e.health and System Medicine: from Evidence Based Medicine to five P Precision Medicine GIAN FRANCO GENSINI

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1 e.health and System Medicine: from Evidence Based Medicine to five P Precision Medicine GIAN FRANCO GENSINI FIRENZE, 26 maggio 2014

2 4 novembre 1992: JAMA

3 What evidence-based medicine is: The practice of EBM requires the integration of individual clinical expertise with the best available external clinical evidence from systematic research patient values Centre for Evidence-based Medicine

4 La medicina basata sulle evidenze, per sua natura, in generale ricerca e ottiene evidenze relative a malattie a definizione ontologica ben circoscritta, con studi clinici focalizzati su pazienti il più possibile privi di altre condizioni cliniche rilevanti che risulterebbero confondenti per le evidenze ricercate.

5 Scandinavian Simvastatin Survival Study (4S) The Lancet, Vol 344, November 19, 1994

6 Coronary Death and Nonfatal MI % o f p a ti e n t s w it h o u t e v 34% Risk Reduction p< Years since randomization Inclusion e Criteria: Prior MI and/or angina pectoris n t s The Lancet, Vol 344, November 19, 1994

7 Baseline Characteristics Placebo (n=2223) Simvastatin (n=2221) The Lancet, Vol 344, November 19, 1994

8 Holmes 2003 Importance+of+co-morbidity Prevalence+and+age+trends+for+selected+co-morbidi7es

9 .in questi 20 anni che cosa è cambiato Progressivo invecchiamento della popolazione Aumento dei pazienti con comorbilità multiple - multimorbilità Queste categorie di pazienti sono solitamente non incluse nei trial clinici

10 LA MEDICINA CLASSICA Conce&o'di'mala-a La$medicina$ha$coniato$il$conce/o$di$ mala1a e$aderisce$a$questo$conce/o$nella$sua$a1vità. Le'mala-e'definite'come'ontologie'in medicina'rappresentano'il'risultato'di'un processo'di'consenso'talora'recentemente esplicito,'in'precedenza'più'frequentemente implicito,'rela;vamente'alla'definizione'di un ontologia.

11 LA MEDICINA CLASSICA! Il!ragionamento!diagnos0co!assume così!le!cara4eris0che!del riconoscimento!di!un impronta digitale:!si!ricercano!i!pun$%di iden$tà!fra!mala:a!conosciuta!e situazione!clinica!del!paziente!e, quando!i!pun0!di!iden0tà!superano un!certo!numero,!!si!definisce!la diagnosi%(approccio%euris$co%al

12 Il fenotipo clinico complesso HYPERTENSION S C A B P C O D M II Aritmie Heart Failure Complicanze periprocedurali I R E P Infezioni su device

13 New York Times 18 sep 2007 Dr. Michael Stern reported in the June issue of Emergency Medicine. By JANE E. BRODY Published: September 18, 2007 A 78-year-old woman was found unconscious on the floor of her apartment by a neighbor who checked on her. The woman could not remember falling but told doctors that before going to bed she had abdominal pain and nausea and had produced a black stool, after which she had palpitations and felt lightheaded.

14 New York Times 18 sep 2007 Her medical history included high blood pressure, coronary artery disease, atrial fibrillation, congestive heart failure and osteoarthritis. She also had a cold with a productive cough. For each condition, she had been prescribed a different drug, and she was taking a few over-the-counter remedies on her own.

15 New York Times 18 sep 2007 PERSONAL HEALTH The Poisonous Cocktail of Multiple Drugs These were the medications: Beta-blocker to control high blood pressure. Digitalis to help the heart pump and control its rhythm. Coumadin to prevent a stroke caused by blood clots. Furosemide, a potent diuretic to lower blood pressure. Statins to lower serum cholesterol. Baby aspirin to reduce cardiac risk from blood clots. Cox-2 inhibitor for arthritis pain. antidepressant for depression and anxiety. Diazepam, as needed, to help her sleep. Levofloxacin, an antibiotic for the cough. Ibuprofen for body aches. Cough medicine.

16 New York Times 18 sep 2007 PERSONAL HEALTH The Poisonous Cocktail of Multiple Drugs These were the medications: Beta-blocker to control high blood pressure. Digitalis to help the heart pump and control its rhythm. Coumadin to prevent a stroke caused by blood clots. Furosemide, a potent diuretic to lower blood pressure. Statins to lower serum cholesterol. Baby aspirin to reduce cardiac risk from blood clots. Cox-2 inhibitor for arthritis pain. antidepressant for depression and anxiety. Diazepam, as needed, to help her sleep. Levofloxacin, an antibiotic for the cough. Ibuprofen for body aches. Cough medicine.

