“fit for the aged“ expert consensus validation f o r t a

1

The JAPAN-F O R T A List “Fit for The Aged“

Expert Consensus Validation 1

F O R T A

A B C D

Farhad Pazan*, Yana Gercke*, Christel Weiß**, Martin Wehling*

*Clinical Pharmacology Mannheim, Center for Geriatric Pharmacology, University of Heidelberg

** Department of Medical Statistics, Biomathematics and Information Processing, Medical Faculty of the University of Heidelberg in Mannheim

2

Disclaimer

Please keep in mind that the FORTA concept was conceived in Germany. While building on an international foundation of medical evidence and experience for

the medications listed, including already existing “negative lists” and classification systems, this version of the FORTA List primarily reflects prescribing

tendencies in Japan. The FORTA labels themselves, being evidence-based, may possibly be subject to change during the course of further consensus evaluation

procedures, depending on the state of evidence and clinical experience for a given substance1. Meanwhile, the FORTA principle has been validated in a randomized

clinical trial (VALFORTA) showing a large improvement of medication quality and amelioration of clinical parameters2.

With the goal of creating a user-friendly clinical tool, a summary of relevant comments is given directly in the FORTA List, drawing on the Delphi experts’

extensive clinical experience and existing evidence. This is however by no means comprehensive and does not necessarily refer to specific evidence or sources.

Therefore, the authors’ selection of suggestions, comments and warnings may be subjective1. ‘No comment’ reflects the absence of noteworthy or relevant words

of information or caution within the context of the expert evaluation. All information herein is believed to be true and accurate. However, the use of the content

does not acquit the reader of critical examination in individual cases. Neither the authors nor the University of Heidelberg or affiliated institutions, as the publishers

of this list, can accept legal responsibility for any errors or omissions made in the contents of this list1. We would also like to point out that the FORTA list has

been developed for physicians and is not suitable for direct use by patients or any other persons.

We welcome all comments and criticism which may contribute to the quality, safety and usability of the FORTA List.

3

The Japan-FORTA expert panel

The following 13 colleagues, representing Japan provided their expertise for purposes of evaluating the proposed FORTA List. They received no honoraria in

connection with this project. All panel members contributed actively to the development of the content of the FORTA List.

Expert Panel Members and their affiliations

Hiroshi Akazawa MD, PhD: Department of Cardiovascular Medicine, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan.

Taro Kojima MD, PhD: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Ryota Kumaki, MS: Division of Social Pharmacy, Department of Healthcare & Regulatory Sciences, Showa University School of Pharmacy, Tokyo, Japan.

Masahiro Akishita MD, PhD: Department of Geriatric Medicine, Graduate School of Medicine, Institute of Gerontology, The University of Tokyo, Japan.

Yasushi Takeya MD: Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.

Yoshiyuki Ohno PhD: Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Takashi Yamanaka MD: Department of Home Care Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Koichi Kozaki MD: Department of Geriatric Medicine, Kyorin University School of Medicine, Tokyo, Japan.

Yusuke Suzuki MD, PhD: Centre for Community Liaison and Patient Consultations, Nagoya University Hospital, Nagoya, Japan.

Katsuyoshi Mizukami MD, PhD: Graduate School of Comprehensive Human Sciences Faculty of Health and Sport Sciences, University of Tsukuba, Tokyo

campus, Tokyo, Japan

Fumihiro Mizokami, PhD: Department of Pharmacy, National Center for Geriatrics and Gerontology, Obu, Japan.

Yoshiyuki Ikeda MD, PhD: Department of Cardiovascular Medicine and Hypertension, Kagoshima University, Japan.

Atsuya Shimizu MD, PhD: Departments of Cardiology, National Center for Geriatrics and Gerontology, Obu, Japan.

4

F O R T A – Physician’s guide1,3,4,7

1. FORTA is evidence-based + real-life-oriented (factors such as compliance issues, age-dependent tolerance and frequency of relative contraindications are considered).

2. Classifications are indication (or diagnosis)-dependent: a medication can receive different FORTA classifications based on differing indications. 3. Contraindications always take precedence over the FORTA-classification (for example, even Class A medications may not be given if allergies are present). 4. FORTA is designed to be a quick and user-friendly clinical tool to aid in the pharmacotherapy of older patients*. The system is not intended to take the place

of individual therapeutic considerations or decisions. As with any simplified model, it does allow for exceptions.

F O R T A – Classification System A-D3,4,5,6,7

Class A

= Indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication

Class B

= Drugs with proven or obvious efficacy in the elderly, but limited extent of effect and/or safety concerns

Class C = Drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs, absence of benefits or emerging side effects; explore alternatives

Class D = Avoid if at all possible in the elderly, omit first and use alternative substances

*FORTA addresses older people and is mainly validated for patients aged 65 y or older with significant comorbidities (3 or more diagnoses and drugs); it should be applied to all patients aged 80 y and above. These are people commonly defined as geriatric patients.

