RAC DIRECTOR’S LETTER

Building Bridges between Healthcare and Public Health From Effcacy Trials in Patients to Those Effective in Populations

Crear puentes entre la atención médica y la salud pública De los ensayos de eficacia en pacientes a los de efectividad en poblaciones

"Working together, clinical medicine and
public health may guarantee that persons
lead active and productive lives much
longer than it was ever thought possible.”

Thomas Frieden

INTRODUCTION

Despite the increase in obesity and physical inactivity, premature death and disability due to non-communicable diseases (NCD) substantially decreased both in the United States as in other high income countries during the period 1990-2010. However, in low income countries, in the same 20-year period, the increase in death and disability due to NCD was 300% higher than the decrease in the load of infectious diseases. Moreover, also in mid-low income countries, the growth of NCD overcame by 33% the reduction in communicable diseases during the same period. (2) Therefore, today NCD are the main cause of death and disability in low income and mid-low income countries, where they have killed almost 8 million persons below 60 years in 2013, at a living and working productive age. (3)

The recent improvement of life expectation in de-veloping countries cannot explain why so many people in these countries are acquiring NCD at a much younger age and with worse outcomes than in richer countries. Although obesity, ultraprocessed food con-sumption, physical inactivity and tobacco are fast in-creasing, their growth, except for tobacco, is far be-low than in most high-income countries. It can then be concluded that in emerging countries premature death and disability for NCD is growing associated to poverty, same as in the poor sectors of the richest countries.

The dramatic changes in urbanization, global companies and consumer markets are developing at a much faster rate in still poor countries than they did in developed countries in the past, associated to the inability of developing country governments to establish health systems and the necessary regula-tory mechanisms to avoid the exponential epidemics of NCD.

If these trends are preserved or accelerated, the toll of lives for NCD on the working-age population

will increase in these countries.

Therefore, it is now essential for us, the health professionals and workers, to build a bridge between medical assistance and public health measures, in or-der to change this devastating trend for our countries in the next decades.

THE DEVELOPMENT OF CONTROLLED RESEARCH IN PATIENTS

For over the past five years epidemiological science has had a predominant position in the development of preventive medicine for non-communicable chronic diseases, since Austin Bradford Hill and Richard Doll made a major contribution with the breakdown in the knowledge of the cancerous effect of tobacco in 1950.

They taught a posterior generation of epidemiologists to think quantitatively and introduce a new re-search methodology with the creation of new designs (controlled clinical trials, case-control designs and large population registries) and the growing influence of medical statistics, following pioneering studies by Karl Pearson, teacher of Bradford Hill, who founded the Department of Applied Statistics at London Uni-versity. (4)

At the beginning of the seventies, with the appointment of Doll as royal professor at Radclife Infirmary hospital, Richard Peto was incorporated. He already had the firm belief that the existing methodology for clinical trials was grossly inadequate to show une-quivocal results, because trials were very complicated, performed in few university centers and with a ridic-ulous number of patients. He thought that knowing the moderate effect of a decrease in mortality (20% to 30%) concerning prevalent chronic diseases as cancer and cardiovascular disease could have a great clinical impact saving thousands or hundreds of thousands of lives. To achieve this end it was necessary to perform large randomized clinical trials, sufficiently simple to include not hundreds but thousands of patients.

In 1975, Peto founded the Clinical Trial Service Unit in Oxford and in 1976 Salim Yusuf went from India to Oxford to work with Peter Sleight, professor of Cardiology, to investigate whether beta-blockers could decrease the complications of acute myocardial infarction. He consulted Richard Peto to perform a large dimension study, 10 to 20 times larger than what was commonly thought at the time. At the begin-ning of the eighties, the ISIS-1 (International Study of Infarct Survival) trial was developed. It was a great challenge carried out in 245 Coronary Care Units of different countries, including more than 16,000 pa-tients. The study finished with the incorporation of a 26-year old research doctor, Rory Collins who, despite the ISIS-1 results were negative, planned the ambitious and bold ISIS-2 trial, considered one of the most important steps in acute myocardial infarction (AMI) management. The idea of the project started with a meta-analysis of the Oxford team on all the small pre-viously negative studies of a drug that dissolved the clot, streptokinase, showing as a whole, 20% reduction in the number of deaths, and another meta-analysis of aspirin in stroke and heart attacks with the concomi-tant reduction of death. The trial decided in a joint meeting in Peter Sleight’s home, a fact that was essen-tial as he was a cardiologist trainer of cardiologists, to perform a study that some cardiologists considered was planned by Martians.

