A meta-analysis of the association between adherence to drug therapy and mortality
Open accessAbstract
OBJECTIVE: To evaluate the relation between adherence to drug therapy, including placebo, and mortality. DESIGN: Meta-analysis of observational studies. DATA SOURCES: Electronic databases, contact with investigators, and textbooks and reviews on adherence. Review methods Predefined criteria were used to select studies reporting mortality among participants with good and poor adherence to drug therapy. Data were extracted for disease, drug therapy groups, methods for measurement of adherence rate, definition for good adherence, and mortality. RESULTS: Data were available from 21 studies (46,847 participants), including eight studies with placebo arms (19,633 participants). Compared with poor adherence, good adherence was associated with lower mortality (odds ratio 0.56, 95% confidence interval 0.50 to 0.63). Good adherence to placebo was associated with lower mortality (0.56, 0.43 to 0.74), as was good adherence to beneficial drug therapy (0.55, 0.49 to 0.62). Good adherence to harmful drug therapy was associated with increased mortality (2.90, 1.04 to 8.11). CONCLUSION: Good adherence to drug therapy is associated with positive health outcomes. Moreover, the observed association between good adherence to placebo and mortality supports the existence of the "healthy adherer" effect, whereby adherence to drug therapy may be a surrogate marker for overall healthy behaviour.
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As adherence with placebo also improves survival, adherence to medication may reflect generally better health behaviour.
“In addition, as adherence with placebo also improves survival, 524 physicians should be aware that adherence to medication may reflect generally better health behaviour.”
From European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) (2012) · cites this paper as [524]
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Krogsbøll, L. T., Jørgensen, K. J., Grønhøj, C., & Gøtzsche, P. C. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009009.pub2 · Cited by 288 · see citing works
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Health Psychology: The Search for Pathways between Behavior and Health
Leventhal, H., Weinman, J. A., Leventhal, E. A., & Phillips, L. A. (2007) · Annual Review of Psychology · doi:10.1146/annurev.psych.59.103006.093643 · Cited by 276 · see citing works
Lima, V. D., Geller, J., Bangsberg, D. R., Patterson, T. L., Daniel, M., Kerr, T. H., Montaner, J. S. G., & Hogg, R. S. (2007) · AIDS · doi:10.1097/qad.0b013e32811ebf57 · Cited by 274 · see citing works
“Depressive symptoms may impact survival and disease progression through biologic factors mediated through CD4þ Tand CD8þ T cells [4,6,8], CD56þ and CD16þ natural killer (NK) cells [14,15] or through health-related behaviors, since it has been shown that patients presenting depressive symptoms are more likely to have a…”
BackgroundImpact of Osteoporosis Treatment Adherence on Fracture Rates in North America and Europe
Siris, E. S., Selby, P. L., Saag, K. G., Borgström, F., Herings, R. M. C., & Silverman, S. L. (2009) · The American Journal of Medicine · doi:10.1016/j.amjmed.2008.12.002 · Cited by 275 · see citing works
Medication Adherence in Cardiovascular Disease
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Walsh, C. A., Cahir, C., Tecklenborg, S., Byrne, C. J., Culbertson, M. A., & Bennett, K. (2019) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14075 · Cited by 273 · see citing works
“unmeasured confounding bias from this healthy adherer effect, due to lack of information in administrative databases, such as smoking status, body mass index etc.(97) It has previously been suggested that use of a new user study design would assist in reducing this confounding, along with adjustment for adherence to m…”
BackgroundMajumdar, S. R., McAlister, F. A., Eurich, D. T., Padwal, R. S., & Marrie, T. J. (2006) · BMJ · doi:10.1136/bmj.38992.565972.7c · Cited by 270 · see citing works
Self-citationCompliance, concordance, adherence
Aronson, J. K. (2007) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2007.02893.x · Cited by 261 · see citing works
Short- and Long-Term Blood Pressure Variability
Mancia, G. (2012) · Hypertension · doi:10.1161/hypertensionaha.112.194340 · Cited by 258 · see citing works
The Placebo Effect: Illness and Interpersonal Healing
Miller, F. G., Colloca, L., & Kaptchuk, T. J. (2009) · Perspectives in biology and medicine · doi:10.1353/pbm.0.0115 · Cited by 254 · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript Some randomized trials have detected an association between compliance with placebo interventions in randomized trials and outcomes such as mortality (Simpson et al. 2006).”
