Study challenges “no pain no gain” requirement for patients with clogged leg arteries

 

Patients with peripheral arterial disease should be given the option of pain-free exercise, according to a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC). Around 200 million people worldwide have peripheral arterial disease (PAD), where arteries in the legs are clogged, restricting blood flow to the legs and raising the chances of stroke and heart attack. Smoking, diabetes, high blood pressure, and high cholesterol all increase the risk of PAD. Around 30% of patients have pain and cramping in their legs when they walk – referred to as intermittent claudication. Exercise is a cornerstone of PAD management, together with smoking cessation, healthy diet, and weight loss.3 It improves symptoms, mobility and quality of life. “For many years the standard exercise prescription for patients with PAD has been to walk towards, and push past, moderate to severe pain,” said study author Edward Lin, of the University of Toronto, Canada. “Research has shown that this approach improves walking distance and quality of life.2 Naturally if you force patients to walk past their pain thresholds and continue to do so, they’re going to get better at walking.” But he added: “Many patients with PAD exercise very little or not at all. It has been suggested that the pain component of conventional exercise programmes is a deterrent. More recent studies have shown that pain-free forms of exercise are equally effective, but patients are not always given the option.” This study compiled the best evidence and compared completion and adherence rates between traditional versus alternative exercise programmes of at least four weeks duration. Completion was defined as the proportion of participants who finished the programme, while adherence was the percentage of exercise sessions done. In the study, traditional programmes consisted of walking until moderate to severe pain was induced, resting until the pain subsided, then repeating the process. Alternative exercises included walking without pain, arm ergometer (an exercise bike for the arms), resistance training, circuit training, lower limb aerobic exercise, and walking with poles. A total of 84 studies and 4,742 patients were included in the analysis, encompassing 64 traditional walking programmes and 58 alternative exercise programmes. Completion rates were 6% higher in programmes with alternative forms of exercise compared to painful walking (80.8% versus 86.6%). Similarly, adherence was 8% greater in alternative programmes compared to painful walking (77.6% versus 85.5%). “Pain played a major role in the completion and adherence rates,” said Mr Lin. “Walking to pain is effective, but only if patients actually do it. Many clinicians and vascular surgeons still prescribe this type of exercise, but it’s important to consider other types of activity, which have also been shown to work.” Mr Lin noted that there is insufficient referral of patients with PAD to cardiac rehabilitation and prevention programmes. An individualised exercise plan that patients are more likely to follow should be developed, considering their preferences for exercise and potential barriers. “Pain is not a necessary part of exercise for patients with peripheral arterial disease,” said Mr Lin. “If patients prefer not to walk to pain, they can be encouraged to do pain-free exercise they enjoy. This should increase the likelihood of maintaining long-term physical activity.”

Atrial fibrillation set to affect more than 14 million over-65s in the EU by 2060

 

: Urgent action is needed to prevent, detect and treat atrial fibrillation to stop a substantial rise in disabling strokes. That’s the main message of a paper published today in EP Europace, a journal of the European Society of Cardiology (ESC),1 during World Heart Rhythm Week. Atrial fibrillation is the most common heart rhythm disorder2 and accounts for 0.28% to 2.6% of healthcare spending in European countries. Patients with atrial fibrillation have a five times higher risk of stroke. And 20% to 30% of strokes are caused by atrial fibrillation. Strokes due to atrial fibrillation are more disabling and more often fatal than strokes with other causes. The study estimates that 7.6 million people over 65 in the EU had atrial fibrillation in 2016 and this will increase by 89% to 14.4 million by 2060. Prevalence is set to rise by 22%, from 7.8% to 9.5%. The proportion of these patients who are over 80 will rise from 51% to 65%. “Atrial fibrillation patients over 80 have even greater risks of stroke so this shift in demography has enormous implications for the EU,” said study author Dr Antonio Di Carlo, of the Italian National Research Council, Florence, Italy. “Older patients also have more comorbidities linked to atrial fibrillation such as heart failure and cognitive impairment.” Prevention of atrial fibrillation is the same as for other cardiovascular conditions. This includes not smoking, exercise, a healthy diet, keeping alcohol under moderation, and controlling blood pressure and diabetes. Screening for atrial fibrillation is important because oral anticoagulation effectively prevents strokes in these patients. Dr Di Carlo said GPs should opportunistically screen for atrial fibrillation by performing pulse palpation during every consultation. Patients with an irregular pulse would have an electrocardiogram (ECG) for confirmation. “The majority of older people see their GP at least once a year, so this is an efficient and effective method to diagnose atrial fibrillation and prevent complications,” he said. GPs can inform patients about symptoms of atrial fibrillation such as palpitations, racing or irregular pulse, shortness of breath, tiredness, chest pain and dizziness.3 And they can teach patients how to check for an irregular pulse using the fingertips, which can be reported and followed-up with an ECG. “I recommend this approach for now,” said Dr Di Carlo. “In future there may be reliable devices for first line screening by the public such as smartwatch apps, but these technologies are not ready for widespread use.” To calculate the numbers of atrial fibrillation patients over 65 anticipated in the EU in the next four decades, the researchers first measured the prevalence in a representative sample of people over 65 in Italy. They then used population projections from the statistical office of the EU (Eurostat) for all 28 Member States. The study was funded by the Italian Ministry of Health, National Centre for Disease Prevention and Control.