A total of 417 hospitals and 16 countries took part of the ISIS-2 randomized, stratified trial with streptokinase and aspirin, consisting of four treat-ment groups: streptokinase or aspirin alone, both drugs, or none, in patients with suspected AMI. In the meantime, Lancet publishes in 1986 the Italian ran-domized, open-label streptokinase and control study with 11,806 patients, from the Italian Group per lo Studio della Streptocinasi nell’ Infarto Miocardico (GISSI) showing a significant reduction of AMI mor-tality. (5) This facilitated the final ISIS-2 recruitment which after 3 years ended with the news that both streptokinase and aspirin moderately reduced mortal-ity saving hundreds of thousands of lives worldwide.

We have taken a major step, but we must now move to a generalization of research on the usual clin-ical practice and on population prevention measures.

A known clinical trial researcher in cardiology has broadened his perspective towards a global epi-demiological investigation. Salim Yusuf says: “In IN-TERHEART and subsequent studies, such as the Pro-spective Urban Rural Epidemiologic (PURE) study, we explored why people have risk factors, the causes of causes. This means looking for the social determinants of health and environmental factors and their influence on health behaviors, risk factors and diseases.” (6)

Looking for the causes of causes is also the turn imprinted in the investigations of Giani Tognoni from the GISSI studies and the Mario Negri Institute and Valentín Fuster from the Mount Sinai Hospital.

EFFECT OF SOCIAL HEALTH DETERMINANTS

In turn, the director of Lancet, Richard Horton, with a selected core of epidemiologists has recently emitted a declaration titled: “From public to planetary health: a manifest”.

This manifest to transform public health calls

upon a social movement to support the collective pub-lic health action at every level of society –personal, community, national, regional, global and planetary.

"Planetary health is an attitude towards life and a life philosophy. It focuses on persons, not on diseases, and equity, not the creation of unfair societies. We seek to minimize the health differences depending on wealth, education, gender and place.

The damages we continue to inflict on our plan-etary systems are a threat for our existence as spe-cies… We have created an unfair economic world sys-tem favoring a reduced elite of rich persons, over a vast number that have so little”. (7)

An urgent transformation of our values and prac-tices is required based on the acknowledgement of our interdependence and the interconnection of the risks we face.

". We need a new vision of cooperative and demo-cratic action at all the society levels and a new princi-ple of welfare in the planet for every person on Earth - a principle that states we must preserve, maintain and make resistant all the planetary systems and hu-mans upon which health depends, giving priority to everybody's welfare.

.The voice of public health and medicine as the independent consciousness of the planet's health must have an essential role to achieve this vision. To-gether with the power of communities, we can face the ingrained interests and forces which endanger our future. A powerful social movement based on the collective action at all the society levels will provide planetary health and, at the same time, will support a sustainable human development."(7)

It is outrageous and disgraceful that 60% of deaths and 35% of births in the world are not recorded in registries, (8) and that in the remaining 40% regis-tered deaths, one out of four is ascribed to vague or illdefined causes. (9)

The WHO Commission on social determinants of health declares: “… the structural determinants and daily life conditions constitute the social determinants of health causing much of the health inequity within and between countries…

Society has traditionally looked at the health sec­tor to take care of its health and disease concerns. Of course, the bad distribution of healthcare – for exam-ple, not providing care to those that most need it- is one of the social determinants of health. But much of the high load of disease leading to a terrifying prema-ture loss of lives stems from the immediate and struc-tural conditions in which people are born, grow, live, work and become old.” (10)

The life expectancy of a person who was born or lives in Japan or Sweden in over 80 years, in Argen­tina 76 years, in Brazil 72, and in India 63 years. In several African countries it is below 50 years.

"Inside countries, the differences in life opportuni-ties are also large."

For example, in Tottenham, life expectancy is 71

In these situations it is necessary to design com-plex samples so that the persons included represent the population we wish to study, using cluster, strati-fied, multistage sampling (15), as usually employed in United States NAHNES (National Health and Nutri-tion Examination Survey) surveys. (16)

Hypertension is the sole condition that annually kills more people than tobacco, more than 9 million per year; however, only around 1 out of 7 persons in the world has controlled hypertension.

