© Henley Business School 2008www.henley.reading.ac.uk

G Favato & V Pieri

Hypolipidemic agents

in chronic therapy. A compliance study in the ASSET cohort

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The issue

• In the 2000-2004 five years period, the Italian SSN invested cumulatively over €3.3. billion to fund the prescribing of statins in primary care [1].

• Based on the Framingham coronary prediction algorithm, the expected return on this considerable investment would be a significant reduction of the Italian population’s risk for Coronary Heart Disease (CHD)

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Statins yield a lower than expected return [2]• The observed 2000-2005 trend of hospital admissions for

AMI seems to confirm the concerns raised by the Majeed et al. about the prescribing of lipid regulating drugs in England. [3]

1.401.31 1.34 1.36

1.30

16.47

24.96

31.61

39.11

52.31

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

2000 2001 2002 2003 200410.00

15.00

20.00

25.00

30.00

35.00

40.00

45.00

50.00

55.00

60.00

AMI admissions/1000 weighted res. Statins DDD/1000 weighted resi.

Linear (AMI admissions/1000 weighted res.) Expon. (Statins DDD/1000 weighted resi.)

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Caveats• While the Framingham algorithm is based on a

10 years risk assessment, the observation period of analysis was significantly shorter

• While we adjusted for ageing population, the impact of other important cardiovascular risk factors, such as cigarette smoking habit, blood pressure and diabetes, was ignored

• We used hospital admissions for acute myocardial infarction as a proxy of Coronary Heart Disease: angina pectoris and coronary disease admissions were ignored to avoid double counting.

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Statins’ DDD growth offsets the impact of generic substitution [1]

€ 1 billion/ year

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Increasing usage prevalence [1]

?

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Compliance: previous research

• 2002: in the ASSR Umbria the median persistence on statins treatment was 5.3 months [4]

• 2005: in the Pavia ASL the mean exposure to statins was > 180 days/year for 70% of treated patients [5]

• 2005: in the ASSR Emilia-Romagna statins’ coverage was 46% [6]

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A closer look at compliance:the ASSET [7] statins compliance study

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The ASSET cohort• Integration of 2 databases:

– Pharmaceutical individual costs– Personal data

• Sample: 3,175,691 Italian residents

• Timeframe: 24 months (January 04/ December 05)

• Data collected:– Age– Sex– Drugs prescribed (ATC 5° level)– Cost paid by the Italian National

Health Service (SSN)

• Data privacy: all personal information were replaced by an univocal numerical code

ASSET cohort Age Men Women Men% Women% < 14 212,014 198,037 6.68% 6.24% 15-24 158,020 151,022 4.98% 4.76% 25-34 222,054 218,140 6.99% 6.87% 35-44 261,120 254,452 8.22% 8.01% 45-54 212,537 216,539 6.69% 6.82% 55-64 185,003 194,651 5.83% 6.13% 65-74 167,297 191,304 5.27% 6.02% >75 127,172 206,329 4.00% 6.50% Total 1,545,217 1,630,474 48.66% 51.34%

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Study objective [8]

Evaluate the % of persistent and compliant subjects twelve month after initiating statins’ treatment

Persistence: rate of subjects without an interval between 2 consecutive Rx < DDDs prescribed + 30 daysCompliance: rate of persistent subjects with total number of DDDs prescribed/365 > 80%

KEY ASSUMPTION: 1 pill = 1 DDD

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Method

• Jan 04-Mar 04 Wash out period equivalent to 2 Rxs x 24 days + 30 days (no carry over)

• Apr 04-Sep 04 Enrolment period. Subject eligibility criterion: 0 statin Rx in Jan-Mar & at least 1 in the enrolment period

• Oct 04-Sep 05 Observation period

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Results• Out of the 33,139 patients enrolled, only 7% were

persistent and 6% compliant (84% of persistent)• The % of persistent patients rapidly increases by relaxing the

time interval between consecutive RXs, while the % of compliant patients is much less elastic to time interval of RXs.

• 13,400 patients (40.4% of total) did not receive any Rx in the observation period

Persistent Compliant Pers % total Compl % total Compl % PersG29 2111 1790 6% 5% 85%G30 2184 1825 7% 6% 84%G39 2925 2029 9% 6% 69%G44 3396 2118 10% 6% 62%G49 3840 2164 12% 7% 56%G59 4813 2232 15% 7% 46%

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Skewed Rx distribution

• >40% of enrolled patients with 0 Rx in the 12 month observation period

• >50% with 1

• 80% with 5 or less

Number of RXs

Patients % of total cum % of total

0 13400 40.4% 40.4%1 3362 10.1% 50.6%2 2751 8.3% 58.9%3 2372 7.2% 66.0%4 2117 6.4% 72.4%5 1857 5.6% 78.0%6 1681 5.1% 83.1%7 1312 4.0% 87.1%8 955 2.9% 89.9%9 763 2.3% 92.2%

10 633 1.9% 94.2%11 500 1.5% 95.7%12 434 1.3% 97.0%13 296 0.9% 97.9%14 209 0.6% 98.5%15 150 0.5% 99.0%16 121 0.4% 99.3%17 70 0.2% 99.5%18 56 0.2% 99.7%19 32 0.1% 99.8%20 18 0.1% 99.8%21 11 0.0% 99.9%22 10 0.0% 99.9%23 7 0.0% 99.9%24 4 0.0% 99.9%25 6 0.0% 100.0%26 2 0.0% 100.0%27 1 0.0% 100.0%28 1 0.0% 100.0%29 3 0.0% 100.0%31 1 0.0% 100.0%32 1 0.0% 100.0%34 3 0.0% 100.0%