BackgroundHo, P. M., Peterson, P. N., & Masoudi, F. A. (2008) · Circulation · doi:10.1161/circulationaha.107.721357 · Cited by 251 · see citing works
Statin Adherence and Risk of Accidents
Dormuth, C. R., Patrick, A. R., Shrank, W. H., Wright, J. M., Glynn, R. J., Sutherland, J., & Brookhart, M. A. (2009) · Circulation · doi:10.1161/circulationaha.108.824151 · Cited by 245 · see citing works
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Placebo effects: clinical aspects and neurobiology
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Impact of adherence to antihypertensive agents on clinical outcomes and hospitalization costs
Dragomir, A., Côté, R., Roy, L., Blais, L., Lalonde, L., Bérard, A., & Perreault, S. (2010) · Medical Care · doi:10.1097/mlr.0b013e3181d567bd · Cited by 221 · see citing works
“The observed relation between good adherence to placebo and mortality supports the importance of the healthy adherer effect, where adherence to medication may be a marker of overall healthy behavior.(37) However, based on the differential class effects of drug adherence on long-term survival, it FIGURE 1.”
BackgroundAssociation between adherence to pharmacotherapy and outcomes in type 2 diabetes: a meta-analysis
Khunti, K., Seidu, S., Kunutsor, S., & Davies, M. (2017) · Diabetes Care · doi:10.2337/dc16-1925 · Cited by 231 · see citing works
“First, our analyses update and extend those of a report examining the association between adherence to drug therapy and mortality across a range of conditions, including HIV, myocardial infarction, heart failure, and hyperlipidemia (19).”
BackgroundMethodResultInfluentialMeasuring, Analyzing, and Managing Drug Adherence in Resistant Hypertension
Burnier, M., Wuerzner, G., Struijker-Boudier, H., & Urquhart, J. (2013) · Hypertension · doi:10.1161/hypertensionaha.113.00687 · Cited by 229 · see citing works
Authors/Task Force Members: Joep Perk (Chairperson) (Sweden)*, G. D. B. (. (2012) · European Journal of Preventive Cardiology · doi:10.1177/2047487312450228 · Cited by 863 · see citing works
Obstructive Sleep Apnea and Cardiovascular Disease
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Clinical decision-making: Patients’ preferences and experiences
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“These process outcomes are desirable both for their own sake and because shared decision-making enhances patients’ adherence to treatment [48] and involvement in their own health care [7], and hence potentially may lead to better health outcomes [49,50].”
BackgroundConn, V. S., Ruppar, T. M., Chase, J. D., Enriquez, M., & Cooper, P. S. (2015) · Current Hypertension Reports · doi:10.1007/s11906-015-0606-5 · Cited by 227 · see citing works
Diabetes knowledge, medication adherence and glycemic control among patients with type 2 diabetes
Al-Qazaz, H., Sulaiman, S. A. S., Hassali, M. A., Shafie, A. A., Sundram, S., Al-Nuri, R., & Saleem, F. (2011) · International Journal of Clinical Pharmacy · doi:10.1007/s11096-011-9582-2 · Cited by 226 · see citing works
“Positive health outcomes and lower mortality among patients with diabetes have been associated with good adherence compared with those patients with poor adherence [16–18].”
ResultAntipsychotic treatment and mortality in schizophrenia.
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Foley, L., Larkin, J., Lombard-Vance, R., Murphy, A. W., Hynes, L., Galvin, E., & Molloy, G. J. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-044987 · Cited by 210 · see citing works
General health checks in adults for reducing morbidity and mortality from disease
Krogsbøll, L. T., Jørgensen, K. J., & Gøtzsche, P. C. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009009.pub3 · Cited by 217 · see citing works
Reminder packaging for improving adherence to self-administered long-term medications
Mahtani, K. R., Heneghan, C. J., Glasziou, P., & Perera, R. (2011) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005025.pub3 · Cited by 201 · see citing works
Development of an illustrated medication schedule as a low-literacy patient education tool
Kripalani, S. B., Robertson, R., Love-Ghaffari, M. H., Henderson, L. E., Praska, J. L., Strawder, A., Katz, M. G., & Jacobson, T. A. (2007) · Patient Education and Counseling · doi:10.1016/j.pec.2007.01.020 · Cited by 199 · see citing works
“Nonadherence has also been linked to significantly higher health care costs, hospitalization, and patient mortality [7,8].”
