Improvement of drug adherence using single pill combinations:

Improvement of drug adherence using single pill combinations: what is the evidence? Prof. Michel Burnier Service of Nephrology and Hypertension, CHUV, Lausanne, Switzerland

Potentialcauses of non-adherence Health system: Disease: Patient : Therapy: Socio-economic: Poor quality of provider-patient relationship Poor communication, lack of access to healthcare Lack of continuity of care Asymptomatic chronic disease, Mental health disorder Physical impairment, cognitive impairment Psychological/behavioral; younger age, race Complexity of regimen, side-effects Low literacy; higher medication costs Poor social support

FDC in Disease Management Patients require multiple medications to reach targets Single pill combinations offer some advantages: Efficacy Adherence Cost Convenience Patient-perceived wellness Side effects

Question In all reviews, single-pill combinations are mentionned as potential tools to improve drug adherence. What is the evidence for this assumption? What is the importance of the effect?

What is known!

Compliance rates by dosing frequency 100 80 Percent Compliance 60 40 20 0 n = 7-11 studies QD BID TID QID P.Ruud, AHJ, 1995

Number of comedications and pharmacies used as factors related to compliance Odds ratio 1.1 1.0 0.9 0.8 0.7 Number of medications 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Number of pharmacies 0.6 Monane et al, AJH, 1997 1-3 4-7 >8 0.3 1 >1

Long-term persistence by initially prescribed drug class 100 80 Patients cumulative persistence rate (%) 60 40 20 ACE inhibitor CCB Beta blocker Diuretic 0 0 1 2 3 4 5 Time (yrs) N= 22,918 newly diagnosed hypertensive patients in Saskatchevan, Canada Caro et al CMAJ, 1999; 160:41-46

Persistence rates by antihypertensive class 100 Patients remainin g on therapy at 1 year (%) 80 60 40 20 64 * 58 50 43 38 0 AIIRAs ACE inhibitors CCBs Beta blockers Diuretic Bloom S. Clin Ther 1998, 20:671-681

One year persistence of use of lipid-lowering medications in USA and Canada Avorn et al, JAMA, 1998 100 80 NewJersey Quebec Days Covered (%) 60 40 20 0 Cholest Niacin Gemfib Probuc Colest Clofib HMG CoA

Compliance to the morning and evening dose of an AT 1 receptor blocker in hypertensive patients 120 100 ** *** * ** Compliance to drug ( %) 80 60 40 20 0 am pm am pm am pm am pm Losartan o.d. Losartan bid Irbesartan o.d. Irbesartan bid Würzner et al, J Hypertens, 2001

Drug adherence varies during the week and during the day Vrijens, B. et al. BMJ 2008;336:1114-1117

Better Persistence of Treatment in Established Hypertensive Patients Caro et al, Can J Med Assoc. 1999; 160:31

The studies! The first studies assessing the potential benefits of single-pill combinations have been performed in the fields of: infectious diseases (Tbc, HIV, malaria ) hypertension diabetes

Connor et al, Bulletin of WHO, 2003

Persistence to Lisinopril/HCTZ Fixed-dose Combination Versus Free Combination Persisten nce (%) 100 90 80 70 60 50 *p<0.05 US pharmacy benefit manager data (n=2,268) 0 1 2 3 4 5 6 7 8 9 10 11 12 Month Lisinopril/HCTZ (single pill) Lisinopril + diuretic (two pills) 68.7% 18.8%* 57.8% Dezii. Manag Care 2000;9 (Suppl):S2 S6

Compliance with Fixed-dose Combination Amlodipine Besylate/Benazepril HCL Versus Component-based Therapy Medication possession ra atio (MPR) 90 80 70 60 50 US database analysis (n=5,732) 82.6 83.6 * * * 80.8 * 77.9 * * * 73.8 * 74.2 74.7 72.1 71.3 71.9 Amlodipine/Benazepril (single pill) Component-based therapy (n=2,754) (n=2,978) *p<0.001 Age group Overall 18 39 40 49 50 59 60 64 Taylor et al. CHF 2003;9:324 32

Persistence to ACE Inhibitor/HCTZ Fixed-dose Combination Versus Free Combination ients on treatment Fraction of pati 1.0 0.8 0.6 0.4 0.2 0 Cohort study of general practice research data (n=755) *p<0.001 0 2 4 6 8 10 12 14 16 18 20 24 Month since start of therapy Fixed dose combination therapy Co-administration of two pills 12%* Sturkenboom. J Hypertens 2005;23 (Suppl 2):S326

Percentage of Patients Fully Compliant with ACE Inhibitor/HCTZ Fixed-dose Combination Versus Free Combination Patients fu ully compliant (%) 100 80 60 40 20 0 Cohort study of general practice research data (n=755) 21% 17% 0 3 6 9 12 15 18 21 24 27 Months since start of therapy Fixed-dose combination therapy Co-administration of two pills Patients on free combination had a higher odds ratio (OR) of being non-compliant than patients on fixed-dose combination OR 2.09 (95% CI, 1.69 2.59) Sturkenboom. J Hypertens 2005;23(Suppl 2):S326

Compliance with Amlodipine/atorvastatin Fixeddose Combination versus Free-Combination in Patients on Multiple Therapies for CV Risk 70 60 AM/AT FD: Amlodipine/atorvastatin (fixed-dose) AM+AT FC: Amlodipine plus atorvastatin (free) OC+OS FC: Other CCB plus other statin (free) Patients compliant (%) 50 40 30 20 10 0 AM/AT FD AM+AT FC OC+OS FC Patel et al. J Hypertens 2006;24(Suppl 6):S65

