Epidemiological strategies for adapting clinical practice guidelines to the needs of multimorbid patients
© Blozik et al.; licensee BioMed Central Ltd. 2013
Received: 26 October 2012
Accepted: 27 August 2013
Published: 16 September 2013
Clinical practice guidelines have been developed to improve the quality of health care. However, adherence to current monomorbidity-focused, mono-disciplinary guidelines may result in undesirable effects for persons with several comorbidities, in adverse interactions between drugs and diseases, conflicting management strategies, and polypharmacy. This is why new types of guidelines that address the problem of interacting medical interventions and conditions in multimorbid patients are needed.
Previous research projects investigated patterns of multimorbidity and were able to identify combinations of the most prevalent chronic conditions, or clusters of comorbidities. These results represent potential methodological starting points for the development of guidelines that account for multimorbidity. The objective of these efforts is to identify frequent reasons for interactions and adverse events that may occur when the current type of guideline is rigorously applied in multimorbid patients.
The epidemiologic approaches described above may help guideline developers as a kind of check list of disease combinations that should systematically be considered during guideline development. Given the risk of worse outcomes in a huge group of vulnerable patients, researchers, guideline developers, and funding institutions should give first priority to the development of guidelines more appropriate for use in multimorbid persons.
KeywordsClinical practice guideline Multimorbidity Chronic conditions
The patients encountered in general practice, particularly those with multimorbidity, present a combination of interacting problems, which make adherence to clinical practice guidelines (CPG) and clinical decision making very difficult when recommendations cumulate across several conditions . Nine out of ten patients seen in general practice have more than one chronic condition [2, 3]. In 2005, Cynthia Boyd and colleagues illustrated the limitations of the current type of CPGs. They aggregated recommendations from relevant clinical guidelines for a hypothetical case of a 79-year-old multimorbid woman and ended up with 12 medications, prescribed in 19 partial doses, and a complicated nonpharmacological regimen . This hypothetical case shows that the current way of designing CPGs is even associated with undesirable effects for persons with several comorbidities, and that adverse interactions between drugs and diseases, conflicting management strategies, and polypharmacy might result . Polypharmacy exponentially increases the risk of experiencing adverse drug-drug or drug-disease interactions and is associated with adverse health outcomes such as mortality, hospitalisation, poor adherence, and geriatric syndromes (e.g. urinary incontinence, cognitive impairment, falls) [6–8].
Since the publication of Boyd’s study, it is widely acknowledged that elder persons and their health problems are not adequately addressed in current mainly mono-morbidity-focused and mono-disciplinary CPGs [5, 9, 10]. Various publications came to the conclusion that most CPGs do not provide guidance on the management of patients with comorbidities, especially for discordant combinations,  and it has been claimed repeatedly that CPGs should become explicit about the applicability of their recommendations to multimorbid patients [12–14]. Recently, Guthrie and colleagues suggested three strategies for adaptation of CPGs to take account of multimorbidity: 1) cross-referencing between CPGs using electronic delivery, 2) providing the suspected magnitude of benefits and harms of medical interventions recommended in CPGs, and 3) better using the existing evidence, e.g. by modeling the effects comorbidities may have on benefits and harms of treatments . Although these adaptations are necessary, we do not consider them to be sufficient. For example, mere cross-referencing between CPGs would become hardly manageable in the presence of more than one comorbidity. The development of new CPGs that include multimorbidity-specific information is desirable. This article presents potential methodological starting points for identifying relevant comorbidities that should be taken into account during CPG development.
Starting from epidemiologic data on prevalence of comorbidities
Given the fact that there are an almost indefinite number of possible disease combinations,  we suggest focusing on the most prevalent combinations of chronic conditions in multimorbid patients. The underlying assumption is that this would help to identify a large part of discrepant management strategies and interactions between treatments and conditions.
