Gender differences in the adverse events’ profile registered in seven observational studies of a wide gender-medicine (MetaGeM) project: the MetaGeM safety analysis

Figures & data

Table 1 MetaGeM observational studies and patients included in the analysis

Area (disease)	Study	Patient population and study objectives	Ongoing specific therapies	FPFV	LPLV	Females		Males		Total
						N	%	N	%	N
CNS	DEEP^Citation18,Citation19 (Early detection of wearing off in Parkinson’s disease)	Assessment of wearing off in patients with Parkinson’s disease under treatment with levodopa and/or dopamine agonists without dementia	Levodopa and/or dopamine agonists	March 2010	November 2010	236	38.3	381	61.8	617
CNS	EVOLUTION^Citation20 (Behavioral symptoms in AD: evaluation of patients treated with ChEI)	Evaluation of changes in cognitive and affective domain severity in mild-to-moderate AD patients undergoing a switch of ChEI for lack or loss of efficacy and/or tolerability/compliance	Switch from one ChEI to another after ≥6 months, due to lack or loss of efficacy (reduction of ≥2 points of MMSE score in the last 6 months) and/or reduced compliance (due to side effects or nonadherence to recommended dosing)	April 2010	September 2011	379	59.7	256	40.3	635
CNS	AXEPT^Citation21 (AD: examination of patient compliance and caregiver satisfaction)	Comparing compliance to treatment of community-dwelling patients with mild-to-moderate AD treated with transdermal or oral drugs and caregiver satisfaction in a real clinical setting	ChEIs (oral or transdermal) or memantine in monotherapy	September 2010	January 2011	544	63.6	311	36.4	855
Infectious diseases	ICEBERG (Natural history of chronic hepatitis B virus infection: an observational study on asymptomatic HBsAg carriers)a	Evaluation of natural history of disease in asymptomatic, untreated HBsAg carriers	NA	December 2008	July 2013	377	42.1	518	57.9	895
Dermatology (psoriasis)	PSYCHAE^Citation16,Citation22 (Psoriasis: survey for the control of anxiety and depression)	Assessing the prevalence and evolution of psychological distress in a large series of Italian patients with psoriasis followed at dermatological centers	Phototherapy, systemic medications, non-pharmacological therapy, topical treatments	February 2002	May 2004	309	39.3	477	60.7	786
Dermatology (psoriasis)	SYNERGY^Citation17 (Observational study of infectious events in psoriasis complicated by active psoriatic arthritis)	Evaluation of infectious events in patients with psoriasis and psoriatic arthritis receiving systemic immunosuppressive therapy, including CsA	CsA ± other immune-suppressants	March 2010	January 2012	104	46.2	121	53.8	225
Dermatology (psoriasis)	GENDER-ATTENTIONb,* (The female in her real dimension: effect of gender and hormonal status on adverse events’ incidence in psoriatic patients treated with CsA)	Evaluation of the differences in side effects’ incidence rate (as patient leaflet) between females (stratified by fertile/menopausal status) and age-matched males in patients with plaque psoriasis treated with CsA
Transplants	CETRA^Citation23 (Complications related to gastro-enteric symptoms in renal transplant patients) (Ponticelli)	Evaluation of the prevalence of gastrointestinal symptoms in patients with functioning, stable renal transplant and no underlying diseases that could cause gastrointestinal symptoms	CsA + azathioprine + CS CsA + MMF CsA + MMF + CS CsA + CS Tacrolimus + MMF + CS Tacrolimus + CS	June 2006	April 2008	309	36.1	548	63.9	857
Transplants	SURF* (Italian Observational Study for the evaluation of Renal Insufficiency in liver transplant patients) (Donato et al, unpublished data, 2013)	Evaluation of the proportion of patients with eGFR <60 mL/min/1.73 m^2 at inclusion visit and 12 months after the inclusion visit
	Total evaluable patients					2,258	46.4	2,612	53.6	4,870

Notes:

* Study not considered in the present analysis.

a Rizzetto et al, unpublished data, 2011; Bandiera et al, unpublished data, 2012.

b Colombo et al, unpublished data, 2013a; Colombo et al, unpublished data, 2013b; Colombo et al, unpublished data, 2014a; Colombo et al, unpublished data, 2014b; Colombo et al, unpublished data, 2016.