5

The F O R T A List1,5,6

Delphi Expert Consensus Validation

Classification of the most frequently used long-term medications† for the pharmacotherapy of older patients

by indication/diagnosis, ranked according to FORTA classification Newly proposed drugs are mentioned under the respective diagnosis and marked by *; they are listed in greater detail in the second part.

(† long-term defined as > 4 weeks. Please note that the distinction between acute/chronic may not always be clear-cut; exceptions are noted)

F O R T A A B C D

6

ARTERIAL HYPERTENSION

FORTA Class (original FORTA

class in parentheses if different from

consensus results)

Nr. of raters

Consensus coefficient,

Round 1 (cutoff 0.800)

Expert ratings on a numerical scale:

A=1, B=2, C=3, D=4

Mean; Mode

Selection of pertinent comments given by participating experts

during the consensus procedure

Substance/Group

Renin-Angiotensin system inhibitors

ACE inhibitors Angiotensin receptor

antagonists

A 10

1.000

1.0; 1

A 10

1.000

1.0; 1

Long-acting calcium antagonists, dihydropyridine type, for example amlodipine

A 10 1.000 1.0; 1

Betablockers B 10 1.000 2.0; 2

Diuretics

B 9

1.000 2.0; 2

Note: In small amounts; Japanese are highly sensitive to salt and diuretics are highly effective. Diuretic is the first-choice medicine for elderly people in Japan. Betablockers is a second-choice medicine because of contraindications and use attention many in elderly people, it is uncomfortable to make it the same classification as betablockers. However, it is a medicine to be warned by elderly people with diuretic drugs, and it is recommended to use them in small amounts

Aliskiren C 10 0.950 2.9; 3

7

Alpha blockers C 10 (R1) 12 (R2)

0.800

3.2; 3 (R1) 3.25; 3 (R2)

Note: Adverse drug reactions are likely to occur; Risk of falls

Spironolactone C 10 0.950 2.9; 3

Urapidil C 8 0.812 3.1; 3

Clonidine D 10 0.950 3.9; 4 Note: Clonidine has been approved as a drug of hypertension in Japan, while having a risk of orthostatic hypotension.

Calcium antagonists, verapamil type

D 10 0.850 3.7; 4

HEART FAILURE



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/Group

Renin-angiotensin system inhibitors

ACE inhibitors

Angiotensin receptor antagonists

A

10

1.000

1.0; 1

A

10 1.000

1.0; 1

Betablockers (metoprolol, carvedilol, bisoprolol)

A

10 1.000

1.0; 1

Note: However, bisoprolol has no indication for heart failure in Japan. Betablockers (metoprolol, carvedilol)

Diuretics B 10 0.950 1.9; 2

8

Spironolactone B 10 1.000 2.0; 2

Digitalis preparations C 9 0.944 3.1; 3 Note: Digitalis use is limited to the cardiac insufficiency patient with atrial fibrillation

Eplerenone*

ACUTE CORONARY SYNDROME



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/Group

Renin-Angiotensin-System- Blocker: ACE-inhibitors

A 10 1.000 1.0; 1

Acetylsalicylic acid A 10 1.000 1.0; 1

Unfractionated heparin and low molecular weight heparin

A 10 1.000 1.0; 1

Frequency-lowering betablockers

A 10 1.000 1.0; 1

Atorvastatin A 10 1.000 1.0; 1

9

Nitroglycerin spray, single use, acute as on-demand medication

A

10 1.000

1.0; 1

Clopidogrel, prasugrel

B 10

9

0.950

0.944

1.9; 2

1.1; 1

Note: FORTA A for stent = limited duration (at least 1 year) based on guidelines

A for stent

Thrombolytics, especially rTPA (recombinant tissue-type plasminogen activator)

B

9 (R1)

12 (R2)

0.777

2.4; 2 (R1)

2.08; 2 (R2)

Nitrates, long-term

C 10 0.900 2.8; 3

CHRONIC THERAPY FOLLOWING MYOCARDIAL INFARCTION



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Renin angiotensin system blockers ACE Inhibitors

A 10

1.000

1.0; 1

Acetylsalicylic acid (100 mg/d)

A 10 1.000 1.0; 1

10

Frequency-lowering beta blockers up to 3 years Frequency-lowering beta blockers longer than 3 years

A 8 1.000 1.0; 1 Note: Japanese guidelines do not have a period of 3 years for the use of betablocker. Instead, the recommended grade is low for patients with low risk, such as maintaining cardiac function.

