- Email: [email protected]
Assessing the link between air pollution and heart failure
Comment
monitor increased coverage of essential interventions, the RMNCH community will hopefully prove Walker and colleagues too conservative in their predictions.
5
6
*J Frederik Frøen, Marleen Temmerman Department of International Public Health, Norwegian Institute of Public Health, N-0403 Oslo, Norway (JFF); and Department of Reproductive Health and Research, WHO, Geneva, Switzerland (MT) [email protected] We declare that we have no conflicts of interest. The views expressed here are those of the authors themselves and they do not necessarily represent the views of the Norwegian Institute of Public Health or WHO. 1
2 3
4
Campbell O, Graham WJ, on behalf of The Lancet Maternal Survival Series steering group. Strategies for reducing maternal mortality: getting on with what works. Lancet 2006; 368: 1284–99. Venis S. Child survival. Lancet 2003; 361: 2172. Bhutta ZA, Yakoob MY, Lawn JE, et al, for The Lancet’s Stillbirths Series steering committee. Stillbirths: what difference can we make and at what cost? Lancet 2011; 377: 1523–38. Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L, for the Lancet Neonatal Survival Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet 2005; 365: 977–88.
7
8
9 10
11 12
The Partnership for Maternal, Newborn, and Child Health. Essential interventions, commodities and guidelines for reproductive, maternal, newborn and child health. 2011. http://www.who.int/pmnch/knowledge/ publications/201112_essential_interventions/en/index.html (accessed Sept 6, 2013). Winfrey W, McKinnon R, Stover J. Methods used in the Lives Saved Tool (LiST). BMC Public Health 2011; 11 (suppl 3): S32. Requejo J, Bryce J, Victora C, et al. Accountability for maternal, newborn and child survival: the 2013 update. 2013. http://www. countdown2015mnch.org/documents/2013Report/Countdown_ 2013-Update_withprofiles.pdf (accessed Sept 6, 2013). Walker N, Yenokyan G, Friberg IK, Bryce J. Patterns in coverage of maternal, newborn, and child health interventions: projections of neonatal and under-5 mortality to 2035. Lancet 2013; 382: 1029–38. UNICEF. Committing to child survival: a promise renewed. http://www. apromiserenewed.org/A_Promise_Renewed.html (accessed Sept 6, 2013). WHO, UNICEF. Ending preventable child deaths from pneumonia and diarrhoea by 2025: the integrated global action plan for pneumonia and diarrhoea (GAPPD). 2013. http://www.who.int/iris/bitstream/10665/ 79200/1/9789241505239_eng.pdf (accessed Sept 6, 2013). Family Planning 2020. London summit. 2012. http://www. familyplanning2020.org/summit.php (accessed Sept 6, 2013). Norwegian Institute of Public Health. The harmonized Reproductive Health Registry (hRHR) Initiative. http://www.fhi.no/hRHR (accessed Sept 6, 2013).