Total 33139 100.0% 100.0%

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Age/sex distribution

from to M F M F M F0 9 0.21% 0.22% 0.00% 0.00% 0.00% 0.00%10 14 0.23% 0.20% 0.00% 0.00% 0.00% 0.00%15 19 0.30% 0.29% 0.05% 0.00% 0.06% 0.00%20 24 0.45% 0.42% 0.05% 0.00% 0.06% 0.00%25 29 0.84% 0.66% 0.05% 0.00% 0.06% 0.00%30 34 1.15% 1.00% 0.38% 0.05% 0.45% 0.06%35 39 1.55% 1.22% 0.52% 0.14% 0.45% 0.17%40 44 2.17% 1.55% 1.37% 0.62% 1.34% 0.67%45 49 2.93% 1.93% 2.27% 0.76% 2.40% 0.67%50 54 3.90% 3.05% 4.64% 2.46% 4.64% 2.57%55 59 5.69% 5.63% 8.67% 5.02% 9.16% 5.14%60 64 5.21% 6.32% 7.72% 5.54% 7.88% 5.53%65 69 6.72% 8.75% 10.37% 8.53% 10.17% 8.44%70 74 6.27% 8.35% 7.82% 8.10% 7.60% 8.16%75 999 8.62% 14.17% 12.08% 12.79% 12.12% 12.23%

46.26% 53.74% 55.99% 44.01% 56.37% 43.63%

Age Enrolled Persistent Compliant

Totale100.00% 100.00% 100.00%

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Compliance by molecule

Persistent Compliant Compl % of Perssimvastatin C10AA01 634 560 88%pravastatin C10AA03 315 268 85%fluvastatin C10AA04 219 201 92%atorvastatin C10AA05 243 124 51%rosuvastatin C10AA07 428 409 96%

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Multiple risk factors do not seem to significantly improve compliance to statins

M F M F M F

Type II diabetes 2586 2606 12.0% 9.7% 10.3% 7.8%

High blood pressure 9403 11339 10.7% 6.7% 9.1% 5.6%

Diabetes & high blood pressure

2034 2218 13.2% 9.8% 11.3% 7.9%

Persistent CompliantEnrolled

Diabetes and high blood pressure identified by the useof concomitant medications (ATC A10 and C)

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Compliance cost• Compliant patients show a mean statins’ cost

significantly higher compared to the total mean:– If every patient were compliant, the SSN burden would

potentially quadruple

• It is conceivable that 80% of the current statins’ prescribing cost has a limited impact in reducing the cardiovascular risk of the Italian population

M F M F M F

Total statins' cost € 2,435,292 € 2,337,214 26% 20% 22% 20%Mean cost € 158.85 € 131.23 € 531.18 € 492.86 € 535.92 € 499.55

StdDev € 196.08 € 167.00 € 160.50 € 151.01 € 164.57 € 152.71

Persistent CompliantEnrolled

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Conclusions• The ASSET cohort shows a mean compliance rate to

statins’ treatment significantly lower than expected on the basis of previous pharmaco-epidemiological studies

• This is possibly due to the definition of compliance rate adopted

• The compliance rate observed in the ASSET cohort– provides a possible explanation to the disappointing

yield of the SSN investment on statins – raises the issue of moral hazard in the prevention of

cardiovascular risk– points out the policy implications for a sustainable

prevention of cardiovascular risk:• rational prescribing• reimbursement subject to compliance

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References[1] Agenzia Italiana del Farmaco AIFA. L’uso dei farmaci in Italia. OSMED reports 2000-

2004. Available online at: http://www.agenziafarmaco.it/aifa/servlet/section.ktml?target=&area_tematica=ATTIVITA_EDITORIALE&section_code=AIFA_PUB_RAP_OSMED&cache_session=true

[2] Favato G and Print C (2008). 2002 mortality rate for coronary heart disease in Italy: a statistical outlier or a sentinel event? Heart, Feb 27. Available online at: http://heart.bmj.com/cgi/eletters/94/2/178#8103

[3] Majeed A, Aylin P, Williams S, Bottle A, Jarman B (2004). Prescribing of lipid regulating drugs and admissions for myocardial infarction in England. BMJ, 2004 329:645, doi: 10.1136/bmj.329.7467.645

[4] Lucioni C, Mazzi S, Cerra C et al (2006), Uno studio di Drug Utilisation delle statine nella recente prassi terapeutica italiana. PharmacoEconomics-IRA. 8(1): 3-17

[5] Abraha I, Montedori A, et al (2003), Statin compliance in the Umbrian population. European Journal of Clinical Pharmacology. Vol. 59 Numbers 8-9.

[6] Poluzzi E, Strahinja P, Lanzoni M, Vargiu A, Silvani M C, Motola D, Gaddi A, Vaccheri A, Montanaro N (2007). Adherence to statin therapy and patients’ cardiovascular risk: a pharmacoepidemiological study in Italy. Eur J Clin Pharmacol

[7] Favato G, Mariani P, Mills RW, Capone A, Pelagatti M, et al. (2007) ASSET (Age/Sex Standardised Estimates of Treatment): A Research Model to Improve the Governance of Prescribing Funds in Italy. PLoS ONE 2(7): e592. doi:10.1371/journal.pone.0000592

[8] Larsen et al.(2002), High persistence of statin use in a Danish population: compliance study 1993-1998, British Journal of clinical Pharmacology, Vol 53, 4: 375-378