BackgroundSussman, J. B., & Hayward, R. A. (2010) · BMJ · doi:10.1136/bmj.c2073 · Cited by 197 · see citing works
“In as treated analyses, participants are analysed entirely on the basis of treatment received (that is, according to their behaviour, not their random assignment). In per protocol analyses, participants who fail to follow the protocol are simply dropped from the study (that is, included or excluded according to their…”
The Association Between Statins and Cancer Incidence in a Veterans Population
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Adherence influencing factors – a systematic review of systematic reviews
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“Adherence is not only a crucial point for the success, but also for the safe and effective use of many therapies [4-6].”
BackgroundGislason, G., Rasmussen, J. N., Abildstrom, S. Z., Schramm, T. K., Hansen, M. L., Buch, P., Sørensen, R., Folke, F., Gadsbøll, N., Rasmussen, S., et al. (2007) · Circulation · doi:10.1161/circulationaha.106.669101 · Cited by 182 · see citing works
Bissonnette, J. M. (2008) · Journal of Advanced Nursing · doi:10.1111/j.1365-2648.2008.04745.x · Cited by 172 · see citing works
“Patient-related consequences include improved morbidity and reduced mortality, conflict resolution, attributional uncertainty, empowerment and possible improvements in quality of life (Buchmann 1997, Wilson et al. 2002, Simpson et al. 2006).”
BackgroundInfluentialVerbrugghe, M., Verhaeghe, S., Lauwaert, K., Beeckman, D., & Van Hecke, A. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2012.12.014 · Cited by 202 · see citing works
Elliott, R. A., Barber, N., Clifford, S., Horne, R., & Hartley, E. (2007) · Pharmacy World & Science · doi:10.1007/s11096-007-9134-y · Cited by 175 · see citing works
“Potential consequences of nonadherence are health benefits forgone[6] and personal and R.”
An introduction to instrumental variable assumptions, validation and estimation
Lousdal, M. L. (2018) · Emerging Themes in Epidemiology · doi:10.1186/s12982-018-0069-7 · Cited by 173 · see citing works
“This type of confounding has been investigated within the fields of oral contraceptives, postmenopausal hormone therapy, statins and influenza vaccines and termed “compliance bias” [6], “prevention bias” [7], “healthy adherer effect” [8] and “healthy user effect/bias” [9].”
BackgroundBeliefs about medicines and self-reported adherence among pharmacy clients
MÅRDBY, A.-C. M., Åkerlind, I., & Jörgensen, T. (2007) · Patient Education and Counseling · doi:10.1016/j.pec.2007.08.011 · Cited by 173 · see citing works
“Medication-related problems caused by non-adherence can lead to unnecessary suffering, hospitalization [2] and mortality [3], resulting in decreased quality of life and increased costs for both the individual and society as a whole [2].”
BackgroundJohnston, N., Bodegård, J., Jerström, S., Åkesson, J., Brorsson, H., Alfredsson, J., Albertsson, P., Karlsson, J., & Varenhorst, C. (2016) · American Heart Journal · doi:10.1016/j.ahj.2016.05.005 · Cited by 174 · see citing works
Sedjo, R. L., & Devine, S. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-0952-6 · Cited by 169 · see citing works
“Adherence to long-term medication therapy for a chronic disease state is pivotal for optimal clinical outcomes [8, 9 ]. As reviewed by Chlebowski and Geller [10], only a few studies have focused on adherence to oral adjuvant endocrine therapy among women with breast cancer in clinical practice.”
BackgroundMethodHealth Literacy, Cognitive Ability, and Functional Health Status among Older Adults
Serper, M., Patzer, R. E., Curtis, L. M., Smith, S. G., O’Conor, R. M., Baker, D. W., & Wolf, M. S. (2014) · Health Services Research · doi:10.1111/1475-6773.12154 · Cited by 169 · see citing works
Wright, D. E., Poon, L. C., Rolnik, D. L., Syngelaki, A., Delgado⋈, J. L., Vojtassakova, D., de Alvarado, M., Kapeti, E., Rehal, A., Pazos, A., et al. (2017) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.08.110 · Cited by 172 · see citing works
Supporting Adherence to Medicines for Long-Term Conditions
Horne, R., Cooper, V., Wileman, V., & Chan, A. H. Y. (2019) · European Psychologist · doi:10.1027/1016-9040/a000353 · Cited by 170 · see citing works
“Chronic Illness: The Need for More Effective Interventions The prescription of a medicine is one of the most common interventions in developed health economies (Kantor, Rehm, Haas, Chan, & Giovannucci, 2015) and is essential to the treatment of most chronic illnesses (Simpson et al., 2006).”
BackgroundF. Piepoli, M. (2017) · International Journal of Behavioral Medicine · doi:10.1007/s12529-016-9583-6 · Cited by 162 · see citing works
“Adherence to medication in individuals at high risk and in pa-tients with CVD is low, resulting in worse outcomes and higher health care costs [487].”