Assessing the link between air pollution and heart failure Published Online July 10, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61167-8 See Editorial page 1000 See Articles page 1039
1008
Ambient air pollution is a well-recognised risk factor for cardiovascular health,1 and it has been shown to be an important trigger of acute myocardial infarction.2 In The Lancet, Anoop Shah and colleagues3 provide a new systematic review of the effects of air pollution on heart failure, a common disorder associated with high morbidity and mortality, especially in elderly people.4,5 Physicians and professionals in public health should be aware that the air pollution experienced in most urban and industrial areas can aggravate cardiovascular health and lead to hospitalisation and death. Shah and colleagues3 estimate that reducing average daily concentrations of particulate matter by 3·9 μg/m³ would prevent around 8000 hospitalisations for heart failure every year in the USA. Heart failure is a complex syndrome.4 It represents the endstage of many cardiac diseases, especially coronary diseases and hypertension. Whatever the initial injury, a progressive development of structural changes and dysfunction in the heart is sustained by complex haemodynamic, neurohumoral, inflammatory, and metabolic mechanisms. Myocytes, extracellular matrix, and coronary vasculature are the key protagonists of the pathological remodelling process that leads to increased ventricular mass and impaired heart muscle.5 Several inflammatory
markers, including cytokines, nitric oxide, chemokines, cyclo-oxygenase, and endothelins, are important in the pathogenesis of heart failure.6 Clinical evidence supports the existence of two distinct phenotypes: systolic heart failure, characterised by abnormalities in left ventricular systolic function—usually associated with progressive chamber dilation and eccentric remodelling—and diastolic heart failure, characterised by a normal or near-normal systolic function and evidence of diastolic dysfunction with concentric remodelling or hypertrophy.4 The two syndromes have differences in the underlying haemodynamic processes, pathophysiology, left ventricular morphology, remodelling process, and epidemiology,7 and their links with air pollution are also likely to be different. As Shah and colleagues3 report, the overall evidence shows a positive association between short-term increases in fine particles and the risk of hospitalisation and death for congestive heart failure. The effect is more evident in patients with pre-existing chronic heart congestion, hypertension, and arrhythmia.8 Recent investigations suggest that air pollution not only exacerbates existing heart conditions but also might have an important role in the development of the disease. An English national cohort study www.thelancet.com Vol 382 September 21, 2013
Comment
found that long-term exposure to particulate matter and nitrogen dioxide was associated with increased incidence of heart failure,9 thus confirming findings that living in proximity to major roadways is linked with cardiac dysfunction10—an effect that had been clearly shown in an animal model.11 Epidemiological findings are somewhat difficult to interpret without a mechanistic explanation. Shah and colleagues3 provide explanations for the shortterm cardiovascular effects of air pollution, as already suggested by the 2010 statement of the American Heart Association.1 The mechanisms include increased systemic blood pressure, pulmonary vasoconstriction, and arrhythmias. A clear vulnerability factor of hypertrophic heart failure to air pollution could be preexisting supraventricular tachycardias (particularly atrial fibrillation), which pose increased risk of ventricular arrhythmias and sudden cardiac death.4 A complex mixture of mechanisms can be proposed also for the long-term effects: systemic oxidative stress and inflammation, imbalance of the systemic autonomic nervous system, and translocation of particulate matter (or particle constituents) into the systemic circulation.1 A cascade of biological responses—including the release of proinflammatory mediators, vasoactive molecules, and neural-mediated reactive oxygen species—can be responsible for endothelial dysfunction, atherosclerosis progression with increased risk of platelet aggregation, vasoconstriction, blood pressure elevation, and arrhythmia (figure). Air pollution can accelerate the development of heart failure by enhancing the systemic inflammatory and oxidative stress mechanisms. The heart is particularly vulnerable to coronary atherosclerosis because of vascular compression reducing coronary flow and perfusion, thus enhancing the risk of subendocardial ischaemia.4 The effect of air pollution can also be mediated by increased activity of the renin-angiotensin-aldosterone system and autonomic nervous system with deleterious consequences on the vascular musculature, coronary endothelium, myocytes, and interstitial matrix that contribute to pathological remodelling and progressive cardiac dysfunction. Moreover, air pollution has been shown to promote ventricular repolarisation and conduction abnormalities in people without cardiovascular diseases.12 Shah and colleagues3 provide us with important information on the burden of air pollution on public www.thelancet.com Vol 382 September 21, 2013
Air pollution
•Systemic oxidative stress and inflammation •Autonomic nervous system imbalance •Vascular dysfunction due to particle translocation
Atherosclerosis
Thrombosis
Elevated blood pressure
Heart injury
Remodelling
Triggers Hypertension, ischaemia, arrhythmia, respiratory infection, exacerbation of chronic lung disease
Chronic heart failure
Decompensated heart failure
Figure: Possible mechanisms linking air pollution and heart failure
health. This report is also timely, since 2013 has been declared the Year of Air by the European Union (EU). The current EU limit for fine particulate matter is 25 μg/m³ (annual average, which is higher than the 10 μg/m³ set by WHO); however, the adverse health effects of air pollution are present even at concentrations well below this limit. The European Respiratory Society’s Ten Principles for Clean Air state that “citizens are entitled to clean air, just like clean water and safe food”.13 In light of Shah and colleagues’ report, these principles should be pursued by all necessary means, especially within the context of EU legislation. *Francesco Forastiere, Nera Agabiti Department of Epidemiology, Lazio Regional Health Service, Via Santa Costanza 53, Rome 00198, Italy [email protected] We declare that we have no conflicts of interest. 1
2
3
Brook RD, Rajagopalan S, Pope CA 3rd, et al, for the American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the American Heart Association. Circulation 2010; 121: 2331–78. Nawrot TS, Perez L, Künzli N, Munters E, Nemery B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 2011; 377: 732–40. Shah ASV, Langrish JP, Nair H, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. Lancet 2013; published online July 10. http://dx.doi.org/10.1016/S01406736(13)60898-3.