C 8 0.812 2.6; 3

Nitroglycerin spray, single use as on-demand medication

A 10 1.000 1.0; 1

Influenza vaccination (inactivated subunit vaccines)

A 10 1.000 1.0; 1

Clopidogrel (12 months after acute coronary syndrome)

A with aspirin intolerance

9 1.000 1.0; 1

Statins

A

9

8

1.000

1.000

1.0; 1

2.0; 2

B for very old (>85 years)

patients

Nitrates, long-term C 10 0.900 2.8; 3

Fibrates C 10 0.900 2.8; 3

Ezetimibe C 10 0.850 2.7; 3 Note: According to the results of the EWTOPIA75 trial

Amiodarone

C 10 0.950 3.1; 3 Note: High risk for fatal arrhythmia

D 10 0.950 3.9; 4

11

All other class-I-III antiarrhythmic agents

Dihydropyridine antagonists (if no hypertension)

D 9 0.888 3.6; 4 Note: A long-acting calcium antagonist is administered for patients suffering from myocardial infarction with clinical manifestations of coronary vasospastic angina or due to coronary spasm, for preventing ischemic attacks.

Niacin D 8 1.000 4.0; 4

STROKE



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/Group

Acetylsalicylic acid A 10 0.950 1.1; 1 Note: Higher risk for gastrointestinal bleeding

Atorvastatin A 10 1.000 1.0; 1

rTPA (recombinant tissue-type plasminogen activator)

A 10 0.950 1.1; 1

Simvastatin A 10 1.000 1.0; 1

12

Anticoagulants including new oral anticoagulants

A 10 0.950 1.1; 1 Note: Benefit depending on the type of stroke

Clopidogrel A 10 1.000 1.0; 1

Dipyridamole plus acetylsalicylic acid

(B) C

7 (R1) 11 (R2)

0.785

2.4; 2 (R1) 2.9; - (R2)

Note: For Japanese, according to JASAP study, this combination was not effective compared to aspirin alone; Higher risk for bleeding

ATRIAL FIBRILLATION



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Frequency-lowering betablockers

A 10 1.000 1.0; 1

New Oral Anticoagulants (NOACs) Except apixaban

B

10

8

0.900

0.937

1.8; 2

1.1; 1

Note: Several Japanese data have been reported, and all NOACs are treated equally.

Note: Less evidence for patients with higher CHADS2 score and frailty. Also, you need to take b.i.d. which might not be the first choice for older patients from the standpoint of drug adherence.

A

13

Digoxin Digitoxin

B

C

10

8

0.850

0.937

2.3; 2

3.1; 3

Note: There are many side effects, and elderly should avoid it. Note: Much higher risk than digoxin because we cannot monitor the plasma concentration

Oral anticoagulants (e.g. warfarin) Alternative: low molecular weight heparin

B

10

0.950

1.9; 2

C

7 1.000

3.0; 3

Diltiazem, verapamil

C

10

0.950

2.9; 3

Class III antiarrhythmic agent amiodarone All other class I/III antiarrhythmic agents

C

9

0.944

3.1; 3

D

10 1.000

4.0; 4

Acetylsalicylic acid (100 mg/d)

D

8 1.000 4.0; 4

14

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Inhalative long-acting parasympatholytic agents

A 10 0.900 1.2; 1 Note: LABA is also recommended as a first-line drug equivalent to LAMA; Effective for stable COPD; May possibly induce anticholinergic adverse reactions

Systemic glucocorticoids, acute, short-term use in cases of exacerbation

A 10 1.000 1.0; 1

Antibiotics (acute) in cases of exacerbation, after calculated selection and, if necessary, according to antibiogram

A 10 1.000 1.0; 1

Long-term administration of oxygen (only in cases of respiratory failure and pulmonary heart disease)

A 10 1.000 1.0; 1

Annual influenza immunizations

A 10 1.000 1.0; 1

15

Pneumococcal immunizations for persons ≥ 65 years

A 10 1.000 1.0; 1

Inhalative glucocorticoids

C

10

0.850

2.7; 3

Note: When asthma is merged, ICS is used together; Effective for patients with %FEV1 below 50% and repeat acute worsening frequently

Inhalative beta 2 mimetic agents

B 10 0.950 1.9; 2 Note: clear evidence on beneficial role of beta-2 agonists; GOLD 2018 guidelines indicate these can be considered first line and even in combination with LAMA

Theophylline C 10 0.950 2.9; 3 Note: not much evidence for benefit. Side effects are common

Mucolytic agents, e,g. acetyl cysteine, bromhexine

C 10 0.950 2.9; 3

Systemic glucocorticoids, chronic use

D 10 0.950 3.9; 4 Note: Needed in case of withdrawing, e.g. IP

Antitussives: opioid A., e.g. codeine; non-opioid A., e.g. butamirate

D 9 1.000 4.0; 4

OSTEOPOROSIS


class in parenteses if

different from consensus

results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



16

Substance/Group

Parenteral bisphosphonates (e.g. ibandronate, IV every 3 months)

A 10 0.950 1.1; 1 Note: Risk of BRONJ (Bisphosphonate-related osteonecrosis of the jaw)