Epidemiologic data from previous studies may help to address either highly frequent combinations of chronic medical conditions or combinations particularly difficult to be handled . For example, van den Bussche et al. found that triads of the six most prevalent individual chronic conditions (hypertension, hyperlipidemia, chronic low back pain, diabetes mellitus, osteoarthritis and chronic ischemic heart disease) cover nearly half on the elderly multimorbid population . When developing or reviewing monomorbid CPGs, we propose to adapt the CPGs in the sense of adding recommendations on how to proceed in the management of the most prevalent associated conditions. For example, a CPG on the management of chronic ischemic heart disease should comment on treatments for hypertension, hyperlipidemia, chronic low back pain, diabetes mellitus, and/or osteoarthritis that interfere with the index disease. The most prevalent combinations of clinical conditions related to the index disease would thus be covered by the CPG.
Other analyses used explorative techniques such as cluster analysis  or factor analysis  to identify multimorbidity patterns. For example, Schäfer et al. investigated a list of 46 ICD10-based chronic conditions and identified overlapping clusters of 1) cardiovascular and metabolic diseases, 2) anxiety, depression, somatoform disorders and pain-related morbidity, and 3) neuropsychiatric disorders . Based on such findings, CPGs might be supplemented with information on frequent interactions between treatments for diseases within one cluster. They could also address problems that may occur in patients with concurrent morbidities attributed to multiple clusters. For example, CPGs for cardiovascular diseases that recommend anticoagulants, antihypertensive, or lipid-lowering drugs (cluster 1) should comment on what should be done if a patient concurrently takes antidepressants, analgesics (to treat conditions included in cluster 2), or neuropsychiatric drugs (to treat conditions included in cluster 3) as interactions between these drugs are frequent or potentially serious.
Applying clusters and triads using the example of Boyd’s case
Comparison of the comorbidities mentioned in Boyd’s case and the triads (van den Bussche 2011) and cluster (Schäfer 2010) model
Boyd 2005 []
van den Bussche 2011 []
Schäfer 2010 []
Included in 9 triads
Included in CMD cluster
Chronic heart failure
Included in CMD cluster
Chronic ischemic heart disease included in 3 triads
Chronic ischemic heart disease included in CMD cluster
Cardiac arrhythmias included in CMD cluster
Lipid metabolism disorder included in 6 triads
Lipid metabolism disorder included in CMD cluster
Included in 3 triads
Included in CMD cluster
Included in 3 triads
Included in ADS/P cluster
Chronic obstructive pulmonary disease
Included in ADS/P cluster
Included in ADS/P cluster
Recommendations for CPG development
Increased applicability for multimorbid populations to be an objective of the CPG
Stratification of trial results by age and health factors
Managing excessive complexity by focusing on context specific CPGs
Cross-referencing to existing instruments
Involvement of all professional groups and patient perspective
Given the fact that a large part of CPG work is done by professional associations with a low budget and by voluntary health experts, strategies for adapting CPGs to multimorbidity should not exponentially increase the work that needs to be done. Apart from focusing on the most prevalent conditions, the complexity and work load could be reduced if international collaboration would be intensified. Clearly, for specific health care settings or patient populations, it is reasonable to interpret the evidence and to consent recommendations on a local level. However, in principle, synthesising the evidence is not specific to individual health systems and may be exchanged across countries. The EUnetHTA Joint Action  and the Guidelines International Network (G-I-N) , for example, are evidence that this type of international cooperation and exchange is feasible.
Limitations and future research
Clearly, the existing epidemiologic research data related to patterns of multimorbidity are not perfect. For example, lists of chronic conditions used in previous research were mainly not weighted for the impact of the listed condition on quality of life, activities of daily living, or prognosis . Future research needs to go beyond studying the prevalence of certain combinations, and should adjust for the extent of comorbidities to compromise function, quality of life, and life expectancy. As many diseases have common risk factors and symptoms and might require similar treatment and prevention strategies, it might be helpful to cluster therapeutic strategies as opposed to conditions .
Limitations are also related to the existing evidence base and to the way evidence in older persons is generated. Current trials rarely include older, multimorbid persons and insufficiently control for confounding factors such as greater disease severity, place of residence, comorbid conditions, or functional limitations . However, drug regulatory authorities increasingly consider the problem of multimorbidity. For example, in 2011 the European Medicines Agency published its geriatric medicines strategy which states that medicines should be studied appropriately in the older population . Specifically, trials are needed that include elderly and comorbid populations, test complex interventions such as appropriate prescribing measures and evaluate relevant endpoints in these populations, e.g. functional outcomes, quality of life, disability, or pain . For weighing risks and benefits of therapeutic interventions, future trials should consequently report absolute effect estimates for benefit and harm including the time period after which the effect is expected to occur. For priority setting with respect to comorbidities that need to be studied, triads and clusters may also be helpful.
