1. POLYPILL: PROMISIUNI ȘI PROVOCĂRI
Prof. dr. Florin Mitu, M.D. F.E.S.C.
Universitatea de Medicina si Farmacie "Gr. T. Popa" Iasi
PROVAS IV
Timișoara, 2016

2. Decese la 1 milion de locuitori în lume (Lancet 1997)
PREMISE
Decese la 1 milion de locuitori în lume (Lancet 1997)
Cunoașterea FRCV a determinat dezvoltarea de strategii de prevenție la nivel populațional și de “high risk“: ghiduri de dietă, promovarea activității fizice, reducerea fumatului, tratamentul HTA, hipercolesterolemiei; totuși BCV continuă să reprezinte ucigașul nr 1
Estimările OMS: în 2025 BCV vor fi prima cauză de mortalitate în ţările în curs de dezvoltare
Murray CJL, Lopez AD. Alternative projection of mortality and morbidity by cause ; Global Burden of Disease Study. Lancet 1997; 349:

3. Consecinţa este o reducere modestă a riscului de BCV în populaţie
PREMISE
Aterotromoza, favorizată de prezenţa factorilor de risc, reduce speranţa de viaţă cu 8 – 12 ani
Terapia medicamentoasă prezentă are ca obiectiv un singur factor de risc (HTA, hipercolesterolemie, DZ) şi este adresată unui grup ţintă restrâns cu nivele anormal de mari ale acestuia cu scopul de a-l scădea la nivele medii populaţionale
Consecinţa este o reducere modestă a riscului de BCV în populaţie
Peeters, et al. Eur Heart J 2002;23:

4. PREMISE Un efect de prevenţie pe scară largă:
Necesită intervenţie asupra tuturor persoanelor cu risc crescut indiferent de nivelele factorilor de risc
Intervenţia să aibă ca ţintă mai mulţi factori de risc concomitent
Reducerea acestor factori de risc să fie cât mai accentuată
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

5. POLYPILL
POLIPILULA:
Statină
Trei droguri antihipertensive (fiecare la ½ doză)
Acid folic
Aspirină
Prof. Nicolas Wald
→ reduce riscul de evenimente cardiace ischemice cu 88% şi de atac cerebral cu 80%
"Această strategie ar fi potrivită pentru persoane cu boală cardiovasculară cunoscută şi pentru oricine peste o anumită vârstă (exemplu 55 ani), fără a necesita măsurarea factorilor de risc"
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

6. ARGUMENTE
Supravieţuirea postinfarct miocardic acut a fost substanţial ameliorată la pacienţii care au primit patru clase terapeutice (aspirină, BB, IECA, statină) comparativ cu cei care au primit 0, 1, 2 sau 3 droguri (Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) registry, n = 6067)
Schuster S, Koch A, Burczyk U, et al. Early treatment of acute myocardial infarct: implementation of therapy guidelines in routine clinical practice, MITRA pilot phase. Z Kardiol 1997;86:273–283

7. ARGUMENTE
Studiu francez: supravieţuirea la 1 an la pacienţi cu IMA a fost semnificativ mai bună la cei care au primit combinaţie de trei medicamente faţă de cei ce au primit un medicament, indiferent de clasa terapeutică (antiplachetar, statină, antihipertensiv)
Danchin N, Cambou JP, Hanania G, et al; USIC 2000 Investigators. Impact of combined secondary prevention therapy after myocardial infarction: data from a nationwide French registry. Am Heart J 2005;150:1147–1153

8. POLYPILL
Wald şi Law au identificat categoriile de droguri şi vitamine cu efect asupra
Funcţie plachetară
LDL TA
Homocisteină
Thiazide BB
IECA
Sartani
BlCa
Acidul folic
Aspirina
Statine
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

9. POLYPILL
Alegerea drogului (şi a dozei) a fost determinată de rezultatele trialurilor şi studiilor de cohortă având ca end-point scăderea mortalităţii CV
Wald şi Law au calculat efectul combinat al modificării celor patru FR şi au estimat anii de viaţă câştigaţi fără boală acută cardiacă sau cerebrală la persoane fără BCV anterioare dacă utilizează Polypill de la vârsta de 55 ani
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