Compliance to the morning and evening dose of an AT 1 receptor blocker in hypertensive patients 120 100 ** *** * ** Compliance to drug ( %) 80 60 40 20 0 am pm am pm am pm am pm Losartan o.d. Losartan bid Irbesartan o.d. Irbesartan bid Würzner et al, J Hypertens, 2001

A 2 nd meta-analysis : characteristics of the studies Bangalore et al, Am J Med, 2007

Fixed doses combinations improve persistence! Bangalore et al, Am J Med, 2007

Fixed doses combinations in randomized controlled studies Bangalore et al, Am J Med, 2007

Fixed doses combinations in hypertension studies Bangalore et al, Am J Med, 2007

A 3 rd meta-analysis: Systolic and diastolic BP reduction with use of an FDC as compared with its free-drug combination Gupta, A. K. et al. Hypertension 2010;55:399-407

Adverse effects associated with the use of an FDC as compared with its free-drug combination Gupta, A. K. et al. Hypertension 2010;55:399-407

What are the limitations of actual studies on FDC? Many studies are retrospective Studies are often too small and do not have enough power The definition of drug adherence is variable and most studies investigated persistence to therapy Most studies are of short duration (6 months) Most studies do not assessed any clinical endpoint Confounding factors are not taken into account

Methods to measure drug adherence Non-invasive methods Electronic monitoring Directly observed therapy Patient interview Patient diary Adherence questionnaire Prescription record review Pill count Drug measurement in body fluids Biomarker measurement in body fluids Invasive methods Less accurate Precision of the method

Effect of home blood pressure monitoring on compliance to antihypertensive therapy 7.0 Vrijens, 1997 6.8 Home BP measurements n = 66 Number of pills per week 6.6 6.4 6.2 6.0 No measurements (n= 61) 0 1 2 3 4 5 6 weeks

Physician visits and comorbid cardiac disease as factors related to compliance Number of visits Presence of CHF or CAD 3.0 2.5 1.30 Odds ratio 2.0 1.5 1.0 1.20 1.10 0.5 0.0 1.00 1-3 4-7 >8 No Yes

Persistence with antihypertensive agents 100 80 Patients 60 persistent with 40 therapy (%) 20 AIIRAs* ACE inhibitors CCBs Beta blockers Diuretics Combination Other 0 6 12 18 24 Time (months) Database from Saskatchewan, Canada. Regimen is initially prescribed class filled between 1/1/95 and 1/9/98. *P<0.001 AIIRAs vs all other classes combined at all time points. Chaput AJ. Can J Cardiol. 2000;16(suppl F):194F.

During multiple drug therapies, is non-adherence homogenous with all drugs?

A clinical example FDC

One year monitoring of compliance in hypertensive patients Compliance (%) 110 100 90 80 70 60 50 Drug A Drug B Drug A Drug B Drug A Drug B 1 2 3 Patient number

The consequences of non-adherence with drug therapy "Rebound" hypertension (e.g., beta blocker stopped suddenly) increases MI risk acutely and perhaps the CV risk. Direct costs to healthcare system Wasted pills (purchased, not taken) "Wasted" doctor visits (advice not taken) Opportunity ("Indirect") costs Tradeoff between not avoiding clinical events and averting the need to treat uncomplicated hypertension

Drug adherence is a very irregular and dynamic process. Arrows indicate days on which medication was not taken Vrijens, B. et al. BMJ 2008;336:1114-1117

Variability of BP during visits and cardiovascular risk Rothwell et al, Lancet 2010

Hazard ratios for risks of stroke and acute coronary events in ASCOT-BPLA patients according to BP variability within visits

Effects of 2 missed doses on blood pressure control 0-2 -4 On-treatment After 2 missed doses 0-2 -4 Changes in BP (mmhg) -6-8 -10-6 -8-10 * -12-12 -14-14 -16-16 -18-18 Diltiazem Amlodipine Diltiazem Amlodipine Leenen et al, 1996

Predicted mean SBP reduction with aliskiren, irbesartan or ramipril for different levels of adherence Palatini et al, J Hum Hypertens 2010, and Burnier et al, submitted

Mean office SBP-lowering effect and off-rate a for aliskiren, irbesartan and ramipril Antihypertensive agent Mean office SBPlowering effect, mmhg Off-rate, a mmhg/day Aliskiren 300 mg 14.1 1.0 Irbesartan 300 mg 13.3 3.6 Ramipril 10 mg 10.1 4.0 a Rate of loss of antihypertensive effect when treatment is stopped. SBP, systolic blood pressure Burnier et al, submitted

Predicted reduction in absolute CVD risk, event for aliskiren, irbesartan or ramipril at different adherence levels 100 90 80 70 60 50 Level of adherence (%) Burnier et al, submitted

Impact of missed doses of single pill combinations Blood Pressure Ttt Missed Doses Rebound? Short acting drug Long acting drug Single-pill combin. Time

Conclusions 1. The evidence that single pill combinations improve drug adherence are relatively weak and the improvement appears to be small. 2. The impact of single pill combinations on clinical endpoints remains to be demonstrated 3. Methodologically adequate prospective studies need to be carried out.