Downloaded from heart.bmj.com on May 8, 2014 - Published by group.bmj.com
Editorial
Influenza and ischaemic heart disease: research challenges and future directions Charlotte Warren-Gash Observational evidence is mounting that influenza and acute respiratory infections can precipitate major adverse cardiovascular events such as acute myocardial infarction (AMI) in vulnerable groups. Influenza viruses cause seasonal epidemics. Around 50% of infections are asymptomatic1; clinically apparent influenza infection is usually mild and self-limiting, with severe systemic illness affecting a small proportion of people. Deaths typically occur in people at the extremes of age or in those with underlying medical conditions.2 Cardiac pathology in acute influenza infection is thought to result either from direct effects of the virus on the myocardium, for example, influenza-associated myocarditis, or through exacerbation of underlying cardiovascular disease.3 Acute infections such as influenza have transient vasoconstrictive and systemic prothrombotic effects, which may contribute to coronary artery plaque disruption and thrombosis.4 Globally, ischaemic heart disease—predominantly due to AMI—is the leading cause of death and is projected to remain so in 2030.5 AMI remains a key challenge in the clinical management of ischaemic heart disease, especially as it can occur in individuals not previously identified to be at high cardiovascular risk. Influenza is associated with all-cause mortality, with the majority of deaths due to respiratory and, to a lesser extent, cardiovascular causes.6 The impact of influenza on AMI burden remains poorly understood. Key questions for patients, clinicians and public health policymakers include what is the evidence that AMI risk is associated with acute respiratory infections such as influenza? Who is most at risk? Which interventions are most effective and costeffective? This important area is the focus of a case–control study by MacIntyre et al.7 A major difficulty for studies investigating associations between influenza and acute cardiovascular events is how to Correspondence to Dr Charlotte Warren-Gash, Research Department of Infection & Population Health, Royal Free London NHS Foundation Trust, Rowland Hill Street, London NW3 2PF, UK; [email protected] Warren-Gash C. Heart December 2013 Vol 99 No 24
define recent influenza. While laboratory testing is usually preferable to symptom report, it is not necessarily straightforward. Tests such as PCR of respiratory specimens rely on isolating influenza virus and therefore require an infection to be current: viral shedding is maximal on day 2 of illness.8 Detecting a fourfold rise in antibody titre between two paired serum samples taken several weeks apart is ideal but logistically challenging. Therefore, recording an influenza antibody titre above a certain threshold on a single serum sample from an unvaccinated individual is sometimes used as a marker of recent influenza, but this may in fact represent historical infection. Lack of precision in measuring influenza, for example, by misclassifying historical infections as recent, reduces exposure specificity and may obscure a true association with outcomes such as acute cardiovascular events. Influenza vaccination as an exposure is less likely to be misclassified, especially when externally validated through medical records. A potentially serious issue, though, with observational studies of influenza vaccine is the problem of bias distorting apparent vaccine effects. In non-randomised studies where vaccine is recommended for whole populations, such as the over 65s, vaccinated people tend to be healthier than their unvaccinated counterparts. Some health differences might be easily measurable, such as smoking status, but many are not, for example, levels of physical activity and nutrition, and these differences might be strongly associated with AMI. There is also a risk that the frailest people may not receive influenza vaccination ( perhaps because potential benefits of vaccination are unlikely to be realised in those with life-limiting disease), which increases apparent vaccine effectiveness.9 It is, therefore, sometimes difficult to unpick the effects of healthy user bias and frailty selection bias when health outcomes are compared directly between vaccinated and unvaccinated individuals in observational studies. In the present study,7 data were collected from 275 inpatients with AMI and 284 controls attending ophthalmology or