You survived a heart attack. Now what about the depression?

: Heart attack patients with prolonged depression or anxiety are at a higher risk of death. That’s the finding of research published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).

“Temporary mood swings, if they are not too frequent or dramatic, are a normal part of life,” said study author Dr Erik Olsson, of Uppsala University, Sweden. “Feeling a little depressed after a heart attack might even be a good thing if it makes you withdraw a bit and get some rest. Emotional states help us regulate our behaviours.”

“On the other hand, chronic emotional distress makes it harder to adopt the lifestyle changes that improve prognosis after a heart attack,” he continued. “These include quitting smoking, being physically active, eating healthily, reducing stress, and taking prescribed medications.”

Previous research has shown that emotional distress, such as depression and anxiety, affects prognosis after a heart attack. This was the first study to examine prognosis according to the duration of distress. The study included 57,602 patients from the national SWEDEHEART registers who survived at least one year after a first heart attack. Emotional distress (including depression and anxiety) was measured at 2 and 12 months after the heart attack. Patients were then followed-up for a median of 4.3 years.

The study shows that persistent emotional distress over 1 year impacts on prognosis, whereas short-term distress does not. Compared to those with no emotional distress, patients who felt depressed or anxious at both time points were 46% and 54% more likely to die from cardiovascular and non-cardiovascular causes, respectively, during follow-up. Patients who felt distressed only at 2 months were not at increased risk.

More than 20% of patients fell into the category of persistent emotional distress. Previous research shows that this state is mainly linked with sociodemographic, rather than clinical, factors.² For example being younger, female, born abroad, and unemployed (versus employed or retired).

“It appears that the Matthew effect³ also applies to cardiac rehabilitation, whereby those who have continue to benefit whereas those without do not,” said Dr Olsson. “Better resources in life including education and cognitive ability enable us to handle difficult patches, while a good job with a good salary gives us more control over our circumstances. This is not the case for people with a tougher life – we know for example that immigrants who have fled from difficult situations are less likely to get the right treatment.”
 
Most cardiac rehabilitation clinics offer some kind of counselling and Dr Olsson said this could be a good opportunity for people with continual feelings of anxiety or depression to get help.

Some 15% of participants felt anxious or depressed at 2 months but then recovered. “These are likely to be people with a higher socioeconomic status who have good coping mechanisms,” said Dr Olsson.

To recover from the initial emotional reaction to a heart attack, he said: “Try to keep doing your usual activities, at least the positive ones. Some patients begin to avoid exercise and sex because they are afraid of triggering another event, but most things that feel risky are not. If you’re in a low mood you may expect less enjoyment from socialising, but then find it is more pleasurable than you predicted. If you haven’t been depressed or anxious before, at least not very often, don’t worry about it. It is likely a normal reaction to a life-threatening event which is also partly biological.”

Dr Olsson noted that 10% of patients in the study felt distressed only at 12 months, and they were 46% more likely to die from non-cardiovascular causes during follow-up. “This distress is unlikely to be related to the heart attack,” he said. “These patients resemble those with persistent distress in terms of education, marital status, and employment, and may be another fragile group.”

In vitro fertilisation linked to deadly heart disease in pregnancy

• • 
    

     

 Women undergoing fertility treatment should urgently see their doctor if they have heart failure symptoms, according to a study presented today at Heart Failure 2019, a scientific congress of the European Society of Cardiology (ESC).

Shortness of breath, swollen legs and waking up in the night to urinate could be warning signs of a pregnancy-associated heart failure called peripartum cardiomyopathy (PPCM). PPCM affects about one in 1,000 pregnant women worldwide and is life-threatening to the mother and baby. The heart becomes enlarged and weak in late pregnancy or after delivery.

“It is very difficult to distinguish normal pregnancy discomfort from heart failure symptoms,” said Dr Tobias Pfeffer, study co-author and cardiologist at Hannover Medical School. “Our study shows that the risk of PPCM is five times higher in women who have fertility treatment so they should be aware that this discomfort may not be benign. PPCM is often diagnosed much too late, with direct consequences on prognosis.”

“In all women who have conceived artificially, gynaecologists and fertility doctors should advise cardiac checks including echocardiography after delivery, or shortly before, to rule out PPCM,” said Professor Denise Hilfiker-Kleiner, the study’s senior author and Hannover’s dean of research in molecular cardiology.
She noted that the pregnancy rate of artificial fertilisation varies between 10% and 50% per cycle according to age and method, meaning that women undergo multiple rounds of treatment if pregnancy doesn’t start or is lost at an early stage. “Lost pregnancies can also induce PPCM,” she said. “Women who have developed signs of cardiac stress or impaired function should know that another cycle may increase their risk of becoming severely ill.”
Rising success rates and affordability have led to a steady increase in the proportion of babies born from assisted reproductive technology (ART) such as in vitro fertilisation (IVF) and intracytoplasmatic sperm injection (ICSI). In Germany for example it rose from 1.6% in 2006 to 2.6% in 2016, and in Denmark from 6.1% in 2012 to 10% in 2018.
The study found high rates of subfertility in patients with PPCM. One-third had difficulty getting pregnant despite regular sexual intercourse over at least six months, compared to around 20% in the general population in Germany. Births using ART were five times more common in women with PPCM: 13% of babies were conceived artificially compared to 2.6% in the general population.
The researchers said the high prevalence of subfertility and births using ART in patients with PPCM could be partly related to shared risk factors. “Women who undergo artificial fertilisation are normally older and delivery is more often by caesarean section, so they already have two risk factors for PPCM,” said Professor Hilfiker-Kleiner. “Fertility treatments altogether induce multiple pregnancies, which also raises the chance of PPCM.”
“We also think there may be genetic alterations that predispose women to both subfertility and PPCM but these analyses are ongoing,” said Manuel List, co-author and medical student at Hannover. “So far there is no clear evidence that hormonal treatment, which is usually part of fertility therapy, increases the risk of PPCM.”
Professor Hilfiker-Kleiner noted that clinical outcomes of PPCM patients in the study were not worse in women with fertility problems, including those who underwent fertility treatment, compared to those with normal fertility. “Having IVF or ICSI is not associated with a worse prognosis from PPCM,” she said. “However, as subsequent pregnancies after PPCM have a high risk for relapse, fertility treatment in PPCM patients bears a high risk for mother and foetus.”
The study was conducted in 111 patients with PPCM. Information on fertility and fertility treatment was obtained using a standardised questionnaire. Fertility centres provided treatment details.