17 New York Times 18 sep 2007 Her medical history included 1. high blood pressure, 2. coronary artery disease, 3. atrial fibrillation, 4. congestive heart failure and 5. osteoarthritis. She also had 6. a cold with a 7. productive cough. For each condition, she had been prescribed a different drug, and she was taking a few over-the-counter remedies on her own.

18 Comorbilità*e*mul-morbilità! Il!termine!comorbilità!è!stato!introdo/o!nel!1970!e!si riferisce!alla!compresenza!di!una!mala9a!aggiun;va!oltre!a quella!indice (Feinstein,)1970)! Con!il!termine!mul+morbilità!invece!ci!si!riferisce!alla coesistenza!di!vari!disturbi!nello!stesso!individuo;!l interesse si!sposta!pertanto!da!una!data!condizione!patologica!indice al!sogge/o!che!soffre!di!patologie!mul;ple!(pa1ent centered) (Batstra)et)al.,)2002)

19 Evalua&on)of)co,morbidity Charlson)co,morbidity)index)(1987) Index)1 Chronic)obstruc&ve)pulmonary)diseases - Cardiovascular,diseases: myocardial-infarc1on,-cardiac-decompensa1on, angina-pectoris,-peripheral-arterial-disease, intermigent-claudica1on,-abdominal-aneurysm Cerebrovascular-diseases: ---cerebrovascular-accident Hypertension-(medically-treated) - Diabetes-mellitus - AutoIimmune-disease Pep1c-ulcera1on Demen1a Liver-func1on-disturbances - - Index)2 Hemiplegia Kidney-func1on-disturbances-(moderate/severe) Diabetes-mellitus-with-terminal-organ-damage Tumours:-solid-tumours,-leukemia,-lymphoma - Index)3 Liver-func1on-disturbances-(moderate/severe) - Index)6 AIDS Metasta1c-cancer - -

20 Evalua&on)of)co,morbidity Charlson)co,morbidity)index)(1987) Index)1 Chronic)obstruc&ve)pulmonary)diseases - Cardiovascular,diseases: myocardial-infarc1on,-cardiac-decompensa1on, angina-pectoris,-peripheral-arterial-disease, intermigent-claudica1on,-abdominal-aneurysm Cerebrovascular-diseases: ---cerebrovascular-accident Hypertension-(medically-treated) - Diabetes-mellitus - AutoIimmune-disease Pep1c-ulcera1on Demen1a Liver-func1on-disturbances - - Index)2 Hemiplegia Kidney-func1on-disturbances-(moderate/severe) Diabetes-mellitus-with-terminal-organ-damage Tumours:-solid-tumours,-leukemia,-lymphoma - Index)3 Liver-func1on-disturbances-(moderate/severe) - Index)6 AIDS Metasta1c-cancer - - -

21 Il"singolo"malato" $potenzialmente$sempre, ma$in$par2colare$oggi$con$il$progressivo invecchiamento$della$popolazione$ $si$può presentare$con$un$quadro"clinico"complesso in$rapporto$alla$coesistenza$di$più$condizioni morbose. $ Questo$complica$e$rende$più$difficile,$e$talora impossibile,$il$processo$di"iden4ficazione"di una"di"queste"mala7e$con$la$condizione complessiva$del$paziente. $

22 Un#approccio#elementare#alla#complessità

23 Holmes 2003 Importance+of+co-morbidity Prevalence+and+age+trends+for+selected+co-morbidi7es

24 Some&common&measures&of&comorbidity Disease&Count&(DC)&(!!!?) Charlson&Index&(CI) Index&of&Co7Existent&Diseases&(ICEDDS)&! Index&of&Disease&Severity&(IDS) Geriatric&Index&of&Comorbidity&(GIC) Di Bari M, et al. J Am Geriatr Soc 2006; 54: 210

25 Etimologia della complessita Complesso, complicato e semplice sono termini che vengono tutti dalla stessa radice indoeuropea: plek- (parte, piega, intreccio).da plek- derivano, in latino: Il verbo plicare = piegare Il verbo plectere = intrecciare Il suffisso plex = parte La parola semplice = sine plex

26 Complex Systems A complex system is a system composed of interconnected parts that as a whole exhibit one or more properties (behavior among the possible properties) not obvious from the properties of the individual parts.

27 Reductionism vs System approach Reductionism System approach The Scientists base their research on a principle hypothesis that complex systems can be understood by seeking out its most fundamental constituents. Complex problems are resolved by dividing them into smaller, simpler and more tractable units. In the last 50 years, the In order to have a better understanding of the system wide behavior, three factors need to be considered: Context: the inclusion of all components involved in a process (and their interactions). Time: to consider the changing characteristics of each component. Space: to account for the topographic

28 The$systems$perspec,ve$is$rooted$in the$assump,on$that the$forest$cannot$be$explained$by studying the$trees$individually.