orthopaedic outpatient clinics at a tertiary referral hospital in Sydney over three influenza seasons from 2008 to 2010. Investigators defined influenza as either a PCR-positive nasopharyngeal swab, a fourfold rise in antibody titre or a single antibody titre >64 at baseline in unvaccinated subjects. A second exposure was GP-reported influenza vaccination status. Recent influenza was found in almost 10% of participants. In unadjusted analysis, both recent influenza and acute respiratory tract infection were more common in AMI patients than controls, although associations were no longer significant after adjusting for potential confounders. Influenza vaccination was strongly protective against AMI in multiply-adjusted models, with vaccine effectiveness estimated at 45% for prevention of AMI (95% CI 15% to 65%). Vaccine effectiveness for AMI prevention was higher in patients aged 40–64 (45%) than those aged over 65 (33%). These results are congruent with those from three reported randomised controlled trials of influenza vaccination for acute cardiovascular events that tend to show a protective effect against adverse cardiovascular outcomes. These relatively small trials were carried out in populations with existing cardiovascular disease (200 AMI patients and 101 elective percutaneous coronary intervention patients,10 658 patients with angiographically confirmed coronary artery disease11 and 439 patients with acute coronary syndrome).12 Across the three studies, 697 participants were randomised to receive influenza vaccination and 701 to placebo. In an update to our published meta-analysis of the two earlier trials,13 a random effects model shows that the relative risk of cardiovascular death associated with influenza vaccination is 0.46 (95% CI 0.21 to 1.02) across all three studies. This represents a protective effect of 54% that just fails to reach statistical significance. The effect on AMI is also protective but similarly nonsignificant—relative risk 0.66 (95% CI 0.39 to 1.13). Although these results marginally fail to reach statistical significance, it would be hard to argue that there is genuine equipoise for conducting further trials in populations with existing cardiovascular disease. There are currently no published trials of influenza vaccination for AMI prevention in ‘healthy’ populations without recorded cardiovascular disease. Observational studies of the cardioprotective effect of influenza vaccine yield mixed results. In the present study,7 although the protective vaccine effect is consistent with other studies, it is hard to 1795
Downloaded from heart.bmj.com on May 8, 2014 - Published by group.bmj.com
Editorial be precise about effect size given the width of CIs. Authors suggest that the study may have been underpowered— despite substantial efforts with recruitment—perhaps partly due to the mild nature of the 2010 influenza season. Previous studies, including our own selfcontrolled case series analysis of UK primary care records (from the General Practice Research Database) linked to cardiac registry data (from the Myocardial Ischaemia National Audit Project), have found an increase in AMI risk after acute respiratory infection. We found an incidence ratio of 4.19 (95% CI 3.18 to 5.53) in days 1–3 after infection, with the effect size tapering over time.14 We also saw a significantly higher risk of AMI associated with infections occurring in time periods when influenza was circulating.14 A range of other observational studies tend to support the hypothesis that influenza and acute respiratory infections can trigger AMI with more limited evidence for an association with cardiovascular death.13 Some studies suggest that elderly people, particularly those aged over 80, are at greatest risk.14–16 The interaction between influenza and other vascular risk factors, and therefore the population most at risk from influenza-associated AMI, however, remains unknown. The risk of first AMI events was increased after acute general practitioner (GP) -attended respiratory infection in two self-controlled case series studies,14 17 which suggests that it is not only people with a previous AMI history who are at risk; tackling influenza may be important for primary as well as secondary prevention of ischaemic cardiac events. Despite limitations that affect most similar observational studies, the current study’s finding that influenza vaccination is associated with AMI protection adds to the growing body of evidence that influenza is an important trigger of acute cardiovascular events. International policy recommends targeting annual influenza vaccinations at nursing home residents, the elderly (typically those aged over 65),
1796
people with chronic medical conditions and other groups such as pregnant women and healthcare workers.2 Vaccine uptake rates in people aged under 65 years with chronic medical conditions such as ischaemic heart disease are historically low. Unusually perhaps, most AMI patients in the MacIntyre study were aged under 65, and authors suggest that extending the routine influenza vaccination programme to include people aged 50–64 should be considered. While it seems clear that reducing the burden of influenza would benefit cardiovascular health, the effectiveness and cost-effectiveness of a populationbased approach to vaccinating younger age groups need to be carefully weighed. Another option would be to explore a phased approach targeting influenza vaccine at people aged 50–64 identified to be at high cardiovascular risk (eg, >20% 10-year risk) rather than just focusing on those with existing ischaemic heart disease. Trials of interventions for primary prevention of influenza-associated AMI would help to provide evidence to support such a policy and define groups most likely to benefit.