Abbreviations: AD, Alzheimer’s disease; ChEI, cholinesterase inhibitors; CNS, central nervous system; CsA, cyclosporine; CS, corticosteroids; eGFR, epidermal growth factor receptor; FPFV, first patient first visit; LPLV, last patient last visit; MMF, mycophenolate mofetil; HBsAg, Hepatitis B surface antigen; MMSE, Mini Mental State Examination; NA, not available.

Table 2 Demographic characteristics of patients

Study	Mean age (years)	Standard deviation	≥50 years N (%)
PSYCHAE^Citation16,Citation22
Females	43.7	13.0	123 (39.8)
Males	45.3	12.1	184 (38.6)
Total	44.7	12.5	307 (39.1)
DEEP^Citation18,Citation19
Females	67.0	8.9	228 (96.6)
Males	66.6	9.4	362 (95.0)
Total	66.8	9.2	590 (95.6)
EVOLUTION^Citation20a
Females	77.2	7.1	378 (99.7)
Males	76.0	6.9	256 (100.0)
Total	76.7	7.0	634 (99.8)
AXEPT^Citation21,b
Females	78.2	6.4	544 (100.0)
Males	76.9	6.6	311 (100.0)
Total	77.7	6.5	855 (100.0)
ICEBERGd
Females	44.9	12.9	158 (41.9)
Males	45.4	11.6	208 (40.2)
Total	45.2	12.2	366 (40.9)
SYNERGY^Citation17
Females	50.8	12.5	54 (51.9)
Males	48.9	12.8	57 (47.1)
Total	49.8	12.7	111 (49.3)
CETRA^Citation23
Females	48.1	11.6	146 (47.2)
Males	49.6	12.2	287 (52.4)
Total	49.1	12.0	433 (50.5)
Total evaluable patientsc
Females	61.2	18.3	1,631 (72.2)
Males	56.3	16.6	1,665 (63.7)
Total	58.6	17.6	3,296 (67.7)

Notes: Student’s t-test P-values (males versus females):

a 0.0427;

b 0.0045;

c 0.0001.

d Rizzetto et al, unpublished data, 2011; Bandiera et al, unpublished data, 2012. Percentages calculated for the total number of evaluable patients.

Table 3 Specific medications taken at inclusion in the study

Study	Medications	Females N (%)	Males N (%)	Total evaluable patients, N (%)
DEEP^Citation18,Citation19	DA	11 (4.7)	15 (3.9)	26 (4.2)
	DA + MAO-B inhibitors	17 (7.2)	36 (9.4)	53 (8.6)
	Levodopa	29 (12.3)	35 (9.2)	64 (10.4)
	Levodopa + DA	59 (25.0)	77 (20.2)	136 (22.0)
	Levodopa + DA + COMT inhibitors	41 (17.4)	73 (19.2)	114 (18.5)
	Levodopa + DA + MAO-B inhibitors	28 (11.9)	56 (14.7)	84 (13.6)
	Levodopa + DA + MAO-B inhibitors + COMT inhibitors	24 (10.2)	28 (7.3)	52 (8.4)
	Levodopa + COMT inhibitors	12 (5.1)	24 (6.3)	36 (5.8)
	Levodopa + MAO-B inhibitors	13 (5.5)	30 (7.9)	43 (7.0)
	Levodopa + MAO-B inhibitors + COMT inhibitors	2 (0.8)	7 (1.8)	9 (1.5)
	Total evaluable patients	236 (100.0)	381 (100.0)	617 (100.0)
EVOLUTION^Citation20	Donepezil (oral)	264 (69.7)	178 (69.5)	442 (69.6)
	Galantamine (oral)	33 (8.7)	18 (7.0)	51 (8.0)
	Rivastigmine (patch)	52 (13.7)	24 (9.4)	76 (12.0)
	Rivastigmine (oral)	30 (7.9)	36 (14.1)	66 (10.4)
	Total evaluable patients	379 (100.0)	256 (100.0)	635 (100.0)
AXEPT^Citation21	Donepezil (oral)	142 (26.1)	78 (25.1)	220 (25.7)
	Galantamine (oral)	21 (3.9)	12 (3.9)	33 (3.9)
	Memantine (oral)	107 (19.7)	70 (22.5)	177 (20.7)
	Rivastigmine (patch)	253 (46.5)	141 (45.3)	394 (46.1)
	Rivastigmine (oral)	21 (3.9)	10 (3.2)	31 (3.6)
	Total evaluable patients	544 (100.0)	311 (100.0)	855 (100.0)
CETRA^Citation23	CsA + AZA + steroids	25 (8.1)	29 (5.3)	54 (6.3)
	CsA + MMF	21 (6.8)	33 (6.0)	54 (6.3)
	CsA + MMF + steroids	42 (13.6)	95 (17.3)	137 (16.0)
	CsA + steroids	31 (10.0)	49 (8.9)	80 (9.3)
	Tacrolimus + MMF + steroids	46 (14.9)	75 (13.7)	121 (14.1)
	Tacrolimus + steroids	20 (6.5)	33 (6.0)	53 (6.2)
	Total evaluable patients	309 (100.0)	548 (100.0)	857 (100.0)
PSYCHAE^Citation16,Citation22	Phototherapy	88 (28.5)	178 (37.3)	266 (33.8)
	Systemic drug therapy	111 (35.9)	192 (40.3)	303 (38.5)
	Non-pharmacologic therapy	83 (26.9)	131 (27.5)	214 (27.2)
	Topical therapy	224 (72.5)	357 (74.8)	581 (73.9)
	Total evaluable patients	309 (100.0)	477 (100.0)	786 (100.0)
SYNERGY^Citation17	Local infiltrations ≤12 months before baseline	1 (1.0)	4 (3.3)	5 (2.2)
	Systemic therapy for psoriasis and PsA ≤12 months before baseline	104 (100.0)	120 (99.2)	224 (99.6)
	Topical therapy for psoriasis and PsA ≤12 months before baseline	79 (76.0)	96 (79.3)	175 (77.8)
	Total evaluable patients	104 (100.0)	121 (100.0)	225 (100.0)