1009
Comment
4
5 6
7
8
Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119: e391–e479. Drazner MH. The progression of hypertensive heart disease. Circulation 2011; 123: 327–34. Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P. Inflammatory cytokines in heart failure: mediators and markers. Cardiology 2012; 122: 23–35. Mureddu GF, Agabiti N, Rizzello V, et al, for the PREDICTOR Study Group. Prevalence of preclinical and clinical heart failure in the elderly. A population-based study in Central Italy. Eur J Heart Fail 2012; 14: 718–29. Colais P, Faustini A, Stafoggia M, et al, for the EPIAIR Collaborative Group. Particulate air pollution and hospital admissions for cardiac diseases in potentially sensitive subgroups. Epidemiology 2012; 23: 473–81.
9
10
11
12
13
Atkinson RW, Carey IM, Kent AJ, van Staa TP, Anderson HR, Cook DG. Long-term exposure to outdoor air pollution and incidence of cardiovascular diseases. Epidemiology 2013; 24: 44–53. Van Hee VC, Szpiro AA, Prineas R, et al. Association of long-term air pollution with ventricular conduction and repolarization abnormalities. Epidemiology 2011; 22: 773–80. Wold LE, Ying Z, Hutchinson KR, et al. Cardiovascular remodeling in response to long-term exposure to fine particulate matter air pollution. Circ Heart Fail 2012; 5: 452–61. Van Hee VC, Szpiro AA, Prineas R, et al. Association of long-term air pollution with ventricular conduction and repolarization abnormalities. Epidemiology 2011; 22: 773–80. Brunekreef B, Annesi-Maesano I, Ayres JG, et al. Ten principles for clean air. Eur Respir J 2012; 39: 525–28.
