Antihypertensive drug therapy and hypoglycemia in elderly diabetic patientstreated with insulin and/or sulfonylureas

Andrea Corsonello1,2, Claudio Pedone3, Francesco Corica1, Alba Malara1,Luciana Carosella3, Antonio Sgadari3, Vittorio Nicita Mauro1, Domenico Ceruso1,Marco Pahor4 & Pierugo Carbonin3 for the Gruppo Italiano di Farmacovigilanzanell'Anziano (GIFA)1Department of Internal Medicine, University of Messina; 2Division of Geriatric Medicine and Neuromotor Rehabilitation ±

Stroke Unit, Italian National Research Centres on Aging (INRCA), Cosenza; 3Department of Internal Medicine and Geri-

atrics, Catholic University, Rome, Italy; 4Sticht Center on Aging, Department of Internal Medicine, Wake Forest University,

Winston Salem, NC, USA

Accepted in revised form 24 September 1999

Abstract. We performed this case±control study toevaluate the risk of hypoglycemia associated with theuse of antihypertensive drugs in older hospitalizeddiabetic patients treated with sulfonylureas and/orinsulin. All diabetic patients admitted during 4months in 1988, 1 month in 1991, 4 months in 1993and 4 months in 1995 (n = 3477, mean age71.4 � 0.2 years, 1542 males and 1935 females) wereenrolled in the study. During the four annual surveys86 patients (mean age 71.1 � 1.4 years, 33 males and53 females) presented hypoglycemia during hospitalstay. The patients who presented hypoglycemia wereless frequently users of sulfonylureas and more fre-quently users of a combination of insulin andsulfonylureas. Use of antihypertensive drugs wassimilar in the two groups studied, and amongpotentially interacting drugs considered in the

analysis, sulfonamides were more frequently used inpatients who experienced hypoglycemia. Moreover,patients with hypoglycemia used a higher number ofdrugs, had a longer length of stay and had a greaterprevalence of hypoglycemia as admission problem.Finally, although not signi®cant, liver and renaldiseases were more frequent among patients withhypoglycemia. In the multivariate analysis, contem-porary use of insulin and sulfonylureas, liver diseaseand length of stay were signi®cantly associated withhypoglycemia, while none of the antihypertensivedrugs showed a signi®cant association with theoccurrence of hypoglycemia during hospital stay. Ourresults indicate that antihypertensive drugs do notincrease the risk of hypoglycemia in elderly diabeticpatients.

Key words: Antihypertensive drugs, Elderly, Hypoglycemia, Non-insulin dependent diabetes mellitus

Abbreviations: ACE = angiotensin-converting enzyme; ADR = adverse drug reaction; ATC = AnatomicalTherapeutic and Chemical codes; GIFA = Gruppo Italiano di Famacovigilanza nell'Anziano ± Italian Groupof Pharmacoepidemiology in the Elderly; ICD-9 CM = International Classi®cation of Diseases, 9th revision,Clinical Modi®cation; NIDDM = non-insulin dependent diabetes mellitus

Introduction

In theory certain antihypertensive drugs may pro-mote hypoglycemia, but the issue remains contro-versial. An increased risk of hypoglycemia is aparticularly concerning problem in older diabeticpatients who have a blunted counterregulatoryhormone response to hypoglycemia [1].

It is a common belief that b-blockers should beavoided in diabetic patients because they mayprolong hypoglycemia and mask hypoglycemicsymptoms. On the other hand, hypertensive diabeticpatients treated with b-blockers and diuretics show asimilar or greater reduction of coronary heart disease

and total cardiovascular events with respect topatients without diabetes [2], and a decreased rate ofsudden death, overall mortality and recurrent myo-cardial infarction has been observed in patients withprevious myocardial infarction [3, 4].