Biomarkers help tailor diuretic use in acute heart failure patients

Adrenomedullin activity predicts which acute heart failure patients are at the greatest risk of death without diuretic treatment post-discharge, according to late breaking research presented today at Heart Failure 2019, a scientific congress of the European Society of Cardiology (ESC).1

“Therapy at discharge often remains unchanged for several weeks and even months in acute heart failure patients,” said first author Dr Nikola Kozhuharov, of the University Hospital Basel, Switzerland. “Our study shows that not re-evaluating the need for diuretics in this critical time period has detrimental consequences for patients.”

Acute heart failure is the most common cause of hospitalisation in people over 50 and up to 30% die in the year after discharge. “This is in part due to the challenge of predicting which patients are at the greatest risk of death and the subsequent uncertainty in defining the appropriate intensity of in-hospital and immediate post-discharge management,” said Dr Kozhuharov.

The study aimed to find biomarkers that predict risk levels in acute heart failure patients discharged from hospital and who would benefit from heart failure drugs. The drugs were diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, and aldosterone antagonists.

For the biomarkers, the study used two components of adrenomedullin, a peptide hormone that is a vasodilator, meaning it dilates (opens) blood vessels. Adrenomedullin was selected after pilot studies suggested it can quantify dysfunction of small blood vessels and the associated mortality risk. In addition, activity of adrenomedullin reflects residual congestion in acute heart failure patients and the researchers hypothesised that this could be used to guide diuretic therapy at discharge.

The two components used to quantify the activity of adrenomedullin were midregional proadrenomedullin (MR-proADM), a stable precursor, and the biologically active form of adrenomedullin (bio-ADM).

The study enrolled 1,886 acute heart failure patients presenting with acute breathlessness to emergency departments of university hospitals in the UK, France, and Switzerland. Plasma concentrations of MR-proADM and bio-ADM were assessed within 12 hours of presentation and at discharge from an acute ward.

A total of 514 patients (27%) died during the 365-day follow-up. Patients with bio-ADM levels above the median had significantly lower survival if they were not receiving diuretics at discharge. A similar result was found for MR-proADM. Both associations remained significant after adjusting for age and plasma creatinine concentration at discharge. Associations with the other drugs were not significant after correction for multiple testing.

Patients with bio-ADM plasma concentrations above the median had an 87% increased risk of death during follow-up compared to those with levels below the median. MR-proADM was even more accurate than bio-ADM for predicting death and the combined risk of death and/or acute heart failure rehospitalisation.

Dr Kozhuharov said: “The observation that patients with high bio-ADM have much higher mortality rates if not treated with diuretics at discharge has immediate clinical consequences. Reasons for stopping diuretics during hospitalisation included worsening renal function and low blood pressure. Our study shows that patients should be reassessed for contraindications before discharge so that diuretics can be restarted if appropriate, particularly if they have elevated bio-ADM.”

Stressed at work and trouble sleeping? It’s more serious than you think.

