Improvement of drug adherence using single pill combinations: what is the evidence? Prof. Michel Burnier Service of Nephrology and Hypertension, CHUV, Lausanne, Switzerland Potential causes of non-adherence Health system: Poor quality of provider-patient relationship Poor communication, lack of access to healthcare Lack of continuity of care Disease: Asymptomatic chronic disease, Mental health disorder Patient : Physical impairment, cognitive impairment Psychological/behavioral; younger age, race Therapy: Complexity of regimen, side-effects Socio-economic: 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 Number of medications 1.1 Number of pharmacies 1.1 1.0 1.0 Odds ratio 0.9 0.8 0.9 0.7 0.8 0.6 0.5 0.7 0.4 0.6 0.3 1-3 Monane et al, AJH, 1997 4-7 >8 1 >1 Long-term persistence by initially prescribed drug class 100 80 Patients’ 60 cumulative persistence 40 rate (%) ACE inhibitor CCB Beta blocker Diuretic 20 0 0 1 2 3 Time (yrs) N= 22,918 newly diagnosed hypertensive patients in Saskatchevan, Canada Caro et al CMAJ, 1999; 160:41-46 4 5 Persistence rates by antihypertensive class 100 * 80 Patients remainin g on therapy at 1 year (%) 64 58 60 50 43 40 38 20 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 NewJersey Quebec 80 Days Covered (%) 60 40 20 0 Cholest Niacin Gemfib Probuc Colest Clofib HMG CoA Compliance to the morning and evening dose of an AT1 receptor blocker in hypertensive patients 120 ** *** * ** 100 Compliance 80 to drug 60 ( %) 40 20 0 am pm am pm am pm am pm Losartan Losartan Irbesartan Irbesartan o.d. bid o.d. 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 US pharmacy benefit manager data (n=2,268) 100 Persistence (%) 90 80 68.7% 70 18.8%* 60 *p<0.05 57.8% 50 0 1 2 3 4 Lisinopril/HCTZ (single pill) Dezii. Manag Care 2000;9 (Suppl):S2–S6 5 6 7 Month 8 9 10 11 Lisinopril + diuretic (two pills) 12 Compliance with Fixed-dose Combination Amlodipine Besylate/Benazepril HCL Versus Component-based Therapy Medication possession ratio (MPR) US database analysis (n=5,732) 90 *p<0.001 * * 83.6 82.6 * 80.8 Age group * 77.9 80 72.1 * 73.8 * 71.3 71.9 * * 74.2 74.7 70 Overall 18–39 40–49 50–59 60–64 60 50 Amlodipine/Benazepril (single pill) (n=2,754) Taylor et al. CHF 2003;9:324–32 Component-based therapy (n=2,978) Fraction of patients on treatment Persistence to ACE Inhibitor/HCTZ Fixed-dose Combination Versus Free Combination Cohort study of general practice research data (n=755) 1.0 0.8 0.6 12%* 0.4 0.2 *p<0.001 0 0 2 4 6 8 10 12 14 16 18 20 24 Month since start of therapy Fixed dose combination therapy Sturkenboom. J Hypertens 2005;23 (Suppl 2):S326 Co-administration of two pills Patients fully compliant (%) Percentage of Patients Fully Compliant with ACE Inhibitor/HCTZ Fixed-dose Combination Versus Free Combination Cohort study of general practice research data (n=755) 100 80 60 21% 40 17% 20 0 0 3 6 9 12 15 18 Months since start of therapy Fixed-dose combination therapy 21 24 27 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 AM/AT FD: Amlodipine/atorvastatin (fixed-dose) AM+AT FC: Amlodipine plus atorvastatin (free) OC+OS FC: Other CCB plus other statin (free) 70 Patients compliant (%) 60 50 40 30 20 10 0 AM/AT FD Patel et al. J Hypertens 2006;24(Suppl 6):S65 AM+AT FC OC+OS FC Compliance to the morning and evening dose of an AT1 receptor blocker in hypertensive patients 120 ** *** * ** 100 Compliance 80 to drug 60 ( %) 40 20 0 am pm am pm am pm am pm Losartan Losartan Irbesartan Irbesartan o.d. bid o.d. bid Würzner et al, J Hypertens, 2001 A 2nd 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 3rd 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 Directly observed therapy Electronic monitoring Pill count Prescription record review Adherence questionnaire Drug measurement in body fluids Biomarker measurement in body fluids Patient diary Invasive methods Patient interview Less accurate Precision of the method Effect of home blood pressure monitoring on compliance to antihypertensive therapy Vrijens, 1997 7.0 Home BP measurements n = 66 6.8 Number of pills per week 6.6 6.4 6.2 No measurements (n= 61) 6.0 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 1.30 2.5 2.0 Odds ratio 1.20 1.5 1.10 1.0 0.5 1.00 0.0 1-3 4-7 >8 No Yes Persistence with antihypertensive agents 100 AIIRAs* ACE inhibitors CCBs Beta blockers Diuretics Combination Other 80 Patients 60 persistent with 40 therapy (%) 20 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 1 Drug A Drug B Drug A 2 Patient number Drug B 3 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 On-treatment Changes in BP (mmHg) After 2 missed doses 0 0 -2 -2 -4 -4 -6 -6 -8 -8 -10 -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-ratea for aliskiren, irbesartan and ramipril Antihypertensive agent Mean office SBP- Off-rate,a mmHg/day lowering effect, mmHg Aliskiren 300 mg −14.1 1.0 Irbesartan 300 mg −13.3 3.6 Ramipril 10 mg −10.1 4.0 aRate 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 Missed Doses Blood Pressure Ttt 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.