Dr Tim Evans/Science Photo Library
Duration of adjuvant trastuzumab: shorter beats longer
Trastuzumab bound to HER2 Published Online July 18, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61448-8 See Articles page 1021
1010
Trastuzumab is a monoclonal antibody that binds to the HER2 tyrosine kinase. When given with chemotherapy, trastuzumab extends survival of breast cancer patients with HER2-positive cancer compared with chemotherapy alone.1–3 The recommended duration of trastuzumab treatment is 12 months in the adjuvant setting,4 but little evidence exists to support this time period. 12 months of treatment became the accepted standard because it was the only duration assessed in the large trials that established safety and efficacy of trastuzumab as an adjuvant treatment for HER2positive breast cancer.1,2,5 In The Lancet, Aron Goldhirsch and colleagues6 report long-awaited results from the HERceptin Adjuvant (HERA) trial. 5102 patients with HER2-positive early breast cancer were randomly assigned after surgery and completion of chemotherapy to observation, adjuvant trastuzumab for 1 year, or adjuvant trastuzumab for 2 years. The patients were followed up for a median of 8 years after study entry. The results confirm the clinical benefit of chemotherapy followed by trastuzumab compared with chemotherapy alone, but the comparison between the two durations of adjuvant trastuzumab is of particular interest. During the first few years of followup, the 2-year treatment group had slightly superior disease-free survival compared with the 1 year group (89·1% vs 86·7% at 3 years after randomisation), but this difference waned with further follow-up. At the time of the study analysis, an identical number (367) of diseasefree survival events had occurred in the two trastuzumab groups (HR 0·99, 95% CI 0·85–1·14), and similar numbers
of patients had died (196 in the 2-year group and 186 in the 1-year group). No difference in either disease-free or overall survival was recorded between the groups that received trastuzumab. Most patients tolerated trastuzumab well, but 2-year treatment was associated with greater toxicity than was 1-year treatment. Cardiac adverse events were recorded more frequently in the 2-year group (136 patients, 8·2%) than in the 1-year group (83 patients, 4·9%). Only 17 (1·0%) patients had a cardiac adverse event recorded in the observation group. Overall, 1 year of adjuvant trastuzumab had similar efficacy to 2 years of adjuvant trastuzumab, but was better tolerated. Treatment costs were not assessed, but the economic winner is evident. The results of the HERA trial are in line with the biology and clinical behaviour of HER2-positive breast cancer. HER2-positive cancers are frequently aggressive tumours that usually recur early, within a few years after detection. These characteristics contrast with oestrogen receptor-positive, HER2-negative cancers that might have a protracted clinical course with recurrence sometimes detected only after the first decade of follow-up.7 Although patients with oestrogen receptor-positive cancer benefit from long, 5–10-year adjuvant treatments with tamoxifen or aromatase inhibitors,8,9 the HERA results lend support to a hypothesis that patients with HER2 amplification do not benefit from long treatment durations with HER2 inhibitors, but might be managed best with effective regimens of short duration. In five randomised trials, investigators are comparing 12 months of adjuvant trastuzumab with shorter www.thelancet.com Vol 382 September 21, 2013
monitor increased coverage of essential interventions, the RMNCH community will hopefully prove Walker and colleagues too conservative in their predictions.
5
6
*J Frederik Frøen, Marleen Temmerman Department of International Public Health, Norwegian Institute of Public Health, N-0403 Oslo, Norway (JFF); and Department of Reproductive Health and Research, WHO, Geneva, Switzerland (MT) [email protected] We declare that we have no conflicts of interest. The views expressed here are those of the authors themselves and they do not necessarily represent the views of the Norwegian Institute of Public Health or WHO. 1
2 3
4
Campbell O, Graham WJ, on behalf of The Lancet Maternal Survival Series steering group. Strategies for reducing maternal mortality: getting on with what works. Lancet 2006; 368: 1284–99. Venis S. Child survival. Lancet 2003; 361: 2172. Bhutta ZA, Yakoob MY, Lawn JE, et al, for The Lancet’s Stillbirths Series steering committee. Stillbirths: what difference can we make and at what cost? Lancet 2011; 377: 1523–38. Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L, for the Lancet Neonatal Survival Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet 2005; 365: 977–88.