We need population sampling to identify whether jointly applied programs both at the individual level (with standardized simplified protocols, available drugs administered to all and the task assigned to nurses or easily accessible non-medical staff) as at the population level with low sodium intake, are successful.

In the United Kingdom, the voluntary negotiation with the industry decreased sodium intake by 15% (1.4 g/day) between 2003 and 2011. A substantial reduc-tion in blood pressure (3.0/1.4 mmHg) was achieved in the overall population and 2.7/1.1 mmHg in the persons without anti-hypertensive treatment, with a concomitant 42% reduction in death due to stroke and 40% reduction of cardiac death. It is estimated that 25% to 33% mortality reduction could be attributed to decreased salt intake. (17)

A “Sentinel System” can also be developed, as in the case of the FDA, to examine in real time the in-formation of systems that use the electronic clinical history to monitor the safety of already proven medi­cal products. It allows answering specific questions about medical products, as the myocardial infarct rate among patients using oral hypoglycemic drugs. The initial Mini-Sentinel system ensures the privacy of data as it uses a distributed data and analysis system, collecting anonymous data through specific programs run at each center, that remains the owner of the orig­inal data. (18)

The social network study

The introduction of public health interventions does not reach all individuals simultaneously because so­cial relationships in the real world are not indifferent, and relationships are established in family, neighbor, working, affinity, friendship, and other networks.

The experience often propagates mouth-to-mouth throughout the population.

It should not be assumed that the diffusion of new health knowledge or protective conducts only requires a cognitive acknowledgement –that the Facebook or Linkedin Internet message can deliver- without face-to-face physical assistance and training, “getting down to it”.

Let us consider the example of the interconnected social network of the Framingham study (Figure 2). The propagation of cigarette was repeatedly examined in 12,067 persons during 32 years. The network was represented by clusters of smokers and non-smokers and this grouping was extended up to the 3rd degree

of separation.

The person quitted smoking in 67% of cases if the spouse also abandoned smoking, in 25% of cases if a sibling quitted the habit, in 36% if a friend did so and in 34% in the case of a workmate. These effects were not seen among neighbors of the same geographical area.

It seems relevant that socially related groups pre-viously abandon this habit in order to quit smoking, as if there were a social agreement. (19)

The person-to-person diffusion of obesity and al­cohol was also explored in the same interconnected social network of 12,067 participants of the Framing-ham study between 1971 and 2003.

A person became obese in 57% of cases if a friend became obese, in 40% in the case of a sibling, and in 37% in the case of the spouse. This mimicking did not occur among geographical neighbors. It should be em-phasized that persons of the same sex had greater in-fluence in obesity. Moreover, it is relevant that obesity seems to propagate by means of close social relation-ships. (20)

When someone changes to excessive alcohol con-sumption it affects others. The influence in a 1st de-gree relationship is 50%, in a 2nd degree relationship 36% and in a 3rd degree relationship 15% (friend of a friend of a friend).

These findings suggest the significant role a social network plays in the inducement to consume alcohol. (21)

Also people connected with many happy people up to a third degree of separation (friend of a friend of a friend) and who are central in the networks will be probably happy in the future. Longitudinal statistical models suggest that extra happiness results from the dissemination of happiness and not from the tendency of people to associate with similar individuals.

Happiness of people depends on the happiness of others with whom they are connected. Happiness, same as health, should be seen as a collective phenomenon. (22)

The use of social networks in public practice

There is a first study comparing strategies focused on networks to promote the diffusion of innovation in social networks face-to-face with the real world. In a rural area of Honduras, with a population of 5,773 villagers, 32 villages (clusters) were assigned to one, both or none of 2 interventions (chlorine to purify water or multivitamin tablets).

Interventions were introduced to 5% of villagers, using the following design: 1) random selection, 2) the most connected persons and 3) the friends of those randomly selected at initiation.

The products were delivered in only one day to the selected participants, who were instructed on their use and taught about the interventions. They were handed out 4 vouchers to be used by others to with-draw the products. Then, each person who received one of the 4 vouchers also went to withdraw the prod-ucts (second wave, cascade effect).