3
4
5
6
7
8
9
10
11
Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
12
To cite Warren-Gash C. Heart 2013;99:1795–1796. Published Online First 22 October 2013
13
14
▸ http://dx.doi.org/10.1136/heartjnl-2013-304320
Heart 2013;99:1795–1796. doi:10.1136/heartjnl-2013-304748
15
16
REFERENCES 1
2
Lau LLH, Cowling BJ, Fang VJ, et al. Viral shedding and clinical illness in naturally acquired influenza virus infections. J Infect Dis 2010;201:1509–16. World Health Organization. Factsheet No. 211: Influenza (Seasonal). WHO website. 2009. http://
17
www.who.int/mediacentre/factsheets/fs211/en/index. html (accessed 19 Sep 2013). Mamas MA, Fraser D, Neyses L. Cardiovascular manifestations associated with influenza virus infection. Int J Cardiol 2008;130:304–9. Mittleman MA, Mostofsky E. Physical, psychological and chemical triggers of acute cardiovascular events: preventive strategies. Circulation 2011; 124:346–54. World Health Organization. Projections of mortality and causes of death, 2015 and 2030. WHO website. 2013. http://www.who.int/healthinfo/global_burden_ disease/projections/en/ (accessed 19 Sep 2013). Wu P, Goldstein E, Ho LM, et al. Excess mortality associated with influenza A and B virus in Hong Kong, 1998–2009. J Infect Dis 2012;206: 1862–71. MacIntyre CR, Heywood AE, Kovoor P, et al. Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study. Heart 2013;99:1843–8. Carrat F, Vergu E, Ferguson NM, et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol 2008;167:775–85. Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis 2007; 7:658–66. Gurfinkel EP, Leon de la Fuente R, Mendiz O, et al. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J 2004;25:25–31. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J 2008;29:1350–8. Phrommintikul A, Kuanprasert S, Wongcharoen W, et al. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur Heart J 2011;32:1730–5. Warren-Gash C, Smeeth L, Hayward AC. The role of influenza as a trigger for acute myocardial infarction or cardiovascular death: a systematic review. Lancet Infect Dis 2009;9:601–10. Warren-Gash C, Hayward AC, Hemingway H, et al. Influenza infection and risk of acute myocardial infarction in England & Wales: a CALIBER self-controlled case series study. J Infect Dis 2012;206:1652–9. Fleming DM, Cross KW, Pannell RS. Influenza and its relationship to circulatory disorders. Epidemiol Infect 2005;133:255–62. Foster ED, Cavanaugh JE, Haynes WG, et al. Acute myocardial infarctions, strokes abnd influenza: seasonal and pandemic effects. Epidemiol Infect 2013;141:735–44. Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351: 2611–18.
