1 Ensuring adherence to prescribed oral anticoagulant intake Γεώργιος Σ. Γκουμάς MD, PhD, FESC Αν. Διευθυντής Καρδιολογικής Κλινικής, Ευρωκλινική Αθηνών
2 ΔΗΛΩΣΗ ΣΥΓΚΡΟΥΣΗΣ ΣΥΜΦΕΡΟΝΤΩΝ Τα προηγούμενα δύο χρόνια έχω λάβει τιμητικές αμοιβές ως σύμβουλος ή ομιλητής από τις ακόλουθες φαρμακευτικές εταιρείες: SANOFI, MENARINI, GALENICA, ASTRAZENECA, VIANEX, BAYER, LILLY, BOEHRINGER, ELPEN, NOVARTIS
3 Definition: Adherence and Persistence Start medication or observation Adherence Persistence The extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen Percentage of doses taken as prescribed Duration of time from initiation to discontinuation of therapy Days taking medication (without exceeding permissible gap) Stop medication or end observation Cramer JA et al. Value Health 2008;11(1):44 47
4 The Need for Anticoagulation in Stroke Prevention AF is a major risk factor for stroke, increasing an individual s risk of stroke ~fivefold 1 Anticoagulation treatment with VKAs or novel OACs prevents blood from clotting and effectively reduces the risk of stroke but is also associated with a risk of bleeding 2,3 Not all OACs are the same: 2 VKAs (e.g. warfarin): Require INR monitoring Have many drug and food interactions Have a long duration of effect Novel OACs (rivaroxaban, dabigatran, apixaban): Do not require routine coagulation monitoring Have fewer drug interactions than VKAs Have a shorter duration of effect than VKAs 1. Wolf PA et al. Stroke 1991;22(8): ; 2. Ageno W et al. Chest 2012;141(2):e44S e88s; 3. mm 1 AFA%20Atrial%20Fibrillation%20&%20Anticoagulation%20Report%20A4.pdf.
5 The Need for Anticoagulation in Stroke Prevention New oral anticoagulants have a very predictable anticoagulant effect. Monitoring of the anticoagulant effect is not required to guide therapy. However, the anticoagulant effect of NOACs fades rapidly h after the last intake. Therefore, strict therapy compliance by the patient is crucial. Physicians should develop ways to optimize compliance, which is known to be 80% for most drugs in daily practice.
6 Poor Adherence to Medication has Severe Consequences Several previous studies have evaluated the impact of medication non-adherence on health outcomes in patients with a history of CVD and have found non-adherence to be associated with poor health outcomes. Two observational studies that evaluated patients after acute myocardial infarction both found non-adherence to be associated with increased risk of adjusted 1-year mortality Jackevicius CA, et al. Circulation 2008;117: Ho PM, et al. Arch Intern Med 2006;166:1842-7
7 Poor Adherence to Medication has Severe Consequences Poor adherence accounts for substantial: Worsening of disease Death Increased healthcare costs In the USA, it has been estimated that 33 69% of all medication-related hospital admissions are due to poor medication adherence The resultant cost of non-compliance is approximately $100 billion/year Osterberg L and Blaschke T. N Engl J Med. 2005;353(5):
8 Why is Adherence to Anticoagulation Therapy Important? VKAs are only effective when the anticoagulation effect is kept within the therapeutic range Quality of VKA control (1990 June 2013)*: meta-analysis and meta-regression 2 61% ~40% of the time, patients are not within therapeutic range 25% 14% *Including randomized controlled trials, prospective cohort studies or retrospective analyses. Mearns ES et al. Thromb J. 2014;12:14 33
9 The Importance of Persistence and Adherence Fixed Dosing Regimen With Novel OACs Fixed dosing regimens with novel OACs are thought to increase adherence; reduced-dose regimens are indicated in certain patients EU approval Rivaroxaban 2 Apixaban 3 Dabigatran 4 Dose 20 mg OD 15 mg OD 5 mg BID 2.5 mg BID 150 mg BID 110 mg BID Dose adjustment 15 mg OD if CrCl ml/min 2.5 mg BID if two of the following criteria apply: age 80 years, weight 60 kg, or creatinine 133 μmol/l (1.5 mg/dl) 110 mg BID if age 80 years or age years with a risk factor for bleeding or receiving verapamil 1. Haynes RB. Cochrane Database Syst Rev. 2001;Issue 1; 2. Rivaroxaban SmPC ; 3. Apixaban SmPC; 4. Dabigatran SmPC.