Abbreviations: AZA, azathioprine; CsA, cyclosporine; COMT, catechol O-methyltransferase; DA, dopamine; MAO, monoamino-oxidase; MMF, mycophenolate mofetil; PsA, psoriatic arthritis; MAO-B, monoamine oxidase-B.

Table 4 AEs according to system organ class (MedDRA)

System organ class MedDRA	Total	%
Infections and infestations	48	18.2
Gastrointestinal disorders	27	10.2
General disorders and administration site conditions	21	8.0
Musculoskeletal and connective tissue disorders	17	6.4
Renal and urinary disorders	17	6.4
Skin and subcutaneous tissue disorders	14	5.3
Metabolism and nutrition disorders	12	4.5
Nervous system disorders	11	4.2
Respiratory, thoracic and mediastinal disorders	10	3.8
Investigations	10	3.8
Injury, poisoning, and procedural complications	8	3.0
Hepatobiliary disorders	7	2.7
Immune system disorders	7	2.7
Blood and lymphatic system disorders	7	2.7
Psychiatric disorders	7	2.7
Neoplasms benign, malignant, and unspecified	6	2.3
Reproductive system and breast disorders	5	1.9
Cardiac disorders	5	1.9
Vascular disorders	5	1.9
Eye disorders	3	1.1
Surgical and medical procedures	3	1.1
SOC not attributed	14	5.3
Total number of occurred AEs	264	100

Abbreviations: AEs, adverse events; MedDRA, Medical Dictionary for Regulatory Activities; SOC, system organ class.