Angiotensin-converting enzyme (ACE) inhibitorsmay increase insulin sensitivity [5, 6]. Case reports[7, 8] and two case±control studies [9, 10] have foundan association between hypoglycemia and use ofACE-inhibitors, but several other studies failed to®nd any e�ect of ACE-inhibitors on glucose metab-olism [11±15]. A recent retrospective cohort studyshowed that antihypertensive drug therapy had littleimpact on the risk of hypoglycemia in elderly diabetic

European Journal of Epidemiology 15: 893±901, 1999.Ó 1999 Kluwer Academic Publishers. Printed in the Netherlands.

patients treated with insulin or sulfonylureas [16], anda case±control study demonstrated that the associa-tion between hypoglycemia and ACE-inhibitors wasrelated to concomitant use of antidiabetic agents [17].ACE-inhibitors reduce the risk of cardiovascular andrenal disease in patients with diabetes [18, 19], and theissue of an excess risk of hypoglycemia is particularlyconcerning.

The purpose of this case±control study was toassess the risk of hypoglycemia associated with theuse of antihypertensive drugs in older hospitalizedpatients treated with sulfonylureas and/or insulin.

Methods

The present study uses data of the Gruppo Italianodi Farmacovigilanza nell'Anziano (GIFA), acollaborative study of adverse drug reactions inhospitalized patients. The study population com-prised all patients with non-insulin dependentdiabetes mellitus (NIDDM) treated with sulfonyl-ureas and/or insulin followed from hospital admis-sion through discharge.

PatientsThe methods of the GIFA have been described indetail elsewhere [20±23]. Brie¯y, all patients admittedto 45 hospital wards from 1 May to 30 June and from1 November to 31 December 1988, to 58 hospitalwards from 15 May to 14 June 1991, to 35 hospitalwards from 1 May to 30 June and from 1 Septemberto 31 October 1993 and to 40 hospital wards from1 May to 30 June and from 1 September to 31 Oc-tober 1995 were enrolled in the study and followeduntil discharge. There were no inclusion or exclusioncriteria. The majority of patients were admitted fromthe Emergency Room at each hospital, and the di-agnosis made by the on-call physician in the Emer-gency Room was recorded. Overall, 81 clinical centersthroughout Italy participated in the study. For eachpatient, a questionnaire was completed at admissionand updated daily by a study physician who receivedspeci®c training for the study. Data recorded in-cluded demographic characteristics, drugs taken priorto admission and during hospital stay, and thoseprescribed at discharge, adverse drug reactions, rou-tine blood examination tests, cognitive function, ad-mission and discharge diagnoses. Data of bloodexamination tests were not collected in 1991, andpatients with missing data were excluded during theanalytical procedure using casewise deletion. All datawere recorded at the clinical center on a microcom-puter by means of a dedicated, user-friendly compiledDBase III program. Such a program controlled thesuitability and the internal consistency of the data sothat impossible values or contradictory informationcould not be entered. The software allowed automaticcoding of diagnoses, of adverse drug reactions

(ADRs) and of drugs by simple typing the descriptionof the disease, of the ADR, or of the commercialname of the drug.

OutcomeHypoglycemia was the primary outcome of this studyand an analytical variable for presence or absence ofhypoglycemia during hospital stay was created bymeans of GIFA database ADRs codes, according tothe World Health Organization classi®cation [24].The attending physician judged if the patient had anevent, and the strength of the association between theevent and the suspected drug was assessed by theNaranjo et al. algorithm [25].

ExposureThe drugs were coded according to the AnatomicalTherapeutic and Chemical (ATC) codes and to spe-ci®c drug product codes of the Italian Ministry ofHealth [26]. An analytical variable was created foruse of sulfonylureas, insulin or combination of insu-lin and sulfonylureas. Similarly, an analytical vari-able was created for use of antihypertensive drugs asfollows: no use, calcium channel blockers, diuretics,angiotensin-converting enzyme inhibitors, b-blockersor others, and associations of antihypertensives (useof two or more antihypertensive drugs taken at thesame time) during hospital stay. We also considered adichotomous variable for use±no use of antihyper-tensive drugs in addition to the multi-level variable.The use of other potentially interacting drugs (all-opurinol, antianginal drugs, H2-receptors antago-nists, digitalis glycosides, salycilates, sulfonamides)was considered in the analysis. Finally, the number ofdrugs that excluded the antihypertensives was calcu-lated.