Sophia Antipolis, 28 April 2019:   Work stress and impaired sleep are linked to a threefold higher risk of cardiovascular death in employees with hypertension. That’s the finding of research published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1 Study author Professor Karl-Heinz Ladwig, of the German Research Centre for Environmental Health and the Medical Faculty, Technical University of Munich, said: “Sleep should be a time for recreation, unwinding, and restoring energy levels. If you have stress at work, sleep helps you recover. Unfortunately poor sleep and job stress often go hand in hand, and when combined with hypertension the effect is even more toxic.” One-third of the working population has hypertension (high blood pressure). Previous research has shown that psychosocial factors have a stronger detrimental effect on individuals with pre-existing cardiovascular risks than on healthy people. This was the first study to examine the combined effects of work stress and impaired sleep on death from cardiovascular disease in hypertensive workers. The study included 1,959 hypertensive workers aged 25–65, without cardiovascular disease or diabetes. Compared to those with no work stress and good sleep, people with both risk factors had a three times greater likelihood of death from cardiovascular disease. People with work stress alone had a 1.6-fold higher risk while those with only poor sleep had a 1.8-times higher risk. During an average follow-up of nearly 18 years, the absolute risk of cardiovascular death in hypertensive staff increased in a stepwise fashion with each additional condition. Employees with both work stress and impaired sleep had an absolute risk of 7.13 per 1,000 person-years compared to 3.05 per 1,000-person years in those with no stress and healthy sleep. Absolute risks for only work stress or only poor sleep were 4.99 and 5.95 per 1,000 person-years, respectively. In the study, work stress was defined as jobs with high demand and low control – for example when an employer wants results but denies authority to make decisions. “If you have high demands but also high control, in other words you can make decisions, this may even be positive for health,” said Professor Ladwig. “But being entrapped in a pressured situation that you have no power to change is harmful.”   Impaired sleep was defined as difficulties falling asleep and/or maintaining sleep. “Maintaining sleep is the most common problem in people with stressful jobs,” said Professor Ladwig. “They wake up at 4 o’clock in the morning to go to the toilet and come back to bed ruminating about how to deal with work issues.” “These are insidious problems,” noted Professor Ladwig. “The risk is not having one tough day and no sleep. It is suffering from a stressful job and poor sleep over many years, which fade energy resources and may lead to an early grave.” "The findings are a red flag for doctors to ask patients with high blood pressure about sleep and job strain", said Professor Ladwig. “Each condition is a risk factor on its own and there is cross-talk among them, meaning each one increases risk of the other. Physical activity, eating healthily and relaxation strategies are important, as well as blood pressure lowering medication if appropriate.” Employers should provide stress management and sleep treatment in the workplace, he added, especially for staff with chronic conditions like hypertension. Components of group stress management sessions: Start with 5 to 10 minutes of relaxation. Education about healthy lifestyle. Help with smoking cessation, physical exercise, weight loss. Techniques to cope with stress and anxiety at home and work. How to monitor progress with stress management. Improving social relationships and social support. Sleep treatment can include: Stimulus control therapy: training to associate the bed/bedroom with sleep and set a consistent sleep-wake schedule. Relaxation training: progressive muscle relaxation, and reducing intrusive thoughts at bedtime that interfere with sleep. Sleep restriction therapy: curtailing the period in bed to the time spent asleep, thereby inducing mild sleep deprivation, then lengthening sleep time. Paradoxical intention therapy: remaining passively awake and avoiding any effort (i.e. intention) to fall asleep, thereby eliminating anxiety.

Want to quit smoking? Partner up

 Kicking the habit works best in pairs. That’s the main message of a study presented today at  EuroPrevent 2019, a scientific congress of the European Society of Cardiology (ESC).1

“Quitting smoking can be a lonely endeavour,” said study author Magda Lampridou, of Imperial College London, UK. People feel left out when they skip the smoke break at work or avoid social occasions. On top of that, there are nicotine withdrawal symptoms. Partners can distract each other from the cravings by going for a walk or to the cinema and encouraging replacement activities like eating healthy food or meditating when alone. Active support works best, rather than nagging.”

Half of coronary patients smoke and 90% of people at high risk of cardiovascular disease are smokers. ESC cardiovascular prevention guidelines advise against tobacco in any form, and people who stop smoking generally halve their risk of cardiovascular disease.2

“Smoking cessation interventions should incorporate couples where possible to achieve a smoke-free household,” said Ms Lampridou.

This study evaluated the supporting role married or cohabiting partners might have in smoking cessation. The study enrolled 222 current smokers who were at high risk of cardiovascular disease or had suffered a heart attack. Partners were also recruited: 99 were current smokers (45%), 40 ex-smokers, and 83 never-smokers.

Couples attended one of four preventive cardiology programmes: EUROACTION, EUROACTION plus, MyAction Galway, and MyAction Westminster. At the start they were asked about current smoking status, history of smoking, and previous quit attempts. Smoking status was validated with a carbon monoxide breath test. During the 16-week programme, couples were offered nicotine replacement therapy with patches and gum. In one programme, participants could choose the prescription drug varenicline instead.

At the end of the programme, 64% of patients and 75% of partners were abstinent – compared to none and 55% at the start, respectively. The odds of quitting smoking at 16 weeks were significantly higher (5.83-fold) in couples who tried to quit together compared to patients who attempted it alone.

“Previous research has shown that ex-smokers can also positively influence their spouse’s attempts to quit, but in this study the effect was not statistically significant,” said Ms Lampridou. “As for non-smoking partners, there is a strong risk that they will adopt their spouse’s habit.”

Ms Lampridou noted that research is needed to confirm the findings in smokers who are otherwise healthy.

Not all weight lifting produces the same benefit

• •  Prolong your life by increasing your muscle power. That’s the main message of a study presented today at EuroPrevent 2019, a scientific congress of the European Society of Cardiology.¹

“Rising from a chair in old age and kicking a ball depend more on muscle power than muscle strength, yet most weight bearing exercise focuses on the latter,” said study author Professor Claudio Gil Araújo, director of research and education, Exercise Medicine Clinic – CLINIMEX, Rio de Janeiro, Brazil. “Our study shows for the first time that people with more muscle power tend to live longer.”

Power depends on the ability to generate force and velocity, and to coordinate movement.² In other words, it is the measure of the work performed per unit time (force times distance); more power is produced when the same amount of work is completed in a shorter period or when more work is performed during the same period.³ Climbing stairs requires power – the faster you climb, the more power you need. Holding or pushing a heavy object (for example a car with a dead battery) needs strength.