Warren-Gash C. Heart December 2013 Vol 99 No 24
Downloaded from heart.bmj.com on May 8, 2014 - Published by group.bmj.com
Influenza and ischaemic heart disease: research challenges and future directions Charlotte Warren-Gash Heart 2013 99: 1795-1796 originally published online October 22, 2013
doi: 10.1136/heartjnl-2013-304748
Updated information and services can be found at: http://heart.bmj.com/content/99/24/1795.full.html
These include:
References
This article cites 15 articles, 9 of which can be accessed free at: http://heart.bmj.com/content/99/24/1795.full.html#ref-list-1
Email alerting service
Topic Collections
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Drugs: cardiovascular system (7607 articles) Acute coronary syndromes (2409 articles) Epidemiology (3084 articles) Tobacco use (543 articles) Venous thromboembolism (420 articles)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Editorial
Influenza and ischaemic heart disease: research challenges and future directions Charlotte Warren-Gash Observational evidence is mounting that influenza and acute respiratory infections can precipitate major adverse cardiovascular events such as acute myocardial infarction (AMI) in vulnerable groups. Influenza viruses cause seasonal epidemics. Around 50% of infections are asymptomatic1; clinically apparent influenza infection is usually mild and self-limiting, with severe systemic illness affecting a small proportion of people. Deaths typically occur in people at the extremes of age or in those with underlying medical conditions.2 Cardiac pathology in acute influenza infection is thought to result either from direct effects of the virus on the myocardium, for example, influenza-associated myocarditis, or through exacerbation of underlying cardiovascular disease.3 Acute infections such as influenza have transient vasoconstrictive and systemic prothrombotic effects, which may contribute to coronary artery plaque disruption and thrombosis.4 Globally, ischaemic heart disease—predominantly due to AMI—is the leading cause of death and is projected to remain so in 2030.5 AMI remains a key challenge in the clinical management of ischaemic heart disease, especially as it can occur in individuals not previously identified to be at high cardiovascular risk. Influenza is associated with all-cause mortality, with the majority of deaths due to respiratory and, to a lesser extent, cardiovascular causes.6 The impact of influenza on AMI burden remains poorly understood. Key questions for patients, clinicians and public health policymakers include what is the evidence that AMI risk is associated with acute respiratory infections such as influenza? Who is most at risk? Which interventions are most effective and costeffective? This important area is the focus of a case–control study by MacIntyre et al.7 A major difficulty for studies investigating associations between influenza and acute cardiovascular events is how to Correspondence to Dr Charlotte Warren-Gash, Research Department of Infection & Population Health, Royal Free London NHS Foundation Trust, Rowland Hill Street, London NW3 2PF, UK; [email protected] Warren-Gash C. Heart December 2013 Vol 99 No 24
define recent influenza. While laboratory testing is usually preferable to symptom report, it is not necessarily straightforward. Tests such as PCR of respiratory specimens rely on isolating influenza virus and therefore require an infection to be current: viral shedding is maximal on day 2 of illness.8 Detecting a fourfold rise in antibody titre between two paired serum samples taken several weeks apart is ideal but logistically challenging. Therefore, recording an influenza antibody titre above a certain threshold on a single serum sample from an unvaccinated individual is sometimes used as a marker of recent influenza, but this may in fact represent historical infection. Lack of precision in measuring influenza, for example, by misclassifying historical infections as recent, reduces exposure specificity and may obscure a true association with outcomes such as acute cardiovascular events. Influenza vaccination as an exposure is less likely to be misclassified, especially when externally validated through medical records. A potentially serious issue, though, with observational studies of influenza vaccine is the problem of bias distorting apparent vaccine effects. In non-randomised studies where vaccine is recommended for whole populations, such as the over 65s, vaccinated people tend to be healthier than their unvaccinated counterparts. Some health differences might be easily measurable, such as smoking status, but many are not, for example, levels of physical activity and nutrition, and these differences might be strongly associated with AMI. There is also a risk that the frailest people may not receive influenza vaccination ( perhaps because potential benefits of vaccination are unlikely to be realised in those with life-limiting disease), which increases apparent vaccine effectiveness.9 It is, therefore, sometimes difficult to unpick the effects of healthy user bias and frailty selection bias when health outcomes are compared directly between vaccinated and unvaccinated individuals in observational studies. In the present study,7 data were collected from 275 inpatients with AMI and 284 controls attending ophthalmology or