Judging from the recovery of vouchers, asking the friends of persons in a random sample of villagers to distribute the vouchers for multivitamin vials led to greater diffusion in these villages than asking better connected persons, or simply the random sample per-sons, to distribute the vouchers.

A total of 74.3% of vouchers were recovered in the villages selected to nominate friends, significantly dif-ferent (p<0.01) from the 66.2% recovery in those with random selection and 61.9% in the ones where the most connected persons were chosen.

This study demonstrates that focusing in the more connected persons does not provide extra benefit in health interventions. Conversely, the technique that selects people by a friendship relationship produces a larger cascade of product adoption and health knowl-edge.

Focusing on the friends of a random sample is clearly simpler and cheaper, as there no need to know the complete previous social network “map” to look for those who are more connected. (23)

In low and medium income countries (LMIC), natural social networks may be essential for health results, building, for example, cascade effects among participants who are not target of the initial interven-tion, and improving their efficiency.

A systematic review identified 17 articles from 10 studies of sociocentric networks examining the health problems in LMIC. Nineteen articles from 10 studies were also selected on welfare development topics.

Human health and welfare are connected by dy-namic social relationships, which are especially important when people depend, directly or indirectly, on the connections that support them. (24)

Improving risk conducts with automatic messages to mobile phones

A first study randomly assigned a messenger program to mobile phones with a semipersonalized automatic strategy focused on simultaneously changing various

lifestyle risk factors, or on standard care. It included 710 patients with proven coronary artery disease from a tertiary hospital in Sidney, Australia. Patients in the intervention group (n=352) only received 4 text mes-sages per week during 6 months, without personal in-teraction.

At 6 months, a significant decrease was found for LDL-cholesterol (-5 mg/dL, p=0.04), systolic blood pressure (-7.6 mmHg, p<0.001), and BMI (-1.3 U, p<0.001), while physical activity increased 293 MET minutes per week and the number of smokers signifi-cantly decreased (RR 0.6, p<0.001).

The messages for each participant were selected from a message base according to baseline characteristics (e.g, if he/she smoked) and sent through an au-tomatic, not interactive, messenger system.

Messages were sent with the preferred participant name and provided advice, motivation and information to improve the diet, increase physical activity and encourage smoking cessation.

We report some of the messages sent:

Smoking (Name) “try to identify the trigger that makes you want to smoke a cigarette and plan to avoid it".

Diet: “Do you know that 90% of people do not eat the daily recommended amount of vegetables (5 serv-ings per day?"

Physical activity: “Hello (Name) walking is cheap. It can be done anywhere. All you need is comfortable shoes and clothes".

General cardiovascular information: “Studies show that stress, anxiety and loneliness may increase the risk of cardiovascular disease. Please, call a health-care professional if you need help". (25)

CONCLUSION

As Thomas Frieden declares in the legend: “Work-ing together clinical medicine and public health may guarantee that persons lead active and productive lives much longer than it was ever thought possible”. (26)

If we persist in this epidemiological framework of new epidemics produced by socio-economic struc-tures, future clinical medicine discoveries would only increase healthcare costs without substantial improvements in health outcomes. But if alternatively we develop new healthcare models and technologies, we may markedly increase a healthy life expectancy.

At the same time, the field of population health should be actively observant to adapt to new changing risk factors and to encourage public health actions which are the core to promote healthy lives. And in addition to the initial success of infectious disease, tobacco and alcohol campaigns, which should be reinforced and extended to be completely successful, the radio of action to control new epidemics due to environmental risk should be expanded, reducing damages produced by changes in the environment, increasing physical activity and above all, substantially improving human nutrition technologies.

"Working together more closely, clinical medicine and public health may mutually help to maximally improve health -and emphasize the responsibility so-ciety has to encourage healthy and consistent environ-ments, as well as high quality care." (26)

It is our responsibility, as physicians in the care of our patients, to promote them.

Dr. Hernán C. Doval^MTsaC

Director of the Argentine Journal of Cardiology

REFERENCES

1.  Lozano R, Mohsen N, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease 2010. Lancet 2012;380:2095-128. http://doi.org/j3w

2.  Bollyky TJ, Emanuel EJ, Goosby E P, Satcher D, Shalala DE, Thompson TG. NCD and an outcome-based approach to global health. Lancet 2014;384:2003-4. http://doi.org/f2wnct

3.  Independent Task Force on Noncommunicable Diseases. The emerging global heath crisis: noncommunicables diseases in low and middle-income countries, Independent Task Force report no 72. New York Council on Foreign Relations Press, 2014.