Professor Araújo said: “Power training is carried out by finding the best combination of speed and weight being lifted or moved. For strength training at the gym most people just think about the amount of weight being lifted and the number of repetitions without paying attention to the speed of execution. But for optimal power training results, you should go beyond typical strength training and add speed to your weight lifts.”
Muscle power gradually decreases after 40 years of age. “We now show that power is strongly related to all-cause mortality. But the good news is that you only need to be above the median for your sex to have the best survival, with no further benefit in becoming even more powerful,” said  Professor Araújo.

The study enrolled 3,878 non-athletes aged 41–85 years who underwent a maximal muscle power test using the upright row exercise between 2001 and 2016 (see photo). The average age of participants was 59 years, 5% were over 80, and 68% were men. The highest value achieved after two or three attempts with increasing loads was considered the maximal muscle power and expressed relative to body weight (i.e. power per kg of body weight). Values were divided into quartiles for survival analysis and analysed separately by sex.
During a median 6.5-year follow-up, 247 men (10%) and 75 women (6%) died. Median power values were 2.5 watts/kg for men and 1.4 watts/kg for women. Participants with a maximal muscle power above the median for their sex (i.e. in quartiles three and four) had the best survival. Those in quartiles two and one had, respectively, a 4–5 and 10–13 times higher risk of dying as compared to those above the median in maximal muscle power.
Professor Araújo noted that this is the first time the prognostic value of muscle power has been assessed. Previous research has focused on muscle strength, primarily using the handgrip exercise. The upright row exercise was chosen for the study because it is a common action in daily life for picking up groceries, grandchildren, and so on. The researchers are currently examining the link between muscle power and specific causes of death including cardiovascular disease and cancer. He added: “Doctors should consider measuring muscle power in their patients and advise more power training.”
How to train to increase your muscle power:

• Choose multiple exercises for the upper and lower body
• Choose a weight with the load to achieve the maximal power (not so easy to lift and not so heavy that you can barely lift it)
• Do one to three sets of six to eight repetitions moving the weight as fast as possible while you contract your muscles (slow or natural speed in returning to initial position)
• Rest for 20 seconds between each set to sufficiently replenish the energy stores in your muscles to start the new set
• Repeat the above for the other exercises (biceps curl, etc.).

How to progress:

• Start with six repetitions in each set and when the exercise becomes easy, try to increase to eight
• If it becomes easy again, increase the weight and go back to six repetitions
• If you unable to complete the repetitions with the proper technique, avoid “cheating” and go back to less repetitions or less weight. This is important to prevent injuries.

Studies give new insights on immunotherapy in elderly patients with advanced NSCLC

Two studies to be reported at ELCC 2019 (1,2) provide new insights on the efficacy and safety of immunotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC), where information has previously been lacking despite being the age group most commonly affected. Immunotherapy with drugs that target immune pathways to enhance the body’s ability to recognise and destroy tumour cells is emerging as an effective treatment option for patients with advanced NSCLC (3). Although around half of all people newly diagnosed with NSCLC are elderly (4) there is currently limited evidence on the efficacy and safety of immunotherapy in this age group because they have been under-represented in clinical trials. There have also been concerns that age-related decline in the immune system might affect the efficacy of immunotherapy in older patients. Real-life study suggests shorter overall survival with immunotherapy in elderly A retrospective study of patients with advanced NSCLC treated with immunotherapy in real-life clinical practice (1) suggested that elderly patients (>70 years) may have shorter overall survival than younger patients but demonstrated that toxicity was similar. Researchers retrospectively reviewed all patients with advanced NSCLC treated with immunotherapy agents at Hospital Universitario Ramon y Cajal in Madrid, Spain, between 2014 and 2018. Just over one in four (27 patients; 27.5%) of the 98 patients treated with immunotherapy agents over this four-year period were aged 70 years or older. PD-L1 status was known in 50% of patients. Overall survival in these elderly patients was significantly shorter than in patients younger than 70 years of age (median 5.5 months vs 13 months, hazard ratio [HR] 3.86, 95% confidence interval [CI] 2.073-7.214, p<0 .0001="" 1.181-3.744="" 2.1="" 3.6="" 95="" also="" ci="" elderly="" hr="" in="" months="" p="0.012).<o:p" patients="" progression-free="" shorter="" significantly="" survival="" than="" vs="" was="" younger="">

Considering toxicity, there were no statistically significant differences in immune-related adverse events between elderly and younger patients (p=0.535).

The study shows that immunotherapy was administered mainly as second-line treatment (61% of patients) or third-line or later (24.5%) across the entire group of 98 patients of all ages. Just over half (52%) were treated with nivolumab.

“Our results suggest that elderly patients could have worse survival outcomes with immunotherapy than younger patients, without differences in terms of toxicity,” said study authors Elena Corral de la Fuente and Arantzazu Barquin Garcia, from the Hospital Universitario Ramon y Cajal, Madrid, Spain. They acknowledged that the study was limited by being an observational retrospective analysis with a small sample size. They suggested, “Prospective randomised clinical trials and more real-world data are needed to answer remaining questions on the use of immunotherapy in elderly patients.”

Pooled analysis demonstrates improved overall survival with immunotherapy

A second study pooling data from three randomised trials (2) shows significantly improved overall survival in elderly patients with advanced NSCLC treated with the immunotherapy agent pembrolizumab compared to those given chemotherapy.