orthopaedic outpatient clinics at a tertiary referral hospital in Sydney over three influenza seasons from 2008 to 2010. Investigators defined influenza as either a PCR-positive nasopharyngeal swab, a fourfold rise in antibody titre or a single antibody titre >64 at baseline in unvaccinated subjects. A second exposure was GP-reported influenza vaccination status. Recent influenza was found in almost 10% of participants. In unadjusted analysis, both recent influenza and acute respiratory tract infection were more common in AMI patients than controls, although associations were no longer significant after adjusting for potential confounders. Influenza vaccination was strongly protective against AMI in multiply-adjusted models, with vaccine effectiveness estimated at 45% for prevention of AMI (95% CI 15% to 65%). Vaccine effectiveness for AMI prevention was higher in patients aged 40–64 (45%) than those aged over 65 (33%). These results are congruent with those from three reported randomised controlled trials of influenza vaccination for acute cardiovascular events that tend to show a protective effect against adverse cardiovascular outcomes. These relatively small trials were carried out in populations with existing cardiovascular disease (200 AMI patients and 101 elective percutaneous coronary intervention patients,10 658 patients with angiographically confirmed coronary artery disease11 and 439 patients with acute coronary syndrome).12 Across the three studies, 697 participants were randomised to receive influenza vaccination and 701 to placebo. In an update to our published meta-analysis of the two earlier trials,13 a random effects model shows that the relative risk of cardiovascular death associated with influenza vaccination is 0.46 (95% CI 0.21 to 1.02) across all three studies. This represents a protective effect of 54% that just fails to reach statistical significance. The effect on AMI is also protective but similarly nonsignificant—relative risk 0.66 (95% CI 0.39 to 1.13). Although these results marginally fail to reach statistical significance, it would be hard to argue that there is genuine equipoise for conducting further trials in populations with existing cardiovascular disease. There are currently no published trials of influenza vaccination for AMI prevention in ‘healthy’ populations without recorded cardiovascular disease. Observational studies of the cardioprotective effect of influenza vaccine yield mixed results. In the present study,7 although the protective vaccine effect is consistent with other studies, it is hard to 1795
Downloaded from heart.bmj.com on May 8, 2014 - Published by group.bmj.com
Editorial be precise about effect size given the width of CIs. Authors suggest that the study may have been underpowered— despite substantial efforts with recruitment—perhaps partly due to the mild nature of the 2010 influenza season. Previous studies, including our own selfcontrolled case series analysis of UK primary care records (from the General Practice Research Database) linked to cardiac registry data (from the Myocardial Ischaemia National Audit Project), have found an increase in AMI risk after acute respiratory infection. We found an incidence ratio of 4.19 (95% CI 3.18 to 5.53) in days 1–3 after infection, with the effect size tapering over time.14 We also saw a significantly higher risk of AMI associated with infections occurring in time periods when influenza was circulating.14 A range of other observational studies tend to support the hypothesis that influenza and acute respiratory infections can trigger AMI with more limited evidence for an association with cardiovascular death.13 Some studies suggest that elderly people, particularly those aged over 80, are at greatest risk.14–16 The interaction between influenza and other vascular risk factors, and therefore the population most at risk from influenza-associated AMI, however, remains unknown. The risk of first AMI events was increased after acute general practitioner (GP) -attended respiratory infection in two self-controlled case series studies,14 17 which suggests that it is not only people with a previous AMI history who are at risk; tackling influenza may be important for primary as well as secondary prevention of ischaemic cardiac events. Despite limitations that affect most similar observational studies, the current study’s finding that influenza vaccination is associated with AMI protection adds to the growing body of evidence that influenza is an important trigger of acute cardiovascular events. International policy recommends targeting annual influenza vaccinations at nursing home residents, the elderly (typically those aged over 65),
1796
people with chronic medical conditions and other groups such as pregnant women and healthcare workers.2 Vaccine uptake rates in people aged under 65 years with chronic medical conditions such as ischaemic heart disease are historically low. Unusually perhaps, most AMI patients in the MacIntyre study were aged under 65, and authors suggest that extending the routine influenza vaccination programme to include people aged 50–64 should be considered. While it seems clear that reducing the burden of influenza would benefit cardiovascular health, the effectiveness and cost-effectiveness of a populationbased approach to vaccinating younger age groups need to be carefully weighed. Another option would be to explore a phased approach targeting influenza vaccine at people aged 50–64 identified to be at high cardiovascular risk (eg, >20% 10-year risk) rather than just focusing on those with existing ischaemic heart disease. Trials of interventions for primary prevention of influenza-associated AMI would help to provide evidence to support such a policy and define groups most likely to benefit.