10 Non-Adherence in NOAC Treatment Compliance and adherence to treatment is crucial, especially since these drugs have a relatively short half-life, such that patients would be left without any anticoagulation protection if more than one dose were missed
11 ROCKET AF: transitioning to open-label VKA R First dose of study drug Last dose of study drug Transition to open-label VKA Followup Rivaroxaban Stop rivaroxaban Suboptimal anticoagulation Start warfarin Warfarin Continue with warfarin Double-blind treatment period Post-treatment observation period R=randomization Study duration
12 ROCKET AF: Events after unblinding and transition to open label therapy 22 Events up to Day 30 6 Events up to Day 30 Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883 91
13 What is clearest from this important subanalysis of the ROCKET AF trial is that bad things will happen to high-risk AF patients if they are left untreated with effective anticoagulant therapy for sustained periods and that in a population as large as this one, it does not take much time for those events to begin to accumulate... Although the black box warning may seem to single out rivaroxaban unfairly in delivering this message, it at least serves as a reminder that interruptions and transitions with short-acting anticoagulant drugs must be planned and managed carefully.
15 Non-Adherence in VKA Treatment We know that in the VKA era Only half of all patients with AF who needed anticoagulation actually received it 50% of those patients stopped VKA therapy within 2 years because of side effects or bleeding complications. Of those who do continue VKA therapy, only 50% to 60% achieved values in the target range.
17 The overall 1-year proportion of days covered (PDC) was 83.9%, with 76.8% of patients having a 1-year PDC in excess of 80%. Patients with a CHA 2 DS 2 -VASc score 2 were more adherent to medication regimes than patients with a CHA 2 DS 2 -VASc score of 1 and generally patients with higher morbidity showed more adherence. This improvement may be attributable to more regular contact with the healthcare system. Patients with prior bleeding were not less adherent to medication regimes than patients with no prior bleeding
19 XANTUS: Prospective Design To collect real world data on adverse events in patients with NVAF treated with rivaroxaban to determine the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in routine clinical practice Primary outcomes: major bleeding (ISTH definition), allcause mortality, any other adverse events Population: Adult patients with NVAF receiving rivaroxaban for stroke/non CNS SE prevention N=6,784 Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly* 1 year Prospective, single arm, observational, non interventional phase IV study Statistical analyses were descriptive and exploratory in nature Final visit: 1 year # *Exact referral dates for follow up visits not defined (every 3 months recommended); # for rivaroxaban discontinuation 1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed 1. Camm AJ et al, Vasc Health Risk Manag 2014;10: ; 2. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466
20 XANTUS Study XANTUS is the first large, international prospective study to describe rivaroxaban use in a broad patient population with NVAF Patients at lower overall risk than in the phase III ROCKET AF trial Over 96% patients receiving rivaroxaban did not experience any of the outcomes of stroke/se, treatment-emergent major bleeding or all-cause death In XANTUS, rivaroxaban demonstrated low rates of stroke/se and major bleeding, including intracranial and GI bleeding Treatment persistence and patient satisfaction were high 80% of patients remained on rivaroxaban 75% reported they were satisfied with their treatment at 1 year 1. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466
21 Persistence with Rivaroxaban in NVAF Patients in Real life the Dresden NOAC Registry Prospective Dresden NOAC registry 1,204 AF patients treated with Rivaroxaban (39.3% switched from VKAs and 60.7% newly treated patients) Patient persistence (%) 81.5 Follow up: median 544 days Persistence rates were similar for newly treated Rivaroxaban patients and patients switched from VKA to Rivaroxaban with discontinuation rates of 14.1%/year and 12.7%/year, respectively Beyer Westendorf J et al. Europace 2015;17(4):
22 Rivaroxaban was associated with a significantly lower risk of treatment non-persistence (HR.0.66; 95% CI: , p ). Laliberte F et al, 2014
23 In Real Life AF Patients Stayed Longer on Rivaroxaban Than on Warfarin Two retrospective U.S. database analyses Matched sample included 3,654 Rivaroxaban and 14,616 Warfarin patients 1 Patient persistence (%) HR 0.66 (95% CI ) p< Rivaroxaban Warfarin 7,259 Rivaroxaban patients were matched 1:1 with Warfarin patients 2 Patient persistence (%) HR 0.63 (95% CI ) p<0.001 Rivaroxaban Warfarin Time to non-persistence (days) Time to non-persistence (days) Patients were significantly more persistent with Rivaroxaban than with Warfarin 1. Laliberté F et al. Curr Med Res Opin. 2014;30(7): ; 2. Nelson WW et al. Curr Med Res Opin. 2014;30(12):
24 The AEGEAN study Assessment of an education and guidance program for apixaban adherence in non-valvular atrial fibrillation The study found there was no additional value of the educational program on either outcome. At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89), and persistence rates were 90.5% and 91.1% respectively (P=0.76). Montalescot G. European Society of Cardiology 2015 Congress. Abstract 2191.