The study compared the efficacy and safety results for 264 elderly patients aged > 75 years in the three trials with results for 2292 participants younger than 75 years. All of the patients had PD-L1 tumour proportion scores (PD-L1 TPS) of 1% or higher and half of the elderly group in this analysis had scores of at least 50% (5).

Results show significantly improved overall survival in elderly patients with PD-L1 tumours scores >1% treated with pembrolizumab compared to those treated with chemotherapy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.56-1.02). The improvement in overall survival with pembrolizumab compared to chemotherapy was even greater in patients with PD-L1 tumour scores >50% (HR 0.41, 95% CI 0.23-0.73).

One-year overall survival rates with pembrolizumab in elderly patients were comparable to those in younger patients (53.7% vs 54.9% in PD-L1 TPS >1% and 61.7% vs 61.7% in PD-L1 TPS >50%).

Fewer elderly patients treated with pembrolizumab had treatment-related adverse events compared to those treated with chemotherapy (68% vs 94%). Grade 3-5 treatment-related adverse events in elderly patients were also less common with pembrolizumab compared to chemotherapy (24% vs 61%). Common treatment-related adverse events with pembrolizumab in elderly patients were fatigue (17.4%), decreased appetite (12.8%) and pruritus (12.8%).

Immune-mediated adverse events and infusion reactions were more frequent with pembrolizumab vs chemotherapy in the elderly group of patients (25% vs 7%) but showed no difference compared to younger patients treated with pembrolizumab (25%).

“In elderly patients with advanced NSCLC with PD-L1–positive tumours, pembrolizumab monotherapy improved overall survival over chemotherapy, together with a more favourable safety profile,” said lead author Kaname Nosaki, from the National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. He added, “Our data support the use of pembrolizumab monotherapy in elderly patients (≥75 years) with advanced PD-L1‒expressing NSCLC.”

Considering potential limitations, Nosaki noted that the elderly patients included in the pooled analysis met the inclusion criteria for each of the individual studies, which would have selected for a relatively fit elderly patient population.

Commenting on the studies, Marina Garassino, Chief of Thoracic Oncology at the Istituto Nazionale dei Tumori, Milan, Italy, said, “The pooled analysis of clinical trials showed no difference in the efficacy and safety of immunotherapy in the elderly compared to younger patients. But the real-world study is an alarm bell potentially suggesting lower efficacy with immunotherapy in elderly patients despite no difference in adverse events.” In terms of limitations, she noted that PL-1 expression was known in only 50% of patients included in the real-world study and that data were collected retrospectively. “Data collected in real-world studies are not controlled as precisely as in randomised trials,” she noted, but added that elderly patients are generally under-represented in clinical trials.

Looking to the future, Garassino concluded, “We need larger, prospective trials or larger real-world studies to gain a more detailed view on the efficacy and safety of immunotherapy in elderly patients with NSCLC.”

-END-

Notes to Editors
Please make sure to use the official name of the meeting in your reports: European Lung Cancer Congress (ELCC) 2019
Official Congress hashtag: #ELCC19

Disclaimer
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of these abstracts. It does not necessarily reflect the views or opinions of ESMO or IASLC who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.

References
1 Abstract 169P_PR ‘Benefit of immunotherapy (IT) in advanced non-small cell lung cancer (NSCLC) in elderly patients (EP)’ will be presented by Elena Corral de la Fuente during the Poster Display Session on Thursday, 11 April 2019, 12:30 (CEST) in Hall 1. Annals of Oncology, Volume 30, 20019 Supplement 2. doi:10.1093/annonc/mdz072
2 Abstract 103O_PR ‘Safety and efficacy of pembrolizumab (Pembro) monotherapy in elderly patients (Pts) with PD-L1-positive advanced NSCLC: Pooled analysis from KEYNOTE-010, -024 and -042’ will be presented by Kaname Nosaki during the ESMO-IASLC Best Abstracts Session on Thursday, 11 April 2019, 14:45 (CEST) in Room B. Annals of Oncology, Volume 30, 20019 Supplement 2. doi:10.1093/annonc/mdz07
The pembrolizumab study pooled results from three randomised, controlled trials:

• KEYNOTE-010 included patients with advanced NSCLC and PD-L1 tumour proportion score > 1%. Patients were randomised to pembrolizumab (2 or 10mg/kg once every three weeks) or docetaxel, as second- or later-line therapy.
• KEYNOTE-042 also included patients with advanced NSCLC and PD-L1 tumour proportion score > 1%. Patients were randomised to first-line pembrolizumab (200mg/kg once every three weeks) or platinum-based chemotherapy.
• KEYNOTE-024 included patients with advanced NSCLC and PD-L1 tumour proportion score > 50%. Patients were randomised to first-line pembrolizumab (200mg/kg once every three weeks) or platinum-based chemotherapy.

3 Planchard D, Popat S, Kerr K et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2018; 29 (supplement 4); iv192-iv237.
4 Pallis AG, Gridelli C, Wedding U et al. Management of elderly patients with NSCLC; updated expert’s opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Annals of Oncology 2014; 25: 1270-1283.
5 PD-L1 TPS measures the proportion of tumour cells expressing PD-L1 (programmed-death ligand 1), which is the main ligand for the key immune checkpoint inhibitory receptor PD-1. A PD-L1 score of >1% means that at least 1% of tumour cells express PD-L1, while a PD-L1 score of >50% indicates high PD-L1 expression, with at least 50% of tumour cells expressing PD-L1.