3
4
5
6
7
8
9
10
11
Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
12
To cite Warren-Gash C. Heart 2013;99:1795–1796. Published Online First 22 October 2013
13
14
▸ http://dx.doi.org/10.1136/heartjnl-2013-304320
Heart 2013;99:1795–1796. doi:10.1136/heartjnl-2013-304748
15
16
REFERENCES 1
2
Lau LLH, Cowling BJ, Fang VJ, et al. Viral shedding and clinical illness in naturally acquired influenza virus infections. J Infect Dis 2010;201:1509–16. World Health Organization. Factsheet No. 211: Influenza (Seasonal). WHO website. 2009. http://
17
www.who.int/mediacentre/factsheets/fs211/en/index. html (accessed 19 Sep 2013). Mamas MA, Fraser D, Neyses L. Cardiovascular manifestations associated with influenza virus infection. Int J Cardiol 2008;130:304–9. Mittleman MA, Mostofsky E. Physical, psychological and chemical triggers of acute cardiovascular events: preventive strategies. Circulation 2011; 124:346–54. World Health Organization. Projections of mortality and causes of death, 2015 and 2030. WHO website. 2013. http://www.who.int/healthinfo/global_burden_ disease/projections/en/ (accessed 19 Sep 2013). Wu P, Goldstein E, Ho LM, et al. Excess mortality associated with influenza A and B virus in Hong Kong, 1998–2009. J Infect Dis 2012;206: 1862–71. MacIntyre CR, Heywood AE, Kovoor P, et al. Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study. Heart 2013;99:1843–8. Carrat F, Vergu E, Ferguson NM, et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol 2008;167:775–85. Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis 2007; 7:658–66. Gurfinkel EP, Leon de la Fuente R, Mendiz O, et al. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J 2004;25:25–31. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J 2008;29:1350–8. Phrommintikul A, Kuanprasert S, Wongcharoen W, et al. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur Heart J 2011;32:1730–5. Warren-Gash C, Smeeth L, Hayward AC. The role of influenza as a trigger for acute myocardial infarction or cardiovascular death: a systematic review. Lancet Infect Dis 2009;9:601–10. Warren-Gash C, Hayward AC, Hemingway H, et al. Influenza infection and risk of acute myocardial infarction in England & Wales: a CALIBER self-controlled case series study. J Infect Dis 2012;206:1652–9. Fleming DM, Cross KW, Pannell RS. Influenza and its relationship to circulatory disorders. Epidemiol Infect 2005;133:255–62. Foster ED, Cavanaugh JE, Haynes WG, et al. Acute myocardial infarctions, strokes abnd influenza: seasonal and pandemic effects. Epidemiol Infect 2013;141:735–44. Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351: 2611–18.
Warren-Gash C. Heart December 2013 Vol 99 No 24
Downloaded from heart.bmj.com on May 8, 2014 - Published by group.bmj.com
Influenza and ischaemic heart disease: research challenges and future directions Charlotte Warren-Gash Heart 2013 99: 1795-1796 originally published online October 22, 2013
doi: 10.1136/heartjnl-2013-304748
Updated information and services can be found at: http://heart.bmj.com/content/99/24/1795.full.html
These include:
References
This article cites 15 articles, 9 of which can be accessed free at: http://heart.bmj.com/content/99/24/1795.full.html#ref-list-1
Email alerting service
Topic Collections
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Drugs: cardiovascular system (7607 articles) Acute coronary syndromes (2409 articles) Epidemiology (3084 articles) Tobacco use (543 articles) Venous thromboembolism (420 articles)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