Denosumab A 10 0.950 1.1; 1 Note: Risk of ARONJ (Anti-resorptive agent-related osteonecrosis of the jaw)

Calcium and vitamin D supplements (as prophylaxis for persons ≥ 65 years)

A

10

0.900

1.2; 1

Note: evidence suggests that supplementation with Calcium and Vitamin D is not necessary, if oral food intake is adequate; no evidence for everyone; no proven benefit for prevention in patients who have adequate dietary calcium intake and normal vitamin D levels; FORTA C based on new 2018 US preventative task force recommendations; calcium increases BMD, but fracture prevention is minimal. Dietary intake preferred. No clear role when dietary intake is adequate and vitamin D level s are normal; inconsistent evidence to support benefit in fracture prevention

Bisphosphonates, orally administered

B 10 0.900 1.8; 2

Raloxifene (for women) B 10 0.900 2.0; 2

Teriparatide C 10 (R1) 10 (R2)

0.750 2.5; 3 (R1) 2.8; 3 (R2)

Alfacalcidol C 10 0.900 2.8; 3

Hormone replacement therapy (HRT): estrogen, except for perimenopausal)

D 10 0.950 3.9; 4

Basedoxifene (for women)*

Eldecalcitol*

17

Menatetrone*

TYPE II DIABETES MELLITUS



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Insulin and insulin analogs (if absolutely necessary)

B 10

0.900

1.8; 2

Note: can be used safely if monitor; avoid in frail, cognitively impaired; insulin is indispensable (when absolutely necessary)

Metformin B

10 0.900 2.0; 2 Note: High risk of lactic acidosis in older people with CKD;

Acarbose B 10 0.850 2.3; 2 Note: Frequently seen side effects (flatulence and diarrhea)

DPP4 (Dipeptidylpeptidase) Inhibitors

(B)

A

10 (R1) 11 (R2)

0.700

1.4; 1 (R1) 1.36; 1 (R2)

Note: It is most used in Japan; Reduces PG safely; Low possibility to cause hypoglycemia

GLP1 (Glucagon-Like Peptide-1) analogs

B 10 1.000 2.0; 2

3rd generation sulfonylureas (for example, glimepiride)

C

10 1.000

3.0; 3

18

Glinides (for example, nateglinide)

C 10 1.000 3.0; 3

PPAR-ɣ Ligands (Peroxisomal Proliferator-Activated Receptor gamma)

Pioglitazone

C

10

1.000

3.0; 3

1st generation sulfonylureas (for example, glyburide/glibenclamide)

D 10 0.950 3.9; 4

SGLT-2 inhibitors D 10 (R1) 11 (R2)

0.800 3.6; 4 (R1) 3.6; 4 (R2)

Note: Effective for the older diabetes patients, but necessary to watch for side effects

DEMENTIA



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Acetylcholinesterase inhibitors e.g. donepezil, galantamine, rivastigmine (in phases when clearly indicated)

B

10

0.900

1.8; 2

Note: Concerns for underuse

19

Memantine (C) B

10 (R1) 10 (R2)

0.500 2.0; 2 (R1) 2.1; 2 (R2)

Note: Effective for hyperactive demented older patient; This agent is effective for cognition and BPSD; Concerns for underuse

Statins D 10 0.900 3.7; 4 Note: FORTA D as a specific treatment of dementia; but management of vascular risk factors is critical in vascular dementia and if patient has known cerebrovascular disease, statins should be part of dementia management as well as aspirin

Selegiline D 9 0.944 3.8; 4

Ginkgo biloba D 8 1.000 4.0; 4

Piracetam D 6 1.000 4.0; 4

Antioxidants: Vitamin E, selenium, vitamin C

D 10 0.950 3.9; 4

Phytotherapeutic agents, e.g. ginseng

D 8 1.000 4.0; 4 Note: No toxicity unless overdose

Hormone preparations, e.g. DHEA (Dehydroepiandrosterone), testosterone

D 10 0.900 3.8; 4 Note: Efficacy not validated but may be used as supplements

Antiphlogistics, e.g. indomethacin

D 10 1.000 4.0; 4

Desferrioxamine D 9 1.000 4.0; 4

Yokukansan*

20

BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD)



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



DEPRESSION

Substance/group

SSRI (Selective Serotonin Reuptake Inhibitors) Citalopram/escitalopram, sertraline in the usual dosages

C

10

1.000

3.0; 3

Mirtazapine (15-45mg/d) C 10 0.950 2.9; 3

SNRI (Serotonin-Noradrenalin-Reuptake-Inhibitors) venlafaxine, duloxetine

C

10

1.000

3.0; 3

BPSD: PARANOIA, HALLUCINATION



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode

Selection of pertinent comments given by participating experts during the consensus procedure

21

Substance/group

Risperidone (initially 0.5-1 mg/d)

C 10 0.950 2.9; 3

Haloperidol (initially 0.5 mg/d, max. 3 mg/d)