10. POLYPILL BENEFICII ESTIMATE:
Table 1 shows the effects of the individual agents. By
use of statins, LDL cholesterol concentration can be
reduced by an average of 1.8 mmol/l. Atorvastatin
10 mg taken at any time of day or simvastatin (or
lovastatin) 40 mg taken in the evening or 80 mg taken
in the morning after about two years of treatment can
reduce the incidence of IHD events at age 60 by an
estimated 61%.1 Higher doses produce little further
gain. The overall reduction in stroke from an LDL
cholesterol reduction of 1.8 mmol/l is about 17%.1
This estimate takes account of the reduction in risk of
stroke in people with and without existing vascular disease
(35% v 11%, a difference which arises because a
stroke in people with vascular disease is more likely to
be thromboembolic, and statins prevent thromboembolic,
but not haemorrhagic, stroke) and also takes
account of the proportion of first strokes that occur in
people with known vascular disease (25%)1 (25% of
35% plus 75% of 11% making 17%).
The five main categories of blood pressure
lowering drugs (thiazide, blockers, ACE inhibitors,
angiotensin II receptor antagonists, and calcium channel
blockers), and the individual drugs within the
categories, produce similar reductions in blood
pressure, given dose as a ratio of standard dose.16 A
combination of three drugs from different categories
in low dose has greater efficacy and fewer adverse
effects than using one or two drugs in standard dose.16
The blood pressure reduction with three drugs in
combination at half standard dose is about 11 mm Hg
diastolic, reducing the incidence of IHD events by 46%
and stroke by 63%.16 17
The maximum effect of folic acid, achieved at a
dose of about 0.8 mg/day,15 18 lowers serum homocysteine
by 3 mol/l (about 25%) and reduces IHD
events by about 16% and stroke by 24%.9
Table 1 shows that changing all four risk factors
together reduces the risk of IHD events by 88% and
stroke by 80%. These results are obtained from the
product of the relative risk estimates relating to
interventions on each risk factor, which is the complement
of the proportion of events prevented; thus, preventing,
say, 61% is equivalent to a relative risk of 0.39.
The following example illustrates the calculation. The
relative risks of an IHD event for the four interventions
in table 1 are 0.39, 0.54, 0.84, and 0.66, the product of
which yields a combined relative risk of 0.12 or an 88%
preventive effect (if 100 people who would have had
IHD events without intervention were treated, statins
would prevent 61 of the 100 events, leaving 39; 46% of
these would be prevented with blood pressure
lowering drugs, leaving 21; 16% of these would be prevented
with folic acid, leaving 18; and 34% of these
would be prevented with aspirin, leaving 12; 88% have
thus been prevented). Reducing one risk factor has a
similar proportional effect on risk irrespective of the
level of other risk factors, as confirmed by cohort studies
and randomised trials.19–22 For example, trials of
LDL cholesterol reduction show similar proportional reductions in risk in people with high and low blood
pressure and in people taking and not taking
aspirin.20 21
Other than the statin (in respect of IHD), omitting
a single component has a relatively minor impact on
the combined effect of the residual components,
illustrating the robustness of the Polypill concept.
Compared with the reductions in IHD events and
stroke of 88% and 80% respectively with all six components,
the reductions were 86% and 74% without folic
acid, 85% and 73% without one blood pressure lowering
drug (two instead of three), and 83% and 77% without
aspirin. So, for example, aspirin prevents 32% of
IHD events when used alone but prevents only an
additional 5% of the original number of expected
events when added to the other components in the
combination.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

11. POLYPILL BENEFICII ESTIMATE:
Table 2 shows the expected proportion of people
who would avoid an IHD event or stroke by taking the
Polypill from age 55 and, in those, the average number
of event-free life years gained. The estimates take
account of deaths from causes other than IHD and
stroke. About a third of people taking the Polypill
would benefit. On average each will gain years of
life free from a heart attack or stroke. The gain in life is
substantial at all ages
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

12. POLYPILL EFECTE ADVERSE ESTIMATE ce pot fi atribuite ASPIRINEI:
Of all the components, aspirin has the most serious
adverse effects, mainly due to haemorrhage (table B on
bmj.com). In our meta-analysis of the trials of low dose
aspirin the increase in haemorrhagic stroke (table A on
bmj.com) was exceeded by the reduction in thrombotic
strokes, producing an overall 16% reduction in stroke.
There was no excess risk of fatal extracranial haemorrhage, with 13 and 15 deaths in the aspirin and placebo
groups respectively in about people in each
(table B on bmj.com), and an excess risk of major nonfatal
extracranial haemorrhage (mainly gastric) of 1.2
per 1000 person years (see table 3)
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

13. POLYPILL
EFECTE ADVERSE ESTIMATE ce pot fi atribuite componentelor Polypill: 8 – 15%
Table 4 uses these data together with
those published in our companion papers1 16 to show
the proportions of people reporting symptoms attributable
to any of the components of the Polypill
(percentage with symptoms in treated groups minus
percentage in placebo groups in trials). If we included
the three classes of blood pressure lowering drugs with
the lowest prevalence of adverse effects (thiazide,
angiotensin II receptor antagonist, and calcium
channel blocker16) in a Polypill formulation, 8% would
be expected to have symptoms attributable to one or
more of the six components of the pill, mostly due to
aspirin. If we used the three least expensive blood pressure
lowering drugs (a thiazide, a blocker, and an
ACE inhibitor) instead, a Polypill including these
would cause symptoms in about 15% of people taking
the pill.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