About the European Society for Medical Oncology (ESMO)
ESMO is the leading professional organisation for medical oncology. With more than 20,000 members representing oncology professionals from over 150 countries worldwide, ESMO is the society of reference for oncology education and information. ESMO is committed to offer the best care to people with cancer, through fostering integrated cancer care, supporting oncologists in their professional development, and advocating for sustainable cancer care worldwide.

About the International Association for the Study of Lung Cancer (IASLC)
The International Association for the Study of Lung Cancer (IASLC) is the only global organisation dedicated solely to the study of lung cancer and other thoracic malignancies. Founded in 1974, the association's membership includes more than 6,500 lung cancer specialists across all disciplines in over 100 countries, forming a global network working together to conquer lung and thoracic cancers worldwide. The association also publishes the Journal of Thoracic Oncology, the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis and treatment of all thoracic malignancies. Visit www.iaslc.org for more information and follow us on Twitter @IASLC.

103O_PR - Safety and efficacy of pembrolizumab (Pembro) monotherapy in elderly patients (Pts) with PD-L1–positive advanced NSCLC: Pooled analysis from KEYNOTE-010, -024, and -042 K. Nosaki1, Y. Hosomi2, H. Saka3, P. Baas4, G. de Castro Jr5, M. Reck6, Y-L. Wu7, J.R. Brahmer8, E. Felip9, T. Sawada10, K. Noguchi10, S.R. Han10, B. Piperdi11, D.A. Kush11, G. Lopes12 1National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan, 2Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan, 3National Hospital Organization Nagoya Medical Center, Nagoya, Japan, 4The Netherlands Cancer Institute and The Academic Medical Hospital Amsterdam, Amsterdam, Netherlands, 5Instituto do Câncer do Estado de São Paulo, Sao Paulo, Brazil, 6Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany, 7Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong, China, 8Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 9Vall d'Hebron University Hospital, Barcelona, Spain, 10MSD K.K., Tokyo, Japan, 11Merck & Co., Inc., Kenilworth, NJ, USA, 12Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA Background: Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced/metastatic. We present a pooled analysis of efficacy and safety in elderly pts (aged ≥75 y) enrolled in 3 randomized controlled trials of pembro monotherapy vs standard chemotherapy (chemo) for PD-L1–positive advanced NSCLC. Methods: Pts were aged ≥18 y with advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥1% (KEYNOTE-010, -042) or TPS ≥50% (KEYNOTE-024). In KEYNOTE-010, pts were randomized to pembro 2 or 10 mg/kg Q3W or docetaxel, as second- or later-line therapy. In KEYNOTE-024 and -042, pts were randomized to first-line pembro 200 mg Q3W or platinum-based chemo. OS was estimated by the Kaplan-Meier method. Results: The 3 trials included 264 pts aged ≥75 (range, 75–90) y with TPS ≥1%; 132 pts had TPS ≥50%. Independent of line of treatment, HRs (95% CI) for OS favored pembro vs chemo: 0.76 (0.56–1.02) in pts with TPS ≥1% and 0.40 (0.25–0.64) in pts with TPS ≥50%. Pembro also improved OS vs chemo in the pooled analysis of pts with TPS ≥50% who received first-line therapy (KEYNOTE-024 and -042): HR, 0.41 (95% CI, 0.23–0.73). Overall, fewer treatment-related AEs across various categories were observed with pembro vs chemo, in particular, grade 3–5 treatment-related AEs in pts aged ≥75 y (Table). Immune-mediated AEs and infusion reactions were more frequent with pembro vs chemo, with similar frequency in pts receiving pembro aged ≥75 y and <75 -024="" -042.="" able="" age="" and="" by="" from="" group="" in="" keynote-010="" o:p="" of="" pd-l1="" pooled="" pts="" results="" safety="" summary="" table.="" tps="" with="" y="">

	Pembro		Chemo
AEs, n (%)	≥75 y n = 149	<75 span="" y=""> n = 1323	≥75 y n = 105	<75 span="" y=""> n = 969
Any treatment-related AE	102 (68)	862 (65)	99 (94)	840 (87)
Grade 3–5 treatment-related AE	36 (24)	224 (17)	64 (61)	379 (39)
Serious treatment-related AE	24 (16)	170 (13)	28 (27)	136 (14)
Treatment-related AEs leading to discontinuation	16 (11)	90 (7)	16 (15)	93 (10)
Treatment-related AEs leading to death	2 (1)	17 (1)	2 (2)	20 (2)
Immune-mediated AEs and infusion reactions	37 (25)	331 (25)	7 (7)	57 (6)

Conclusions: In this pooled analysis of pts aged ≥75 y with PD-L1–positive advanced NSCLC, pembro monotherapy improved OS vs chemo, both in pts with PD-L1 TPS ≥1% and PD-L1 TPS ≥50%. The safety profile of pembro was similar in pts aged ≥75 y and <75 3="" aes="" chemo.="" grade="" lower="" o:p="" of="" rates="" treatment-related="" vs="" with="" y="">

Clinical trial identification: NCT01905657 (KEYNOTE-010); NCT02142738 (KEYNOTE-024); NCT02220894 (KEYNOTE-042)