In the absence of specific recommendations for older, multimorbid patients treatment decisions are mainly based on expert opinion rather than on scientific evidence. The epidemiologic approaches described above may constitute a scientific basis for CPG developers to systematically consider disease combinations that are highly prevalent in the multimorbid population. The objective of these efforts is to identify frequent reasons for interactions and adverse events that may occur when the current type of CPG is rigorously applied in multimorbid patients, which has major implications for the weighting of benefits and harms of recommended interventions. Case vignettes selected based on epidemiologic data may present a practical link between recommendations in CPGs and the heterogenetic nature of multimorbidity in clinical practice. Given these suggestions will increase the complexity of CPG development, international collaboration and cross-reference to existing instruments should be intensified to balance the additional workload.
CPGs are not intended to replace the setting of diagnostic, therapeutic, and preventive priorities on the individual patient-doctor level. However, it is intolerable that providing health care in compliance with current CPGs might result in worse outcomes and increased cost for a huge group of vulnerable patients. Researchers, guideline developers, and funding institutions should give first priority to developing such a new type of CPGs. This will require the joint effort of all related societies and specialties.
Clinical practice guideline
European network for Health Technology Assessment
Guidelines International Network
10th revision of the International Statistical Classification of Diseases and Related Health Problems
Screening Tool to Alert doctors to Right Treatments
Screening Tool of Older People’s potentially inappropriate Prescriptions
- VanWeel C, Knottnerus JA: Evidence-based interventions and comprehensive treatment. Lancet. 1999, 353: 916-918. 10.1016/S0140-6736(98)08024-6.View Article
- Fortin M, Bravo G, Hudon C, Vanasse A, Lapointe L: Prevalence of multimorbidity among adults seen in family practice. Ann Fam Med. 2005, 3: 223-228. 10.1370/afm.272.PubMedPubMed CentralView Article
- van den Bussche H, Koller D, Kolonko T, Hansen H, Wegscheider K, Glaeske G, von Leitner EC, Schäfer I, Schön G: Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? results of a claims data based cross-sectional study in Germany. BMC Publ Health. 2011, 11: 101-10.1186/1471-2458-11-101.View Article
- Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW: Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005, 294: 716-724. 10.1001/jama.294.6.716.PubMedView Article
- Cox L, Kloseck M, Crilly R, McWilliam C, Diachun L: Underrepresentation of individuals 80 years of age and older in chronic disease clinical practice guidelines. Can Fam Physician. 2011, 57: e263-e269.PubMedPubMed Central
- Ruggiero C, Dell’Aquila G, Gasperini B, et al: Potentially inappropriate drug prescriptions and risk of hospitalization among older, Italian, nursing home residents: the ULISSE project. Drugs Aging. 2010, 27: 747-758. 10.2165/11538240-000000000-00000.PubMedView Article
- Klarin I, Wimo A, Fastbom J: The association of inappropriate drug use with hospitalisation and mortality: a population-based study of the very old. Drugs Aging. 2005, 22: 69-82. 10.2165/00002512-200522010-00005.PubMedView Article
- Fulton MM, Allen ER: Polypharmacy in the elderly: a literature review. J Am Acad Nurse Pract. 2005, 17: 123-132. 10.1111/j.1041-2972.2005.0020.x.PubMedView Article
- Shaneyfelt TM, Centor RM: Reassessment of clinical practice guidelines: go gently into that good night. JAMA. 2009, 301: 868-869. 10.1001/jama.2009.225.PubMedView Article