7
8
9 10
11 12
The Partnership for Maternal, Newborn, and Child Health. Essential interventions, commodities and guidelines for reproductive, maternal, newborn and child health. 2011. http://www.who.int/pmnch/knowledge/ publications/201112_essential_interventions/en/index.html (accessed Sept 6, 2013). Winfrey W, McKinnon R, Stover J. Methods used in the Lives Saved Tool (LiST). BMC Public Health 2011; 11 (suppl 3): S32. Requejo J, Bryce J, Victora C, et al. Accountability for maternal, newborn and child survival: the 2013 update. 2013. http://www. countdown2015mnch.org/documents/2013Report/Countdown_ 2013-Update_withprofiles.pdf (accessed Sept 6, 2013). Walker N, Yenokyan G, Friberg IK, Bryce J. Patterns in coverage of maternal, newborn, and child health interventions: projections of neonatal and under-5 mortality to 2035. Lancet 2013; 382: 1029–38. UNICEF. Committing to child survival: a promise renewed. http://www. apromiserenewed.org/A_Promise_Renewed.html (accessed Sept 6, 2013). WHO, UNICEF. Ending preventable child deaths from pneumonia and diarrhoea by 2025: the integrated global action plan for pneumonia and diarrhoea (GAPPD). 2013. http://www.who.int/iris/bitstream/10665/ 79200/1/9789241505239_eng.pdf (accessed Sept 6, 2013). Family Planning 2020. London summit. 2012. http://www. familyplanning2020.org/summit.php (accessed Sept 6, 2013). Norwegian Institute of Public Health. The harmonized Reproductive Health Registry (hRHR) Initiative. http://www.fhi.no/hRHR (accessed Sept 6, 2013).
Assessing the link between air pollution and heart failure Published Online July 10, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61167-8 See Editorial page 1000 See Articles page 1039
1008
Ambient air pollution is a well-recognised risk factor for cardiovascular health,1 and it has been shown to be an important trigger of acute myocardial infarction.2 In The Lancet, Anoop Shah and colleagues3 provide a new systematic review of the effects of air pollution on heart failure, a common disorder associated with high morbidity and mortality, especially in elderly people.4,5 Physicians and professionals in public health should be aware that the air pollution experienced in most urban and industrial areas can aggravate cardiovascular health and lead to hospitalisation and death. Shah and colleagues3 estimate that reducing average daily concentrations of particulate matter by 3·9 μg/m³ would prevent around 8000 hospitalisations for heart failure every year in the USA. Heart failure is a complex syndrome.4 It represents the endstage of many cardiac diseases, especially coronary diseases and hypertension. Whatever the initial injury, a progressive development of structural changes and dysfunction in the heart is sustained by complex haemodynamic, neurohumoral, inflammatory, and metabolic mechanisms. Myocytes, extracellular matrix, and coronary vasculature are the key protagonists of the pathological remodelling process that leads to increased ventricular mass and impaired heart muscle.5 Several inflammatory
markers, including cytokines, nitric oxide, chemokines, cyclo-oxygenase, and endothelins, are important in the pathogenesis of heart failure.6 Clinical evidence supports the existence of two distinct phenotypes: systolic heart failure, characterised by abnormalities in left ventricular systolic function—usually associated with progressive chamber dilation and eccentric remodelling—and diastolic heart failure, characterised by a normal or near-normal systolic function and evidence of diastolic dysfunction with concentric remodelling or hypertrophy.4 The two syndromes have differences in the underlying haemodynamic processes, pathophysiology, left ventricular morphology, remodelling process, and epidemiology,7 and their links with air pollution are also likely to be different. As Shah and colleagues3 report, the overall evidence shows a positive association between short-term increases in fine particles and the risk of hospitalisation and death for congestive heart failure. The effect is more evident in patients with pre-existing chronic heart congestion, hypertension, and arrhythmia.8 Recent investigations suggest that air pollution not only exacerbates existing heart conditions but also might have an important role in the development of the disease. An English national cohort study www.thelancet.com Vol 382 September 21, 2013
Comment