29 la#visione#sistemica#è#apparsa#come una#pericolosa#ed#a#tra2#inquietante modalità#di#allontanamento#dalla rassicurante##e#ordinata#capacità#di analisi#dello#specialismo. La#complessità#pertanto#è#un#tema sostanzialmente#al#momento#non presente#in#modo#organico#nella formazione#curriculare#e#post: curriculare.

30 La medicina basata sulle evidenze, per sua natura, in generale ricerca e ottiene evidenze relative a malattie a definizione ontologica ben circoscritta, con studi clinici focalizzati su pazienti il più possibile privi di altre condizioni cliniche rilevanti che risulterebbero confondenti per le evidenze ricercate.

31 EVIDENZE?

32

33 ALLHAT Cumulative Event Rates for the Primary Outcome (Fatal Coronary Heart Disease or Nonfatal Myocardial Infarction) Chlorthalidone Amlodipine Lisinopril (n=15,255) (n=9,048) (n=9,054)! Enrollment criteria Hypertension + 1 risk factor!(previous MI, or other CVD, LVH, type 2 diabetes, smoking, HDLChol <35 mg/dl) ALLHAT Collaborative Research Group. Group. JAMA. 2002; 288:

34 ALLHAT Effects of ACE inhibitor based and Diuretic based treatments on Blood Pressure and Outcomes Lisinopril vs Chlortalidone Outcomes RR (95% CI) CV mortality - All cause mortality 1.00 ( ) Myocardial infarction 0.99 ( ) Stroke 1.19 ( )* Heart failure 1.20 ( )* 35% * = p<0.01 of enrolled patients were blacks Clin Med Card Fi ALLHAT Collaborative Research Group. JAMA. 2002; 288:

35 !! Chlortalidone vs Lisinopril stroke BP (mmhg) All patients - 15% - 2 mmhg Blacks - 40% - 4 mmhg effect of race p<0.01 ALLHAT Collaborative Research Group. JAMA. 2002; 288:

36 BI#DIL conclusions The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure. Circulation. 2007;115:

37 Fino%ad%oggi%il%processo%decisionale medico%prevedeva%una%"catena%di esclusioni"%di%quadri%patologici%per arrivare%alla%diagnosi.%ne%è%esempio%il pensiero%"euris8co":%il%medico%di elevata%esperienza%ricerca%nella%propria memoria%il%quadro%più%simile%a%quello che%gli%è%di%fronte,%escludendo%gli%altri.

38 I"percorsi"(diagnos/co0terapeu/ci)"sequenziali abituali"giungono"alla"diagnosi"di"mala9a"a:raverso l esclusione!(guidate!dalla!evidence'based+medicine) di!altre. Di"fronte"alla"complessità,"al"processo"di"esclusione gerarchica"deve"essere"associata"la"capacità"di includere"i"diversi"elemen/,!poiché!tu3 contribuiscono!alla!genesi!del!quadro.! Il"solo"approccio"ridu9vo"si"associa"ad"una"rilevante, e"spesso"deviante,"perdita"di"informazioni"preziose.

39 L approccio) inclusivo )rappresenta(quindi(il solo(approccio(che(rispe1(l'interezza(dei descri5ori (necessari(per(garan8re(l'efficacia della(medicina(clinica. Non(è(tu5avia(da(tralasciare(un(altro(elemento 8pico(della(medicina(clinica:(la(convergenza)di condizioni)cliniche)diverse)su)di)un)unico elemento)clinico)dominante.(dispnea,(febbre, anemia).

40 La#complessità#di#un#elemento#clinico: ### ###La#dispnea

41 DISPNEA ACUTA (ENTRO POCHI MINUTI) Cause polmonari Pneumotorace Embolia polmonare Asma, broncospasmo o patologia reattiva delle vie aeree Inalazione di un corpo estraneo Lesione tossica delle vie aeree (p. es., inalazione di cloro, solfuro di idrogeno) Cause cardiache Ischemia miocardica acuta o infarto Disfunzione o rottura dei muscoli papillari Insufficienza cardiaca Altre cause Paralisi del diaframma Disturbo d ansia con iperventilazione DISPNEA SUBACUTA (ENTRO ORE O GIORNI) Cause polmonari Polmonite Esacerbazione di BPCO Cause cardiache Angina o coronaropatia Versamento pericardico o tamponamento

42 DISPNEA CRONICA (DA ORE AD ANNI) Cause polmonari Patologia polmonare ostruttiva Patologia polmonare restrittiva Patologia polmonare interstiziale Versamento pleurico Cause cardiache Insufficienza cardiaca Angina o coronaropatia Altre cause Anemia Decondizionamento fisico

