg groups. There was almost no change in the SPARCC scores in the placebo group.

Patients in the study were randomized to tofacitinib 2mg, 5 mg, or 10 mg twice daily (n=52) or placebo (n=51) for 12 weeks and followed for an additional 4 weeks.  Mean disease duration at baseline was 6.3 years. Over 85 percent of patients were HLA-B27 positive and a fairly large proportion of patients were taking disease-modifying antirheumatic drugs (DMARDs).

There were no new safety signals with tofacitinib beyond those observed in other rheumatic diseases. Dose-dependent changes in laboratory outcomes were observed in the tofacitinib groups but levels returned to baseline at study end. Also very few patients in the tofacitinib groups discontinued treatment.

Given these promising results, further investigation of JAK inhibitors for AS in large phase III trials is warranted.

Tofacitinib is FDA-approved for rheumatoid arthritis and has been explored in several phase III studies for the treatment of psoriasis.

Rheumatoid arthritis patients suffer sexual dysfunction


Over one-third of patients with rheumatoid arthritis are sexually dysfunctional and suffer from low libido, painful intercourse, orgasmic dysfunction, and overall sexual dissatisfaction, according to research presented during the European League Against Rheumatism (EULAR) annual congress held recently in London, England.

“Sexuality is an important dimension of personality and human body, therefore any involvement in this area should be considered as important,” the researchers said. “Sexual disturbances in rheumatoid arthritis patients are poorly described in literature.”

The researchers interviewed a sample of 1.290 patients from a specialized rheumatoid arthritis clinic of whom 1,048 (80.74 percent) were women and 250 (19.26 percent) were men. Average disease activity was low and average age was 55.1 years. The researchers did not control the study with non-rheumatoid arthritis patients. [EULAR 2016, abstract OP0308-HPR]

Forty percent of women reported no sexual activity. Of the sexually active women (59.8 percent), 60.1 percent reported satisfactory sexual activity while 16.1 percent reported no satisfactory sexual activity, 7.8 percent reported lack or loss of sexual desire, 13.7 percent reported dyspareunia, and 2.2 percent reported orgasmic dysfunction.

Thirty-one percent of men reported no sexual activity. Of the sexually active men (69.2 percent), 49.1 percent reported satisfactory sexual activity while 12.1 percent reported premature ejaculation, 13.2 percent reported no satisfactory sexual activity, 5.8 percent reported a lack or loss of sexual desire, 16.1 percent reported orgasmic dysfunction, and 3.4 percent reported dyspareunia.

“There was statistical significance between patients reporting no sexual activity and higher disease activity,” the researchers said.

Though there were no statistically significant precipitating factors associated with sexual disorders and disease activity, and in a majority of patients there were no precipitating factors at all, non-significant precipitating factors included infidelity, insecurity in sexual role, and biological or physical causes, all of which were more common among women.

Maintenance factors were similarly statistically non-significant and in the minority, but these included biological causes, infidelity, changes in relationship, partner’s sexual dysfunction, and depression and anxiety, again, more common among women than men.

“There are many factors that may influence the prevalence and worsening of sexual disturbances; higher [disease activity score] is correlated with [less] sexual activity,” said lead author Dr. Pedro Santos-Moreno of the Biomab, Center for Rheumatoid Arthritis in Bogota, Colombia, citing prior work that showed improving disease activity does improve patients’ sexual drive, but that drug therapy may not be enough.

Santos-Moreno suggested clinics with a high volume of rheumatoid arthritis patients might benefit from the presence of a psychologist familiar with sexuality issues.