found that long-term exposure to particulate matter and nitrogen dioxide was associated with increased incidence of heart failure,9 thus confirming findings that living in proximity to major roadways is linked with cardiac dysfunction10—an effect that had been clearly shown in an animal model.11 Epidemiological findings are somewhat difficult to interpret without a mechanistic explanation. Shah and colleagues3 provide explanations for the shortterm cardiovascular effects of air pollution, as already suggested by the 2010 statement of the American Heart Association.1 The mechanisms include increased systemic blood pressure, pulmonary vasoconstriction, and arrhythmias. A clear vulnerability factor of hypertrophic heart failure to air pollution could be preexisting supraventricular tachycardias (particularly atrial fibrillation), which pose increased risk of ventricular arrhythmias and sudden cardiac death.4 A complex mixture of mechanisms can be proposed also for the long-term effects: systemic oxidative stress and inflammation, imbalance of the systemic autonomic nervous system, and translocation of particulate matter (or particle constituents) into the systemic circulation.1 A cascade of biological responses—including the release of proinflammatory mediators, vasoactive molecules, and neural-mediated reactive oxygen species—can be responsible for endothelial dysfunction, atherosclerosis progression with increased risk of platelet aggregation, vasoconstriction, blood pressure elevation, and arrhythmia (figure). Air pollution can accelerate the development of heart failure by enhancing the systemic inflammatory and oxidative stress mechanisms. The heart is particularly vulnerable to coronary atherosclerosis because of vascular compression reducing coronary flow and perfusion, thus enhancing the risk of subendocardial ischaemia.4 The effect of air pollution can also be mediated by increased activity of the renin-angiotensin-aldosterone system and autonomic nervous system with deleterious consequences on the vascular musculature, coronary endothelium, myocytes, and interstitial matrix that contribute to pathological remodelling and progressive cardiac dysfunction. Moreover, air pollution has been shown to promote ventricular repolarisation and conduction abnormalities in people without cardiovascular diseases.12 Shah and colleagues3 provide us with important information on the burden of air pollution on public www.thelancet.com Vol 382 September 21, 2013
Air pollution
•Systemic oxidative stress and inflammation •Autonomic nervous system imbalance •Vascular dysfunction due to particle translocation
Atherosclerosis
Thrombosis
Elevated blood pressure
Heart injury
Remodelling
Triggers Hypertension, ischaemia, arrhythmia, respiratory infection, exacerbation of chronic lung disease
Chronic heart failure
Decompensated heart failure
Figure: Possible mechanisms linking air pollution and heart failure
health. This report is also timely, since 2013 has been declared the Year of Air by the European Union (EU). The current EU limit for fine particulate matter is 25 μg/m³ (annual average, which is higher than the 10 μg/m³ set by WHO); however, the adverse health effects of air pollution are present even at concentrations well below this limit. The European Respiratory Society’s Ten Principles for Clean Air state that “citizens are entitled to clean air, just like clean water and safe food”.13 In light of Shah and colleagues’ report, these principles should be pursued by all necessary means, especially within the context of EU legislation. *Francesco Forastiere, Nera Agabiti Department of Epidemiology, Lazio Regional Health Service, Via Santa Costanza 53, Rome 00198, Italy [email protected] We declare that we have no conflicts of interest. 1
2
3
Brook RD, Rajagopalan S, Pope CA 3rd, et al, for the American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the American Heart Association. Circulation 2010; 121: 2331–78. Nawrot TS, Perez L, Künzli N, Munters E, Nemery B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 2011; 377: 732–40. Shah ASV, Langrish JP, Nair H, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. Lancet 2013; published online July 10. http://dx.doi.org/10.1016/S01406736(13)60898-3.
1009
Comment
4
5 6
7
8
Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119: e391–e479. Drazner MH. The progression of hypertensive heart disease. Circulation 2011; 123: 327–34. Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P. Inflammatory cytokines in heart failure: mediators and markers. Cardiology 2012; 122: 23–35. Mureddu GF, Agabiti N, Rizzello V, et al, for the PREDICTOR Study Group. Prevalence of preclinical and clinical heart failure in the elderly. A population-based study in Central Italy. Eur J Heart Fail 2012; 14: 718–29. Colais P, Faustini A, Stafoggia M, et al, for the EPIAIR Collaborative Group. Particulate air pollution and hospital admissions for cardiac diseases in potentially sensitive subgroups. Epidemiology 2012; 23: 473–81.