C 10 1.000 3.0; 3

Quetiapine (25-200 mg/d) C 10 0.900 3.0; 3 Note: (12.5-100 mg/d)/25-100 mg/d in Japan

Aripiprazole (2-15 mg/d) (D)

C

10 (R1) 11 (R2)

0.750 3.5; - (R1) 3.4; 3 (R2)

Note: Recommended by the ministry’s guideline in Japan, 3-9 mg/d; Used for hyperactive paranoia or hallucination; mild side effect of extrapyramidal symptoms

Clozapine (10-50 mg/d) D 10 1.000 4.0; 4

Yokukansan*

BPSD: RESTLESSNESS, AGITATION, (AGGRESSIVENESS)



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Trazodone (50-200 mg/d) C 10 0.900 2.8; 3

22

Risperidone (initiallly 0.5-1 mg/d, Maximum 3 mg/d)

C 10 0.950 2.9; 3

Quetiapine (25-200 mg/d) C

10 0.950 2.9; 3

Yokukansan*

Olanzapine (2.5-10 mg/d)*

BPSD: SLEEP DISORDERS



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Zopiclone

C 10 0.950 2.9; 3

Tetracyclic antidepressant Mirtazapine (15-30mg)

C 13 1.000 3.0; 3 Note: very commonly used as an adjunct agent for improved sleep (at 7.5-15 mg nightly) and as an appetite stimulant. Side effect profile minimal compared to benefits

23

Zolpidem

C

13

0.950

2.9; 3

Note: risks outweigh benefits in older adults; avoid if possible due to risk of psychomotor impairment, delirium, falls, fractures, MVAs. Adverse effects similar to benzodiazepines. Minimal efficacy; not recommended for use due to exacerbation of dementia/cognitive impairment; increased risk of falls/fractures; avoid; can worsen cognitive status; not aware of studies examining efficacy for this indication; risk for falls and delirium; although non-dependence forming, same risks as BZDs. Risks clearly outweigh benefits.

Ramelteon*

Suvorexant*

Trazodone*

Eszopiclone*

DEPRESSION Prophylaxis and therapy for patients with moderate to major depression



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

24

SSRIs (Selective Serotonin Reuptake Inhibitor) Sertraline Escitalopram

B

9

1.000

2.0; 2

Note: very commonly used - very effective, especially when dose is optimized to patient response and tolerability

B

9 1.000

2.0; 2

Note: very commonly used - very effective, especially when dose is optimized to patient response and tolerability

Tricyclic antidepressant Nortriptyline

C 9 0.944 3.1; 3 Note: risks outweigh benefits, especially when newer, safer agents have been available for some time now; due to increased risk of anticholinergic effects, sedation, delirium, orthostasis and overall poor tolerability at antidepressant doses. Should be avoided if at all possible; avoid because of ADEs; safer alternatives; risks clearly outweigh benefits. While better tolerated than amitriptyline, still highly anticholinergic and may cause confusion, falls; much safer alternatives available

Tetracyclic antidepressant Mirtazapine

C 9 (R1) 11 (R2)

0.777

2.5; 3 (R1) 2.9; 3 (R2)

Note: relatively low anticholinergic

SNRIs (Serotonin-Noradrenalin Reuptake Inhibitors) Venlafaxine Duloxetine

C

7

0.928

2.8; 3


C

9

0.888

2.7; 3


Trazodone C 9 0.944 2.8; 3

Olanzapine C 9 0.944 3.1; 3

25

Quetiapine C 9 0.944 3.1; 3 Note: No indication for depression

Benzodiazepines: General Long-acting, Short-acting

D 9

0.944

3.8; 4

D 9

1.000

4.0; 4

C

9

0.944

3.1; 3

St. John’s Wort D 5 1.000 4.0; 4

Aripiprazole*

BIPOLAR DISORDER



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Quetiapine B 6 0.833 2.3; 2

Lamotrigine C 6 1.000 3.0; 3

Valproic acid C 6 1.000 3.0; 3

Lithium C 6 1.000 3.0; 3

26

Carbamazepine D 6 0.916 3.8; 4

INSOMNIA / SLEEP DISORDERS



consensus results)

Nr. of raters


Round 1 cutoff 0.800)


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Tetracyclic antidepressant Mirtazapine

C 10 1.000 3.0; 3

ω1-Benzodiazepine agonists Zolpidem

C

10

1.000

3.0; 3

Non-benzodiazepine hypnotic zopiclone

C 10 0.950 2.9; 3

Benzodiazepines, Triazolam (very short half-life)

D

13

0.950

3.9; 4

27

Antihistamine Diphenhydramine

D 13 1.000 4.0; 4

Ramelteon*

Survorexant*

CHRONIC PAIN



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Paracetamol (acetaminophen)