14. POLYPILL Care este populaţia ţintă?
Toţi pacienţii cu BCV cunoscută: IM, AP, AVC, AIT, BAP, DZ
Persoanele peste 55 ani (96% din decesele de cauză cardiacă sau cerebrală apar la vârsta peste 55 ani)
Nu este necesară determinarea FR înaintea iniţierii tratamentului (intervenţia este eficientă indiferent de nivelul FR)
Nu este necesară monitorizarea efectelor tratamentului
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

15. POLYPILL
COSTURI:
Utilizarea produselor generice ar scădea costul (ex simvastatin, HCZ, atenolol, enalapril, acid folic, aspirină)
Disponibilitatea mai multor formule terapeutice pentru a creşte toleranţa şi acceptabilitatea
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003;326:

16. Prevalenţa BCV în India
STUDII ?
Prevalenţa BCV a crescut de 9 ori în ultimii 40 ani
Risc crescut de 5 – 10 ori la persoane tinere (sub 40 ani) indiferent de sex sau clasă socială
În 2020 va avea cea mai mare povară a BCV
Prevalenţa BCV în India
→ Interesul faţă de Polypill care ar reduce riscul CV este mai ridicat
Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet, 2009, 373: 1341–51
Enas EA, Mehta J. Malignant coronary artery disease in young Asian Indians: Thoughts on pathogenesis, prevention and therapy. Coronary Artery Disease in Asian Indians (CADI) study. Clin Cardiology 1995;18(3):131-5

17. STUDII ? 2053 persoane fără BCV, cu 1 FR, 45 – 80 ani, 12 săpt
In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged
45–80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412)
consisting of low doses of thiazide (12·5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin
(100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone,
hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering
drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were LDL for the eff ect of
lipids, blood pressure for antihypertensive drugs, heart rate for the eff ects of atenolol, urinary 11-dehydrothromboxane
B2 for the antiplatelet eff ects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to
treat. This study is registered with ClinicalTrials.gov, number NCT
HCZ 12,5 mg / atenolol 50 mg / ramipril 5 mg / aspirin 100 mg / simvastatin 20 mg
Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009, 373: 1341–51

18. STUDII ? ↓ TA cu 7,4 / 5,6 mmHg ↓ LDL cu 0,7 mmol/l
Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood
pressure by 7·4 mm Hg (95% CI 6·1–8·1) and diastolic blood pressure by 5·6 mm Hg (4·7–6·4), which was similar
when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure
increased with the number of drugs used (2·2/1·3 mm Hg with one drug, 4·7/3·6 mm Hg with two drugs, and
6·3/4·5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0·70 mmol/L (95% CI 0·62–0·78), which
was less than that with simvastatin alone (0·83 mmol/L, 0·72–0·93; p=0·04); both reductions were greater than for
groups without simvastatin (p<0·0001). The reductions in heart rate with Polycap and other groups using atenolol
were similar (7·0 beats per min), and both were signifi cantly greater than that in groups without atenolol (p<0·0001).
The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283·1 ng/mmol creatinine, 95% CI
229·1–337·0) compared with the three blood-pressure-lowering drugs plus aspirin (350·0 ng/mmol creatinine,
294·6–404·0), and aspirin alone (348·8 ng/mmol creatinine, 277·6–419·9) compared with groups without aspirin.
Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with
increasing number of active components in one pill.
↓ FC cu 7 bătăi/min
Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009, 373: 1341–51

19. STUDII ? Efecte secundare şi motive de întrerupere a medicaţiei
Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood
pressure by 7·4 mm Hg (95% CI 6·1–8·1) and diastolic blood pressure by 5·6 mm Hg (4·7–6·4), which was similar
when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure
increased with the number of drugs used (2·2/1·3 mm Hg with one drug, 4·7/3·6 mm Hg with two drugs, and
6·3/4·5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0·70 mmol/L (95% CI 0·62–0·78), which
was less than that with simvastatin alone (0·83 mmol/L, 0·72–0·93; p=0·04); both reductions were greater than for
groups without simvastatin (p<0·0001). The reductions in heart rate with Polycap and other groups using atenolol
were similar (7·0 beats per min), and both were signifi cantly greater than that in groups without atenolol (p<0·0001).
The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283·1 ng/mmol creatinine, 95% CI
229·1–337·0) compared with the three blood-pressure-lowering drugs plus aspirin (350·0 ng/mmol creatinine,
294·6–404·0), and aspirin alone (348·8 ng/mmol creatinine, 277·6–419·9) compared with groups without aspirin.
Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with
increasing number of active components in one pill.
Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009, 373: 1341–51