Table 5 Occurrence of AEs during the study

Study	Patients with 1 AE N (%)	Patients with 2 AEs N (%)	Patients with ≥3 AEs N (%)	Total AEs N	Mild intensity AEs, N	Moderate intensity AEs, N	High intensity AEs, N
PSYCHAE^Citation16,Citation22
Females	2 (0.6)	0 (0)	0 (0)	2	0	1	0
Males	3 (0.6)	1 (0.2)	0 (0)	5	2	1	1
Total	5 (0.6)	1 (0.1)	0 (0)	7
DEEP^Citation18,Citation19
Females	1 (0.4)	1 (0.4)	0 (0)	3	1	2	0
Males	3 (0.4)	0 (0)	0 (0)	3	2	1	0
Total	4 (0.6)	1 (0.2)	0 (0)	6
EVOLUTION^Citation20
Females	12 (3.2)	0 (0)	3 (0.8)	24	12	6	6
Males	10 (3.9)	1 (0.4)	0 (0)	12	5	3	2
Total	22 (3.5)	1 (0.2)	3 (0.5)	36
AXEPT^Citation21
Females	1 (0.2)	0 (0)	0 (0)	1	0	0	0
Males	0 (0)	1 (0.3)	0 (0)	2	2	0	0
Total	1 (0.1)	1 (0.1)	0 (0)	3
ICEBERGa
Females	3 (0.8)	0 (0)	0 (0)	3	2	0	1
Males	6 (1.2)	1 (0.2)	0 (0)	8	2	1	5
Total	9 (1.0)	1 (0.1)	0 (0)	11
SYNERGY^Citation17
Females	7 (6.7)	0 (0)	0 (0)	7	2	4	0
Males	5 (4.1)	3 (2.5)	0 (0)	11	5	6	0
Total	12 (5.3)	3 (1.3)	0 (0)	18
CETRA^Citation23
Females	17 (5.5)	15 (4.9)	6 (1.9)	68	ND	ND	ND
Males	44 (8.0)	8 (1.5)	16 (2.9)	115	ND	ND	ND
Total	61 (7.1)	23 (2.7)	22 (2.6)	183
Total evaluable patients
Females	43 (1.9)	16 (0.7)	9 (0.4)	108
Males	71 (2.7)	15 (0.6)	16 (0.6)	156
Total	114 (2.3)	31 (0.6)	25 (0.5)	264

Notes: Percentages calculated over total number of evaluable patients.

a Rizzetto et al, unpublished data, 2011; Bandiera et al, unpublished data, 2012.

Abbreviations: AE, adverse event; ND, not determined.

Figure 1 Evolution of AEs by gender.

Note: Percentages calculated over total number of AEs during observation with available data on evolution (N=256).
Abbreviation: AEs, adverse events.

Table 6 Serious adverse events (SAEs) occurred during study

Study	Patients with ≥1 SAE during in the study	Females N (%)	Males N (%)	Total evaluable patients, N (%)
DEEP^Citation18,Citation19	No SAE	236 (100.0)	381 (100.0)	617 (100.0)
	Total evaluable patients	236 (100.0)	381 (100.0)	617 (100.0)
EVOLUTION^Citation20	No SAE	378 (99.7)	253 (98.8)	631 (99.4)
	≥1 SAE	1 (0.3)	3 (1.2)	4 (0.6)
	Total evaluable patients	379 (100.0)	256 (100.0)	635 (100.0)
AXEPT^Citation21	No SAE	544 (100.0)	311 (100.0)	855 (100.0)
	Total evaluable patients	544 (100.0)	311 (100.0)	855 (100.0)
CETRA^Citation23	No SAE	299 (96.8)	526 (96.0)	825 (96.3)
	≥1 SAE	10 (3.2)	22 (4.0)	32 (3.7)
	Total evaluable patients	309 (100.0)	548 (100.0)	857 (100.0)
PSYCHAE^Citation16,Citation22	No SAE	309 (100.0)	477 (100.0)	786 (100.0)
	Total evaluable patients	309 (100.0)	477 (100.0)	786 (100.0)
SYNERGY^Citation17	No SAE	104 (100.0)	120 (99.2)	224 (99.6)
	≥1 SAE	0 (0)	1 (0.8)	1 (0.4)
	Total evaluable patients	104 (100.0)	121 (100.0)	225 (100.0)
ICEBERGd	No SAE	375 (99.5)	513 (99.0)	888 (99.2)
	≥1 SAE	2 (0.5)	5 (1.0)	7 (0.8)
	Total evaluable patients	377 (100.0)	518 (100.0)	895 (100.0)
	Total pts with ≥1 SAEa	13 (0.6)	31 (1.2)b	44
	Total SAE	13 (28)	34 (72)c	47
	Deaths	0	2	2
	Persistent or significant disability or inability	0	2	2
	Hospitalizations	13	27	40
	Life-threatening events	0	3	3
	Total evaluable patients	2,258 (100.0)	2,612 (100.0)	4,870 (100.0)

Notes:

a χ² test, P=0.0246.

b Percentages calculated for the total number of evaluable patients.

c Percentages calculated for the total number of SAEs.

d Rizzetto et al, unpublished data, 2011; Bandiera et al, unpublished data, 2012.

Abbreviation: pts, patients.

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