Editorial acknowledgement: Medical writing and editorial assistance was provided by Michael S. McNamara, MS, of C4 MedSolutions, LLC (Yardley, PA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Funding: This research was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure:

K. Nosaki: Honoraria: AstraZeneca, Chugai Pharmaceutical, Eli Lilly, MSD; Institutional research funding: MSD. Y. Hosomi: Personal fees: MSD, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb. H. Saka: Grants/research support: AstraZeneca, MSD, Ono Pharmaceutical; Honoraria: AstraZeneca, MSD, Ono Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Kyorin Pharmaceutical. P. Baas: Consulting role: Genentech/Roche, Merck, Bristol-Myers Squibb, Pfizer; Research support: Bristol-Myers Squibb, Roche, Merck. G. de Castro Jr: Consulting/advisory role: AstraZeneca, MSD, BMS, Roche, Novartis, Boehringer Ingelheim; Speakers’ bureau: MSD, BMS, Novartis, AstraZeneca; Travel/accommodation expenses: MSD, BMS, Roche, Bayer, Novartis, Boehringer Ingelheim, AstraZeneca. M. Reck: Personal fees: Amgen, Hoffmann-La Roche, Lilly, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, MSD, Merck, Novartis, Pfizer, AbbVie. Y-L. Wu: Honoraria: AstraZeneca, Eli Lilly, Roche, Pierre Fabre, Pfizer, Sanofi; Consulting/advisory role: AstraZeneca, Roche, Merck, Boehringer Ingelheim; Research funding to institution: Boehringer Ingelheim, Roche. J.R. Brahmer: Grant, personal fees, Advisory boards, consulting: Merck; Uncompensated advisor and consultant: Bristol-Myers Squibb; Grants: Bristol-Myers Squibb, MedImmune/AstraZeneca; Personal fees: Amgen, Celgene, Lilly. E. Felip: Consulting, advisory role, speaker’s bureau: AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; Research funding: Fundación Merck Salud; Grant for Oncology Innovation EMD Serono. T. Sawada, K. Noguchi, S.R. Han: Employee: MSD K.K., Tokyo, Japan. B. Piperdi, D.A. Kush: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. G. Lopes: Research funding to institution: Merck & Co., Inc., EMD Serono, AstraZeneca.

169P_PR - Benefit of immunotherapy (IT) in advanced non-small cell lung cancer (NSCLC) in elderly patients (EP)

E. Corral de la Fuente¹, A. Barquín García², C. Saavedra Serrano³, M.E. Olmedo García³, R. Martin Huertas², J.J. Serrano Domingo², V. Albarrán Artahona², A. Gómez Rueda³

¹Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain, ²Hospital Universitario Ramon y Cajal, Madrid, Spain, ³Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain

Background: Despite EP (aged ≥70 years) represent the majority of patients with advanced NSCLC, the efficacy and toxicity rates of IT remain poorly described, as they are under-represented in clinical trials. Furthermore, the age-related decline in the immune system might affect efficacy of IT.

Methods: We retrospectively reviewed advanced NSCLC patients treated with IT (antiPD-1, anti-PD-L1) monotherapy as first, second and subsequent-line settings, between 2014 and 2018 in our hospital. Patient and tumor features, irAEs, concomitant and subsequent treatments were collected. Stata 14.1 was used for the analysis.

Results: 98 patients were included. Mean age was 62 years (41-85). 73.5% were men. 73.5% had >30 smoked pack-years (py), 64.3% were adenocarcinoma (ADC), of which 41% were KRAS mutated; and 25.5% were squamous (SCC). PDL1 was known in a 50% of patients (11% <1 1-49="" 13="" 25="">50%). IT was administered mainly as a second line (61%) and third or later (24.5%). Most employed drug was nivolumab (52%) (Table1). Response Rate (RR) was 32.7% (partial response 28%, complete response 5%). Disease control rate (DCR) was 55%. Overall Survival (OS) was significantly lower in EP compared to patients aged <70 -="" 0.244="" 0.45="" 0.840="" 1.181="" 13="" 2.073-="" 2.1="" 3.6m="" 3.744="" 3.86="" 30.6="" 5.5m="" 7.214="" and="" associated="" better="" between="" development="" differences="" ep="" for="" hr="" ic="" impact="" in="" iraes="" m="" months="" no="" o:p="" of="" on="" os.="" p="0.012)" patients="" pfs="" progression-free="" regarding="" reported.="" significant="" significantly="" statistically="" survival="" terms="" than="" the="" there="" toxicity="" vs="" was="" were="" with="" without="" worse="" years="" younger="">

Table 1
Feature	N (%)
Sex Male Female	72 (73.5) 26 (26.5)
Age <70 o:p="">

71 (72.5) 27 (27.5)

Tobacco ≥30 py <30 never="" o:p="" py="" unknown="">

72 (73.5) 17 (17.4) 2 (2) 7 (7)

Histology SCC ADC Unspecified

25 (25.5) 63 (64.29) 10 (10)

PDL1 <1 1-49="" o:p="" unknown="">

11 (11.2) 13 (13.3) 25 (25.5) 49 (50)

Conclusions: Our results suggest that EP could have worse survival outcomes than younger patients, without differences in terms of toxicity, but prospective trials are needed to confirm this hypothesis.

Legal entity responsible for the study: Elena Corral de la Fuente
Funding: Has not received any funding
Disclosure: All authors have declared no conflicts of interest.