20. STUDII ?
Reducerea estimată a riscului în TIPS comparativ cu estimările Wald şi Law
Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009, 373: 1341–51

21. STUDII ?
UMPIRE (Use of Multidrug Pill in Reducing cardiovascular Events) study:
studiu de fază III, durata – 2 ani (Londra, Dublin, Utrecht, New Delhi), 2004 adulţi cu BCV sau risc înalt;
Pacienţii au primit tratament standard sau una din cele două versiuni ale Red Heart Pill:
Versiunea 1: aspirina 75 mg  simva 40  lisinopril 10 mg  atenolol 50 mg
Versiunea 2: aspirina 50 mg  simva 40  lisinopril 10 mg  HCZ
Obiective: aderenţa la medicaţie, modificările TA şi ale col
Rezultatele publicate în 2013
Thorn S et al. JAMA 2013

22. STUDII ?
UMPIRE (Use of Multidrug Pill in Reducing cardiovascular Events) study:
Thorn S et al. JAMA 2013

23. STUDII ?
UMPIRE (Use of Multidrug Pill in Reducing cardiovascular Events) study: aderența la medicație
Thorn S et al. JAMA 2013

24. STUDII ?
Studii similare iniţiate în 2010: Noua Zeelandă, Australia, Brazilia, Canada, China, Africa de Sud
Populaţie inclusă: aprox 7000 pacienţi din 10 ţări

25. STUDII ?
Studii similare iniţiate în 2010: Noua Zeelandă, Australia, Brazilia, Canada, China, Africa de Sud
Populaţie inclusă: aprox 7000 pacienţi din 10 ţări
Selak V et al. BMJ 2014

26. STUDII ?

27. ADERENȚA
Adherence is the key mediator between medical practice and patient outcomes.
Kravitz RL, Melnikow J. Medical adherence research: time for a change in direction. Med Care. 2004; 42;

28. ADERENȚA A combination pill is a cost efective strategy
Meta-analysis of studies with combination pills showing to reduce BP and estimate of reduction of CV events
A combination pill is a cost efective strategy
Working Group. European Heart journal (2014) 35,
Laba.MJA 2014

29. Conceptul ″Polypill″ in ghiduri
“Physicians should be aware that adherence to medication reflect generally better health behaviour”

30. Caracteristicile unui Polypill viabil
Indicații clinice viabile
Componente cu proprietăți fizico-chimice cunoscute
Stabilitate farmaceutică
Doze și farmacokinetică compatibile
Interacțiuni predictibile; lipsa interacțiunilor negative
Eficacitate cunoscută
Efecte adverse predictibile
Accesibil ca preț
DiMasi JA et al. The price of Innovation: new estimates of drug development costs. J Health Econ 2003;22:151

31. Probleme Profilul de siguranţă (funcţia hepatică, renală)
Determinarea dificilă a componentei care poate da efecte secundare
Problema dozei optime individualizate
Polypill nu înlocuieşte măsurile de modificare a stilului de viaţă
The Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009; published online March 30. DOI: /S (09)

32. Atitudinea medicilor de familie
Studiu US 2010:
Nivel ridicat de acceptare a prescrierii Polypill la pacienţii cu risc cardiovascular crescut şi moderat la cei cu risc cardiovascular moderat
Cunoştinţele mai multe legate de Polypill determină acceptarea mai uşoară a prescrierii
Posibilitatea modificării dozelor substanţelor din Polypill
Viera AJ. Et al. Acceptance of a polypill approach to prevent cardiovascular disease among a sample of US physicians. Preventive medicine 2011;52:10

33. Analiza cost-eficienţă
Cost-eficienţa polypill variază în funcţie de nivelul de risc.
În prevenţia primară trebuie să dovedească eficienţă similară aspirinei şi substituienţilor de nicotină; să fie disponibil la preţ mai mic decât cel al aspirinei şi statinei
În prevenţia secundară este cost-eficient
Franco OH et al. The polypill: at what price would it become cost effective? J Epidemiol Community Health 2006; 60:213

34. Mesaje
Polypill este mai mult decât o capsulă, reprezintă o strategie de prevenție cardiovasculară.
Conceptul farmacologic: combinație de droguri ce acționează asupra mecanismelor de dezvoltare a aterosclerozei, la doze eficiente, diminuând riscul.
Reducerea unor factori de risc scade proporțional riscul CV, independent de nivelul inițial al riscului.
Strategia polypill este cost-eficientă.