A 10 0.950 1.1; 1 Note: Risk of liver dysfunction should be considered

Opioids, e.g. Buprenorphine, oxycodone, hydromorphone Morphine

B

10 (R1) 11 (R2)

0.800

2.4; 2 (R1)

2.36; 2 (R2)

Note: Mostly used for cancer-related pain in Japan; Buprenorphine, Tramadol hydrochloride / Acetaminophen, codeine, morphin and phentanyl are approved for chronic pain

C

10

1.000

3.0; 3

Tramadol C 10 0.950 2.9; 3

28

SSRI (Selective Serotonin Reuptake Inhibitors) / SNRI (Serotonin- Norepinephrine-Reuptake Inhibitor), e.g. venlafaxine (only if absolutely necessary)

C 10 1.000

3.0; 3

Note: Venlafaxine is not approved for chronic pain

Tilidine/Naloxone

C 7 0.928 3.1; 3

Oxycodone/Naloxone C 8 1.000 3.0; 3

Antiepileptic agents (only for neuropathic pain) Pregabalin/gabapentin

Carbamazepine

C

10 1.000

3.0; 3

Note: has place in therapy for patients with neuropathic pain – diabetics, neurodegenerative diseases, etc. Renal dosing is needed, and careful assessment for possible potentiating effects with other agents that may be sedating or centrally depressing.

D

10

0.850

3.7; 4

Note: Indicated for trigeminal neuralgia; May be tried for trigeminal pain in the absence of alternatives

Tricyclic antidepressant amitriptyline

D 9 0.944 3.8; 4 Note: Indicated for peripheral neuropathic pain

NSAIDs (nonsteroidal anti-inflammatory drugs, for long-term use), e.g. naproxen

D

10 0.900

3.8; 4

29

Cox-2 inhibitors, e.g. celecoxib

(D)

C

10 (R1) 11 (R2)

0.600 3.2; 4 (R1) 3.2; 3 (R2)

Note: Cox-2 inhibitor is associated with a lower incidence of symptomatic ulcers and ulcer complications combined compared with conventional NSAIDs. JAMA 2000, (284), 1247; Relatively low risk of gastrointestinal hemorrhage compared to NSAIDs; Commonly used in Japan; May be used with caution

EPILEPSY



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Levetiracetam B 9 0.944 2.1; 2

Lamotrigine B 9 0.888 2.2; 2

Gabapentin B 9 0.944 2.1; 2

Topiramate B 8 0.937 2.1; 2

Lorazepam (emergency use) Lorazepam (long-term use)

B

8

0.937

2.1; 2

D

8 1.000

4.0; 4

Lacosamide C 5 1.000 3.0; 3

30

Zonisamide C 8 1.000 3.0; 3

Valproic acid C 9 0.944 2.8; 3

Pregabalin C 8 1.000 3.0; 3 Note: Pregabalin has no indication for epilepsy in Japan.

Carbamazepine C 9 1.000 3.0; 3

Midazolam (emergency use) Midazolam (long-term use)

C

9 1.000 3.0; 3

D 8 1.000 4.0; 4

Diazepam (emergency use) Diazepam (long-term use)

C 9 1.000 3.0; 3

D 9 1.000 4.0; 4

Phenobarbital D 9 1.000 4.0; 4

Phenytoin D 9 0.944 3.8; 4

Ethosuximide D 7 1.000 4.0; 4

31

PARKINSON’S DISEASE



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

L-DOPA

A

10

1.000

1.0; 1

COMT (Catechol-O-Methyltransferase) Inhibitor entacapone

B 8 0.937 1.8; 2

Dopamine agonists, e.g. ropinirole pramipexole rotigotine

B 8 1.000

2.0; 2

B

8 1.000

2.0; 2

B

8

1.000

2.0; 2

Note: piribedil & quinagolide not available in Japan

MAO-B inhibitors

selegiline rasagiline

C 9

1.000

3.0; 3

C 6

1.000

3.0; 3

32

Bromocriptine, cabergoline D 10 0.950 3.9; 4

Glutamate antagonists Amantadine

D 10 0.850 3.7; 4

Biperidene

D 10 1.000 4.0; 4 Note: Only for dyskinesia

Lower urinary tract symptoms (LUTS), includes benign prostate hyperplasia and incontinence



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

5α-reductase inhibitors B 8 1.000 2.0; 2

Mirabegron C 10 0.850 2.7; 3

Antimuscarinics except: fesoterodine

C 10

6

1.000

1.000

3.0; 3

2.0; 2

B

33

immediate-release oxybutynin

D

9

0.944

3.8; 4

α1-blockers except: silodosin and tamsulosin

D 10

10

0.900

1.000

3.8; 4

3.0; 3

C

GASTROINTESTINAL ILLNESSES/ CONCOMITANT THERAPY WITH NSAIDs



consensus results)