New Prescription Medication Gaps: A Comprehensive Measure of Adherence to New Prescriptions
Karter, A. J., Parker, M. M., Moffet, H. H., Ahmed, A. T., Schmittdiel, J. A., & Selby, J. V. (2009) · Health Services Research · doi:10.1111/j.1475-6773.2009.00989.x · Cited by 166 · see citing works
“…been associated with poorer glycemic, blood pressure, and lipid control (Morris et al. 1997; Ho et al. 2006a), higher rates of acute metabolic events (Morris et al. 1997), and increased risk of hospitalization and mortality (Ho et al. 2006a, b; Simpson et al. 2006; Jackevicius, Li, and Tu 2008).”
BackgroundBrundisini, F. K., Vanstone, M. G., Hulan, D., DeJean, D., & Giacomini, M. K. (2015) · BMC Health Services Research · doi:10.1186/s12913-015-1174-8 · Cited by 167 · see citing works
“clinical care of Type 2 diabetes because it directly contributes to the effectiveness of patients’ treatment and wellbeing [1, 2].”
Backgroundvon Seidlein, L., Peto, T. J., Landier, J., Nguyen, T.-N., Tripura, R., Phommasone, K., Pongvongsa, T., Lwin, K. M., Keereecharoen, L., Kajeechiwa, L., et al. (2019) · PLoS Medicine · doi:10.1371/journal.pmed.1002745 · Cited by 159 · see citing works
“Some of the observed higher impact in people who adhered to the complete 3 rounds of MDA compared to people who took part in none or fewer than 3 rounds could be due to the people adhering to the 3 rounds being healthier than the people who did not adhere [66,67].”
BackgroundMedication nonadherence: health impact, prevalence, correlates and interventions
Stewart, S.-J., Moon, Z., & Horne, R. (2022) · Psychology and Health · doi:10.1080/08870446.2022.2144923 · Cited by 180 · see citing works
“…World Health organisation (WHo) estimated that around half of medicines prescribed for long-term conditions were not taken as advised (Sabaté, 2003; Simpson et al., 2006), and a 2018 report from the organisation for economic Co-operation and Development estimated that poor adherence results in…”
BackgroundTommelein, E., Mehuys, E., Hees, T. J. V., Adriaens, E., Bortel, L. M. V., Christiaens, T. C., Tongelen, I. V., Remon, J., Boussery, K., & Brusselle, G. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12242 · Cited by 157 · see citing works
Wampold, B. E., & Budge, S. L. (2012) · The Counseling Psychologist · doi:10.1177/0011000011432709 · Cited by 157 · see citing works
Parekh, N., Ali, K., Stevenson, J. M., Davies, G., Schiff, R., van der Cammen, T. J. M., Harchowal, J., Raftery, J. P., Rajkumar, C., & on behalf of the PRIME study group (2018) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13613 · Cited by 154 · see citing works
Why are we failing to implement effective therapies in cardiovascular disease?
Nieuwlaat, R., Schwalm, J.-D., Khatib, R., & Yusuf, S. (2013) · European Heart Journal · doi:10.1093/eurheartj/ehs481 · Cited by 152 · see citing works
- Authors
- Simpson, S. H., Eurich, D. T., Majumdar, S. R., Padwal, R. S., Tsuyuki, R. T., Varney, J., & Johnson, J. A.
- Affiliations
- University of Alberta (CA)
- Institute of Health Economics (CA)
- Corresponding author
- Simpson, Scot H
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2006-06-21
- Volume
- 333
- Issue
- 7557
- Pages
- 15
- ISSN
- 0007-1447 (ISSN-L)
- 0959-8138
- 1468-5833
- PMC
- PMC1488752
- OpenAlex
- W2147982456
- Cited by
- 1,353
- References
- 39
- Citations by year
- 2026: 37 · 2025: 40 · 2024: 57 · 2023: 56 · 2022: 55 · 2021: 83 · 2020: 55 · 2019: 74 · 2018: 90 · 2017: 91 · 2016: 69 · 2015: 71 · 2014: 83 · 2013: 77 · 2012: 86
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- BMJ (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Family Practice › Medication Adherence and Compliance
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacy and Medical Practices
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Keywords
- medication adherence, pharmacotherapy, mortality, adherence measurement methods
- MeSH terms
- Drug Therapy, Epidemiologic Methods, Humans, Patient Compliance, Prognosis, Randomized Controlled Trials as Topic
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