9
10
11
12
13
Atkinson RW, Carey IM, Kent AJ, van Staa TP, Anderson HR, Cook DG. Long-term exposure to outdoor air pollution and incidence of cardiovascular diseases. Epidemiology 2013; 24: 44–53. Van Hee VC, Szpiro AA, Prineas R, et al. Association of long-term air pollution with ventricular conduction and repolarization abnormalities. Epidemiology 2011; 22: 773–80. Wold LE, Ying Z, Hutchinson KR, et al. Cardiovascular remodeling in response to long-term exposure to fine particulate matter air pollution. Circ Heart Fail 2012; 5: 452–61. Van Hee VC, Szpiro AA, Prineas R, et al. Association of long-term air pollution with ventricular conduction and repolarization abnormalities. Epidemiology 2011; 22: 773–80. Brunekreef B, Annesi-Maesano I, Ayres JG, et al. Ten principles for clean air. Eur Respir J 2012; 39: 525–28.
Dr Tim Evans/Science Photo Library
Duration of adjuvant trastuzumab: shorter beats longer
Trastuzumab bound to HER2 Published Online July 18, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)61448-8 See Articles page 1021
1010
Trastuzumab is a monoclonal antibody that binds to the HER2 tyrosine kinase. When given with chemotherapy, trastuzumab extends survival of breast cancer patients with HER2-positive cancer compared with chemotherapy alone.1–3 The recommended duration of trastuzumab treatment is 12 months in the adjuvant setting,4 but little evidence exists to support this time period. 12 months of treatment became the accepted standard because it was the only duration assessed in the large trials that established safety and efficacy of trastuzumab as an adjuvant treatment for HER2positive breast cancer.1,2,5 In The Lancet, Aron Goldhirsch and colleagues6 report long-awaited results from the HERceptin Adjuvant (HERA) trial. 5102 patients with HER2-positive early breast cancer were randomly assigned after surgery and completion of chemotherapy to observation, adjuvant trastuzumab for 1 year, or adjuvant trastuzumab for 2 years. The patients were followed up for a median of 8 years after study entry. The results confirm the clinical benefit of chemotherapy followed by trastuzumab compared with chemotherapy alone, but the comparison between the two durations of adjuvant trastuzumab is of particular interest. During the first few years of followup, the 2-year treatment group had slightly superior disease-free survival compared with the 1 year group (89·1% vs 86·7% at 3 years after randomisation), but this difference waned with further follow-up. At the time of the study analysis, an identical number (367) of diseasefree survival events had occurred in the two trastuzumab groups (HR 0·99, 95% CI 0·85–1·14), and similar numbers
of patients had died (196 in the 2-year group and 186 in the 1-year group). No difference in either disease-free or overall survival was recorded between the groups that received trastuzumab. Most patients tolerated trastuzumab well, but 2-year treatment was associated with greater toxicity than was 1-year treatment. Cardiac adverse events were recorded more frequently in the 2-year group (136 patients, 8·2%) than in the 1-year group (83 patients, 4·9%). Only 17 (1·0%) patients had a cardiac adverse event recorded in the observation group. Overall, 1 year of adjuvant trastuzumab had similar efficacy to 2 years of adjuvant trastuzumab, but was better tolerated. Treatment costs were not assessed, but the economic winner is evident. The results of the HERA trial are in line with the biology and clinical behaviour of HER2-positive breast cancer. HER2-positive cancers are frequently aggressive tumours that usually recur early, within a few years after detection. These characteristics contrast with oestrogen receptor-positive, HER2-negative cancers that might have a protracted clinical course with recurrence sometimes detected only after the first decade of follow-up.7 Although patients with oestrogen receptor-positive cancer benefit from long, 5–10-year adjuvant treatments with tamoxifen or aromatase inhibitors,8,9 the HERA results lend support to a hypothesis that patients with HER2 amplification do not benefit from long treatment durations with HER2 inhibitors, but might be managed best with effective regimens of short duration. In five randomised trials, investigators are comparing 12 months of adjuvant trastuzumab with shorter www.thelancet.com Vol 382 September 21, 2013