- Fortin M, Contant E, Savard C, Hudon C, Poitras ME, Almirall J: Canadian guidelines for clinical practice: an analysis of their quality and relevance to the care of adults with comorbidity. BMC Fam Pract. 2011, 12: 74-10.1186/1471-2296-12-74.PubMedPubMed CentralView Article
- Lugtenberg M, Burgers JS, Clancy C, Westert GP, Schneider EC: Current guidelines have limited applicability to patients with comorbid conditions: a systematic analysis of evidence-based guidelines. PLoS One. 2011, 6: e25987-10.1371/journal.pone.0025987.PubMedPubMed CentralView Article
- Steinman MA, Hanlon JT: Managing medications in clinically complex elders: "there's got to be a happy medium". JAMA. 2010, 304: 1592-1601. 10.1001/jama.2010.1482.PubMedPubMed CentralView Article
- Fried TR, Tinetti ME, Iannone L: Primary care clinicians' experiences with treatment decision making for older persons with multiple conditions. Arch Intern Med. 2011, 171: 75-80.PubMedPubMed Central
- Blaum C, Cigolle CT, Boyd C, Wolff JL, Tian Z, Langa KM, Weir DR: Clinical complexity in middle-aged and older adults with diabetes: the health and retirement study. Med Care. 2010, 48: 327-334. 10.1097/MLR.0b013e3181ca4035.PubMedPubMed CentralView Article
- Guthrie B, Payne K, Alderson P, McMurdo ME, Mercer SW: Adapting clinical guidelines to take account of multimorbidity. BMJ. 2012, 345: e6341-10.1136/bmj.e6341.PubMedView Article
- Marengoni A, Fratiglioni L: Disease clusters in older adults: rationale and need for investigation. J Am Geriatr Soc. 2011, 59: 2395-2396. 10.1111/j.1532-5415.2011.03687.x.PubMedView Article
- Schäfer I, von Leitner EC, Schön G, Koller D, Hansen H, Kolonko T, Kaduszkiewicz H, Wegscheider K, Glaeske G, van den Bussche H: Multimorbidity patterns in the elderly: a new approach of disease clustering identifies complex interrelations between chronic conditions. PLoS One. 2010, 5: e15941-10.1371/journal.pone.0015941.PubMedPubMed CentralView Article
- Hanlon JT, Schmader KE, Samsa GP, Weinberger M, Uttech KM, Lewis IK, Cohen HJ, Feussner JR: A method for assessing drug therapy appropriateness. J Clin Epidemiol. 1992, 45: 1045-1051. 10.1016/0895-4356(92)90144-C.PubMedView Article
- American Geriatrics Society 2012 Beers Criteria Update Expert Panel: American geriatrics society updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012, 60: 616-631.View Article
- Amann U, Schmedt N, Garbe E: Prescribing of potentially inappropriate medications for the elderly: an analysis based on the PRISCUS list. Dtsch Arztebl Int. 2012, 109: 69-75.PubMedPubMed Central
- Gallagher PF, O'Connor MN, O'Mahony D: Prevention of potentially inappropriate prescribing for elderly patients: a randomized controlled trial using STOPP/START criteria. Clin Pharmacol Ther. 2011, 89: 845-854. 10.1038/clpt.2011.44.PubMedView Article
- Wong K, Yu SK, Holbrook A: A systematic review of medication safety outcomes related to drug interaction software. J Popul Ther Clin Pharmacol. 2010, 17: e243-e255.PubMed
- The EUnetHTA Joint Action: http://www.eunethta.eu.
- Guidelines International Network: http://www.g-i-n.net.
- Tinetti ME, McAvay G, Chang SS, Ning Y, Newman AB, Fitzpatrick A, Fried TR, Harris TB, Nevitt MC, Satterfield S, Yaffe K, Peduzzi P: Effect of chronic disease-related symptoms and impairments on universal health outcomes in older adults. J Am Geriatr Soc. 2011, 59: 1618-1627. 10.1111/j.1532-5415.2011.03576.x.PubMedPubMed CentralView Article
- Starfield B: Point: the changing nature of disease: implications for health services. Med Care. 2011, 49: 971-972. 10.1097/MLR.0b013e318233a0c1.PubMedView Article
- European Medicines Agency: Medicines for older people: [http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000249.jsp&mid=WC0b01ac058004cbb9]
- Lindley RI: Drug trials for older people. J Gerontol A Biol Sci Med Sci. 2012, 67: 152-157.PubMedView Article
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/13/352/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.