43 DISPNEA ACUTA (ENTRO POCHI MINUTI) Cause polmonari Pneumotorace Embolia polmonare Asma, broncospasmo o patologia reattiva delle vie aeree Inalazione di un corpo estraneo Lesione tossica delle vie aeree (p. es., inalazione di cloro, solfuro di idrogeno) Cause cardiache Ischemia miocardica acuta o infarto Disfunzione o rottura dei muscoli papillari Insufficienza cardiaca Altre cause Paralisi del diaframma Disturbo d ansia con iperventilazione DISPNEA SUBACUTA (ENTRO ORE O GIORNI)

44 DISPNEA CRONICA (DA ORE AD ANNI) Cause polmonari Patologia polmonare ostruttiva Patologia polmonare restrittiva Patologia polmonare interstiziale Versamento pleurico Cause cardiache Insufficienza cardiaca Angina o coronaropatia Altre cause Anemia Decondizionamento fisico

45

46 TICAGRELOR

47 Polmonite Embolia polmonare Esacerbazione,di BPCO DISPNEA Insufficienza cardiaca,,,, Decondiziona6 mento7fisico Anemia Versamento pleurico

48 Il fenotipo clinico complesso HYPERTENSION ATRIAL FIBRILLATION B P C O D M II Heart Failure I R E P

49 An!Evolving!Scenario Integrated)Care)supported)by)ICT ICT!as!enabler!of!a!new!model!of!care 4P!medicine Predic+ve Personalized! Preven+ve Par$cipatory Efficient!pa+ent!management Modula+on!of!disease!progress

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51 GUIDELINES

52 MINDLINES

53 Construction of mindlines BMJ 30 Oct 2004

54 Geographical+Informa/on+System System+Medicine

55 Systems biology approach to medicine creates network medicine. C on tin uu m De Keulenaer G W, Brutsaert D L Circulation 2011;123:

56 System approach to disease states The use of systems biology approaches to characterize disease states is just at the beginning stages.application of systems biology to disease states will occur at multiple organizational levels with a simultaneous focus on gene network, transcriptome network, protein network and metabolic networks.

57 System approach to disease states Delineation of the systems biology of various cardiovascular diseases, including heart failure, is particularly challenging due to the involvement of multiple organ systems in these disorders, each with a particular systems biology. Human heart failure is a syndrome involving multiple clinical phenotypes which share an undetermined number of common pathophysiological mechanisms. Each of these clinical phenotypes is characterized by multiorgan derangements involving multiple biochemical pathways and numerous molecular elements in each phenotype. Clearly, pathophysiological changes would involve numerous biomedomic domains, each requiring detailed description.

58 Towards System Medicine Genomic/Transcriptomic Sensoring Proteomic Metabolomic Social Network

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61 Towards System Medicine Sensoring Genomic/Transcriptomic Proteomic Metabolomic Social Network

62 Feno%pizzazione*del*comportamento Lo#studio'del'comportamento#rappresenta#una#sfida#par.colare#per#la fenomica#in#quanto#dipende#dal#contesto#e#dal#tempo#ed#è#chiaramente molto#variabile. Le#tecnologie#a;ualmente#disponibili#combinano#sistemi#di#localizzazione basa.#su#gps#(global#posi.on#systems),#accelerometri,#e#strumen.#per#il monitoraggio#dell'a3vità'neuronale.#lo#studio#del#comportamento#umano può#anche#essere#effe;uato#mediante#strumen.#basa.#su#web'e smartphone.

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64 Il fenotipo clinico complesso HYPERTENSION S C A B P C O D M II Aritmie Heart Failure Complicanze periprocedurali I R E P Infezioni su device

65 Il fenotipo clinico complesso HYPERTENSION ATRIAL FIBRILLATION B P C O D M II Heart Failure I R E P

66 An Evolving Scenario Integrated Care supported by ICT ICT as enabler of a new model of care 4P medicine Predictive Personalized Preventive Participatory Efficient patient management Modulation of disease progress

67 UNA QUINTA P : PRECISION MEDICINE Researchers and health-care providers must have access to vary large sets of health and diseaserelated data linked to individual patients. These data are also critical for the development of the Information Commons, the Knowledge Network of Disease, and the development and validation of the New Taxonomy, different from the usual Diseasebased Taxonomy.

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75 New York Times 18 sep 2007 Her medical history included 1. high blood pressure, 2. coronary artery disease, 3. atrial fibrillation, 4. congestive heart failure and 5. osteoarthritis. She also had 6. a cold with a 7. productive cough. For each condition, she had been prescribed a different drug, and she was taking a few over-the-counter remedies on her own.