Nr. Of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

Proton pump inhibitors (PPI), only if absolutely necessary

B 10 0.950 1.9; 2

34

H2 receptor antagonists C 10 0.950 3.1; 3

Anemia



consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Substitution (iron, vitamin B12, folic acid in cases of deficiency)

A

10

0.950

1.1; 1

Erythropoetin-stimulating agents (ESA) in patients with renal insufficiency

A

10

1.000

1.0; 1

Iron substitution in patients with cardiac insufficiency Proof of iron deficiency No proof of iron deficiency

A

10

0.950

1.1; 1

(B)

C

9 (R1)

11 (R2)

0.777

2.4; 2 (R1) 2.5; 2 (R2)

Note: No high-quality evidence for patients>70

35

ONCOLOGICAL SUPPORTIVE THERAPY

FORTA Class

(original FORTA class in

parentheses if different from

consensus results)

Nr. of raters




A=1, B=2, C=3, D=4

Mean; Mode



Substance/group

G-CSF (Granulocyte Colony Stimulation Factor)

A 3 1.000 1.0; 1

Antiemetic agents (e.g. 5-HT receptor inhibitors)

A 3 1.000 1.0; 1

Erythropoesis Stimulating Agents, ESA

B 3 1.000 2.0; 2

*This substance or indication was suggested by the participating experts during the course of Round 1 and evaluated by the experts during Round 2, see second

table below. R1= Round 1 R2= Round 2

36

Delphi Expert Consensus Validation1

NEW SUBSTANCES/INDICATIONS SUGGESTED BY EXPERTS Results to be corroborated in future consensus/research projects

Classification of long-term medications†

for the pharmacotherapy of older patients by indication/diagnosis, ranked according to FORTA classification

(†long-term defined as > 4 weeks. Please note that the distinction between acute/chronic may not always be clear-cut; exceptions are noted)

F O R T A A B C D

EXISTING INDICATION Heart failure (cardiac insufficiency)

Rater-based FORTA Class (bold if: κ > 0.500 and label distance < 2)

Nr. Of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Eplerenone

C 10 0.786 2.9; 1 Note: Aldosterone blocker similar to spironolactone

37

EXISTING INDICATION OSTEOPOROSIS


Nr. Of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Basedoxifene (for women) B 9 0.466 2.3; 1 Note: recommended for osteoporosis treatment as adjunct to drug therapy; efficacy data unclear, but good safety profile (with vitamin D)

Eldecalcitol B 10 0.324 2.2.; 2 Note: Stronger effect on bone mineral density and preventing vertebral fracture compared to alfacalcidol

Menatetrone

C 9 0.762 3.1; 3 Note: not effective

EXISTING INDICATION DEMENTIA


Nr. Of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Yokukansan C 8 0.257 2.5; 3

38

EXISTING INDICATION INSOMNIA / SLEEP DISORDERS:


Nr. Of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Ramelteon B 10 0.534 2.1; 2 Note: Melatonin receptor agonist. Mild effect

Survorexant B 10 0.398 2.2; 3 Note: Lower risk of side effects compared to benzos or non-benzos.

EXISTING INDICATION BPSD: RESTLESSNESS, AGITATION, (AGGRESSIVENESS)


Nr. of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Yokukansan

B

11

0.301

2.3; 3

Note: The first-line drug for BPSD in Japan (Chinese herbal medicine). Mild effect; Effective with relatively safe for hyperactive BPSD with demented older patients

Olanzapine (2.5-10 mg/d) C 11 0.806 2.9; 3 Note: Recommended by the ministry’s guideline in Japan.

39

EXISTING INDICATION BPSD: SLEEP DISORDERS


Nr. of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Ramelteon B 11 0.806 2.1; 2 Note: Melatonin receptor agonist. Mild effect

Suvorexant B 11 0.534 2.3; 2

Trazodone

C 11 0.709 2.8; 3 Note: Frequently used for insomnia in patients with BPSD

Eszopiclone C 11 0.650 2.8; 4

EXISTING INDICATION BPSD: PARANOIA, HALLUCINATION


Nr. of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

40

Yokukansan B 9 0.099 2.2.; 2 Note: must do NPI questionnaire and if positive then use is appropriate

EXISTING INDICATION DEPRESSION Prophylaxis and therapy for patients with moderate to major depression


Nr. of raters

κ-Index


A=1, B=2, C=3, D=4

Mean; Mode


Substance/group

Aripiprazole C 10 1.000 3.0; 3 Note: must do NPI questionnaire and if positive then use is appropriate

41

SUMMARY OF STATISTICAL METHODS

(The following descriptions of the statistical methods and calculations are based on the first version of the FORTA List1. Former definitions and

explanations are adopted unchanged.)