4.  Keating C. The social history of ISIS-2: the early history. Lancet 2015;386:646-7. http://doi.org/f3hh26

5.  Keating C. The social history of ISIS-2: trial and tribulation. Lan-cet 2015;386:648-9. http://doi.org/f3hh26

6.  Lane R. Salim Yusuf: global leader in cardiovascular disease re-search. Lancet 2015;386:645. http://doi.org/f3hh25

7.  Horton R, Beaglehole R, Bonita R, Raeburn J, McKee M, Wall S. From public to planetary health: a manifesto. Lancet 2014;383:847 http://doi.org/f2qqf3

8.   Lo S, Horton R. Everyone counts-so count everyone. Lancet 2015;386:1313-4. http://doi.org/f3jgpb

9.  Editorial. Toward 2030: counting and accountability matter. Lancet 2015;386:1312; http://doi.org/f3jgn8

10.  Marmot M, Friel S, Bell R, Houweling TA, Tailor S. Closing the gap in a generation: health equity through action on the social de-terminants of health. Lancet 2008;372:1661-9. http://doi.org/d7krt8

11.  Doval HC. Estrategias de salud: del oficio médico a la medicina social. Rev Argent Cardiol 2015;83:365-75. http://doi.org/9md

12.  Lurie N, Fremont A. Building bridges between medical care and public health. JAMA 2009;84:86.http://doi.org/cvs6q8

13.  Llorca J, Fariñas-Álvarez C., Delgado-Rodriguez M. Fracción atri-buible poblacional: cálculo e interpretación. Gac. Sanit. 2001;15:61-7. http://doi.org/f2njnb

14.  Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, et al. Explaining the decrease in U. S. deaths from coronary disease, 1980-2000. N Engl J Med 2007;356:2388-98. http://doi.org/ ftsn7g

15.  Silva Aycaguer LC. Diseño razonado de muestras y captación de datos para la investigación sanitaria. Diaz de Santos 2000.

16.  NHANES web site: http/www.cdc.gov/nhanes

17.  He FJ, Pombo-Rodrigues S, MacGregor GA. Salt reduction in England from 2003 to 2011: its relationship to blood pressure, stroke and ischaemic heart disease mortality. BMJ Open 2014;4:e004549. http://doi.org/9mh

18.  Behrman RE, Benner JS, Brown JS, McClellan M, Woodcock J, Platt R. Developing the sentinel system – A national resource for evidence development. N Engl J Med 2011;364:498-9. http://doi.org/ dqm258

19.  Christakis NA, Fowler JH. The collective dynamics of smoking in a large social network N Engl J Med 2008;358:2249-58. http://doi. org/fb2hmf

20.  Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med 2007;317:370-9. http://doi.org/ dmrgt6

21.  Rosenquist JN, Murabito J, Fowler JH, Christakis NA. The spread of alcohol consumption behavior in a large social network. Ann Intern Med 2010;152:426-33. http://doi.org/9mk

22.  Fowler JH, Christakis NA. Dynamic spread of happiness in a large social network: longitudinal analysis over 20 years in the Framingham Heart Study. BMJ Online First 2008;337:a2338. http:// doi.org/cxb238

23.  Kim DA, Hwong AR, Satfford D, Hughes DA, O´Malley AJ, Fowler JA, et al. Social network targeting to maximise population behaviour change: a cluster randomized controlled trial. Lancet 2015;386:145-53.http://doi.org/9mm

24.  Perkins JM, Subramanian S V, Christakis NA. Social networks and health: S systematic review of sociocentric network stud-ies in low- and middleincome countries. Social Science & Med 2015;125:60-78.

25.  Chow CK, Redfern J, Hillis GS, Thakkar J, Santo K, Hackett ML, et al. Effect of lifestyle-focused text messaging on risk factor modifi-cation in patients with coronary heart disease: A randomized clinical trial. JAMA 2015;314:1255-63. http://doi.org/9mn

26.    Frieden TR. The future of public health. N Engl J Med
2015;373:1748-54. http://doi.org/9c2