26 Effect of Adherence to OAC on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation Yao X. et al J Am Heart Assoc 2016 Fewer than half of patients with atrial fibrillation adhere to their anticoagulant regimen in a real clinical-practice setting, even if prescribed one of the new oral anticoagulants (NOACs) rather than a vitamin-k antagonist such as warfarin At the yearlong median follow-up, 47.5% of patients taking one of the NOACs had adhered to treatment for 80% or more of the study interval. That was modestly although significantly better than adherence among patients taking warfarin, in whom just 40.2% had 80% or more days covered by anticoagulation (P<0.001).
27 Effect of Adherence to OAC on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation Yao X. et al J Am Heart Assoc 2016 Among patients with CHA 2 DS 2 -VASc score 2, better adherence was associated with lower stroke risk and a relatively small increase in bleeding risk in particular, no significant increase in intracranial bleeding Among patients with CHA 2 DS 2 -VASc score 0 or 1, better adherence was associated with no significant change in the risk of stroke but an increased risk of bleeding
28 Comparing Adherence of Once-daily (OD) Versus Twice daily (BID) Dosing Regimens
29 OD Regimens Offer Better Adherence vs. BID Dosing Across Different Therapeutic Areas U.S. study of >1 million CV patients in 2007 Annual adherence rate (MPR) *OD vs. BID MPR=medication possession ratio: days for which medication was supplied/365 days Bae JP et al. Am J Manag Care 2012;18(3):
30 OD is Associated with Higher Adherence than BID: for Chronic CVD Medications Adherence (%) 6.9 ( 11.2, 2.6) p< ( 19.9, 8.1) p< ( 33.1, 12.7) p< Dosing frequency Less stringent Number of bottle cap openings divided by the prescribed number of doses Coleman CI et al. Curr Med Res Opin. 2012;28(5): Percentage of days with the appropriate number of doses taken Percentage of near optimal inter administration intervals More stringent
31 Patients Often Do Not Take BID Doses at Standard Intervals U.S. study including 464 patients who were asked how long they would wait between doses for BID medications There is evidence to suggest that with BID dosing, patients do not take their medication at regular intervals (e.g. 12 hours apart) For BID drugs, participants averaged 10.3 hours (SD ± 3.0 hours) between doses (morning to evening) Minimum interval = 1 hour Maximum interval = 18 hours Wolf MS et al. Arch Intern Med. 2011;171(4):
32 Higher Persistence with Rivaroxaban vs. Dabigatran in Patients with NVAF Retrospective U.S. database analysis 7,259 Rivaroxaban patients were matched 1:1 with Dabigatran patients Probability of persistence % 81% 70% 74% ahr 0.89 (95% CI ) p< % 64% Rivaroxaban Dabigatran Time to event (days) Use of Rivaroxaban led to higher rates of persistence compared to Dabigatran among patients with AF Nelson WW et al. Curr Med Res Opin 2015;doi: /
33 Persistence with Rivaroxaban vs. Dabigatran or Apixaban in NVAF Patients Retrospective U.S. database analysis Rivaroxaban vs. Dabigatran: p<0.001 Apixaban: p=0.076 Rivaroxaban vs. Dabigatran: p<0.001 Apixaban: p=0.037 Rivaroxaban (n=4,194) Dabigatran (n=5,489) Apixaban (n=265) Crivera C et al. Curr Med Res Opin 2015;doi: /
34 Dresden NOAC Registry: In Real Life AF Patients Stayed Longer on Rivaroxaban than on Dabigatran Two analyses of the prospective Dresden NOAC registry Treatment Discontinuation with Rivaroxaban and Dabigatran Discontinuation (%/yr) Median follow up: 544 days 1204 AF patients treated with rivaroxaban 1 Median follow up: 715 days 341 AF patients treated with dabigatran 2 Treatment discontinuation with Rivaroxaban was lower than discontinuation with Dabigatran (two different analyses from the same registry) 1. Beyer Westendorf J et al. Europace 2015;17(4): ; 2. Beyer Westendorf J et al. Thromb Haemost. 2015;113(6):
35 Simple Communication and Regimen Influences Adherence
36 Canadian Journal of Cardiology % of physicians spontaneously stated rivaroxaban as their preferred agent (vs. 25% apixaban) Patients prescribed and taking once daily medications (rivaroxaban or warfarin) showed better compliance with their OAC therapy (~30% of twice daily medications being taken once daily, with significantly more missed doses compared to once daily medications) and were less likely to consider stopping their OAC
37 One-Third of BID Prescribed Medications Were Being Taken OD Therapy adherence 1 Taking OAC OD Taking OAC BID
41 Non-Adherence in VKA Treatment Unfortunately, most patients know little about the disease and the risk of stroke. Making sure that patients understand the diagnosis is a major challenge. For many patients AF is just a chance finding. They are usually asymptomatic or, if they are symptomatic, may simply feel palpitations and complain about a bit of an irregular heartbeat or possibly exhaustion, but it doesn t feel life-threatening to them.