Consensus Coefficient1

Consensus parameters were generated by calculating the percentage of experts’ FORTA ratings (minus abstentions) agreeing with the original FORTA values,

both overall and for each item separately (n = 195). The coefficients were then corrected (cons_corr) to weight the degree of deviation between the experts’

individual FORTA ratings, expressed in terms of range class, from 0-3 as defined:

• Range = 0: unanimity among all experts (no deviation);

• Range = 1: greatest range only from A to B or B to C, or C to D (neighboring classes), ½ weight;

• Range = 2: greatest distance from A to C or B to D, 2/3 weight;

• Range = 3: greatest distance from A to D, full weight.

Frequency of substances in defined range groups according to degree of consensus

Range Frequency

(n total=195) %

0 91 46.67

1 82 42.05

2 20 10.26

3 2 1.03

Cons_corr coefficients ranged from 0.500 to 1.000 (mean 0.950, median 0.950). Substances falling short of our established cons_corr cutoff of 0.800 underwent

re-evaluation in a second round: n=12

42

Confirmation/determination of FORTA labels1

In order to compare the rater-based FORTA labels with the original author-based labels, the labels A, B, C and D were transformed as follows1:

A→ 1

B → 2

C → 3

D → 4

These numerical “grades” were used for the calculation of arithmetic mean. The mode (=grade appearing most frequently for rated item) is also shown. For the

12 re-evaluated items, grading was performed twice. The rater-based FORTA labels are derived from the arithmetic mean from Round 1, or if re-evaluated,

from Round 2. The range for each grade was set at:

If 1 ≤ m < 1.5 → FORTA Class A

If 1.5 ≤ m < 2.5 → FORTA Class B

If 2.5 ≤ m < 3.5 → FORTA Class C

If m ≥ 3.5 → FORTA Class D

m= arithmetic mean based on the grades 1-4

The results of The Delphi Consensus Validation Procedure confirmed the original FORTA labels for 96.9% of all substances (n=195); for 6 of the 195 substances

(3.1%), the FORTA labels changed over the course of two rounds. All consensus-based FORTA ratings are listed in bold print: A B C D, and the original author-

based FORTA ratings are supplied in parentheses: (A) (B) (C) (D).

43

Asterisks in the first table mark substances or indications suggested by the panel members during the course of Round 1 and

assessed by the experts during Round 2.

Selection process for new substances and indications1

• A total of 15 substances were accepted for potential addition to the revised FORTA List. Selection criteria: 1) acceptance of all substances

suggested by ≥ 1 experts during Round 1, and all suggested indication areas; 2) acceptance of all substances/indication areas affirmed by >50%

of experts during Round 2 that the substance/indication should be included in the FORTA List; 3) acceptance of all substances assigned a

FORTA label by ≥ 4 raters (excluding abstentions) during Round 2. The 15 substances included:

o 15 new substances belonging to pre-existing FORTA indications

• A kappa index was generated for each of those added substances to analyze the distribution of the raters’ FORTA labels given. The kappa

index is defined as the (proportion of “matching” labels – 0.25) / 0.75. This gives due consideration to the fact that a figure of 25% can

theoretically be attained by chance alone with this particular constellation (the choice of 4 distinct labels, as with multiple choice).

Mean and mode were calculated according to the numerical scale used for the original FORTA substances

A → 1

B → 2

C → 3

D → 4

If 1 ≤ m < 1.5 → FORTA Class A

If 1.5 ≤ m < 2.5 → FORTA Class B

If 2.5 ≤ m < 3.5 → FORTA Class C

If m ≥ 3.5 → FORTA Class D

44

m= arithmetic mean based on the grades 1-4

• Only 9 of the 15 new substances had a kappa index higher than 0.500. Suggesting a high level of inter-rater agreement for 60.0% these

substances.

45

REFERENCES

1. Kuhn-Thiel AM. et al. Consensus validation of the FORTA (Fit fOR The Aged) List: a clinical tool for increasing the appropriateness of pharmacotherapy

in the elderly. Drugs Aging. 2014; 31:131-140.

2. Wehling M. et al. VALFORTA: a randomized trial to validate the FORTA (Fit fOR The Aged) classification. Age Ageing, 2016;45:262-7.

3. Wehling M. Drug therapy in the elderly: too much or too little, what to do? A new assessment system: fit for the aged FORTA. Dtsch Med Wochenschr

2008; 133: 2289-91.

4. Wehling M. Multimorbidity and polypharmacy: how to reduce the harmful drug load and yet add needed drugs in the elderly? Proposal of a new drug

classification: fit for the aged. J Am Geriatr Soc 2009; 57: 560-561.

5. Wehling M, Burkhardt H. Arzneitherapie für Ältere. Springer-Verlag, Heidelberg, 4. Auflage 2016.

6. Wehling M, Ed., Drug Therapy for the Elderly. Springer-Verlag, Wien 2013

7. Wehling M. How to Use the FORTA ("Fit fOR The Aged") List to Improve Pharmacotherapy in the Elderly. Drug Res. 2016;66:57-62.

“fit for the aged“ expert consensus validation f o r t a

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