43 Non-Adherence in VKA Treatment Whether asymptomatic or symptomatic, patients with AF are usually completely unaware that their main risk is stroke. This has to be made clear from the beginning, because most of our treatment strategies will be directed toward stroke prevention. Patients will not follow the treatment plan unless they have a clear understanding of why it is so important to take anticoagulant therapy.
45 Non-Adherence in VKA Treatment The concept of a warfarin clinic is different from that of a typical general practice environment, and practically we don t have any in Greece. In countries like Italy, The Netherlands, and the United Kingdom, warfarin clinics are well established. Although warfarin clinics involve quite a setup where they are available, they have been shown to greatly improve patient quality of care and INR stability.
46 Warfarin Clinic in Greece
47 Forgetfulness is a Key Patient Barrier to Adherence and Can Be Overcome Barriers to adherence : Forgetfulness Other priorities Decision to quit dose Lack of information Lack of understanding Emotional reasons Complexity of treatment regimen Improving adherence: Emphasizing the value of taking the anticoagulant Using a simple regimen Adapting regimen to patient s lifestyle Providing the patient with channels of communication Regular follow-up visits Osterberg L and Blaschke T. N Engl J Med. 2005;353(5):
50 Ensuring compliance with NOAC intake A once daily (qd) dosing regimen was related to greater adherence vs. bid regimen in cardiovascular patients, and in AF patients (for diabetes and hypertension drugs) It is likely that also for NOACs a qd dosing regimen is best from a compliance perspective It is unknown whether any regimen is superior in guaranteeing the clinical thromboembolic preventive effects and the safety profile as seen in the clinical trials Europace 2013:15,
51 Ensuring compliance with NOAC intake Patient education on the importance of strict adherence is of outmost importance. Many simultaneous approaches should be employed in this regard: leaflets and instructions at initiation of therapy a patient anticoagulation card group sessions reeducation at every prescription renewal There is room and potentially a need to develop new tools to enhance compliance with NOACs. Family members should be involved in this education, so that they too understand the importance of adherence, and help the patient in this regard. Europace 2013:15,
52 Ensuring compliance with NOAC intake Although INR monitoring is not required, there should be a prespecified follow-up schedule between general practitioner, cardiologist, or electrophysiologist, and the responsibility of each concerning compliance should be clearly communicated. There is emerging interest in nurse-coordinated AF centres that may specifically focus on compliance issues during patient follow-up. Europace 2013:15,
53 Ensuring compliance with NOAC intake Some countries have a highly networked pharmacy database, which can help track the number of NOAC prescriptions that individual patients claim. In such countries, pharmacists could be involved in compliance monitoring. Europace 2013:15,
54 Ensuring compliance with NOAC intake Many technological aids are being explored to enhance compliance: the format of the blisters medication boxes (conventional or with electronic verification of intake) Smartphone applications, and/or SMS messages that alert the patient about the next intake Again, their long-term effects are unknown and one tool may not fit all patients. The prescribing physician, however, should consider individualization of these aids. Europace 2013:15,
55 Ensuring compliance with NOAC intake Some patients may prefer INR monitoring to no monitoring. This needs to be discussed with the patient before starting/converting to NOAC therapy. In some patients, there may be a preference for VKA treatment from this perspective. Europace 2013:15,
56 Ensuring compliance with NOAC intake In NOAC patients in whom low compliance is suspected despite proper education and additional tools, conversion to VKAs could be considered. Europace 2013:15,
58 Conclusions Strict adherence to any OAC therapy and long-term persistence is critical to avoid stroke and improve outcomes in patients with AF...medications benefit only those who are taking them...