Potential confoundersThe hospital diagnoses were coded according toInternational Classi®cation of Diseases, 9th revision,Clinical Modi®cation (ICD-9 CM) codes [27]. Toquantify comorbidity, the Charlson comorbidityindex score was computed by adding the scores thatwere assigned to speci®c discharge diagnoses [28, 29].A score of 1 was attributed to myocardial infarction(codes 410±410.9, 412), congestive heart failure (codes428±428.9), peripheral vascular disease (codes 443.9,441±441.9, 785.4, V43.4), cerebrovascular disease(codes 430±438), dementia (codes 290±290.9), chronicpulmonary disease (codes 490±496, 500±505, 506.4),rheumatologic disease (codes 710.0, 710.1, 710.4,714.0±714.2, 714.8, 725), peptic ulcer disease (codes531±534.9, 531.4±531.7, 532.4±532.7, 533.4±533.7,534.4±534.7), mild liver disease (codes 571.2, 571.5,571.6, 571.4), and diabetes (codes 250±250.3, 250.7).The following diseases scored 2: diabetes with chroniccomplications (codes 250.4±250.6), hemiplegia orparaplegia (codes 344.1, 342±342.9), renal disease(codes 582±582.9, 583±583.7, 585, 586, 588±588.9),

894

any malignancy, including leukemia and lymphoma(codes 140±172.9, 174±195.8, 200±208.9). Moderateor severe liver disease (codes 572.2±572.8, 456.0±456.2) scored 3. Finally, a score of 6 was assigned tometastatic solid tumor (codes 196±199.1) and AIDS(codes 042±044.9). In addition, speci®c dischargediagnoses, such as congestive heart failure (codes428±428.9), diabetes with chronic complications(codes 250.4±250.6), chronic liver disease (codes571.2, 571.5, 571.6, 571.4, 572.2±572.8, 456.0±456.2)and renal disease (codes 582±582.9, 583±583.7, 585,586, 588±588.9) were analyzed as separate variables.Furthermore, the diagnosis of hypoglycemia asadmission problem (codes 251.0, 251.2) was consid-ered as a potential confounder.

Height and weight were measured on admission,and body mass index (BMI) was calculated by di-viding body weight expressed in kilograms by thesquared height expressed in meters. Plasma glucose(mg/dl) and albumin (g/l) measured at the admissionwere also considered in the analysis. For men, thecreatinine clearance (ml/min) estimate was calculatedwith the following formula [30]: ([140)age] ´ weightin kg)/(72 ´ serum creatinine in mg/dl). For women,the value was reduced to 85% of that estimated withthis equation.

Finally, type of ward (geriatric, medicine or others)was also evaluated and length of hospital stay wascalculated.

Data analysisAll analyses were performed using SPSS V 7.5 sta-tistical software package (SPSS, Chicago, IL, USA).In univariate analyses, for categorical variables, thep-value for the association with hypoglycemia wascalculated by means of the Fisher's Exact test anddata were presented as number of cases with percentin parentheses. The unpaired t-test was used tocompare continuous variables and data werepresented as mean � standard error of the mean. Toassess independent predictors of hypoglycemia, age,sex, antihypertensive drugs and those risk factorssigni®cant at the p < 0.2 level in the univariateanalyses were entered into the multivariate logisticregression summary. The odds ratios (ORs) and their95% con®dence intervals (CI) were calculated. Two-tailed p-values were reported.

Results

The total number of patients enrolled in this studywas 24,575. Among these, 3477 were using antidia-betic drugs, mean age was 71.4 years, 1542 weremales and 1935 females. During the four annualsurveys, 86 patients (2.47%) presented a hypoglyce-mia during hospital stay. In univariate analysis, nostatistically signi®cant di�erence was found betweenthose with and without hypoglycemia as regards age,

sex, BMI, albuminemia, creatinine clearance, fastingplasma glucose, Charlson comorbidity score and typeof ward. The patients who presented hypoglycemiawere less frequent users of sulfonylureas and morefrequent users of a combined therapy. Use of anti-hypertensive drugs was similar in the two groupsstudied, and among potentially interacting drugsconsidered in the analysis, sulfonamides were morefrequently used in patients who experienced hypo-glycemia, and a similar, but not signi®cant, trend wasobserved for the use of antianginal drugs. Moreover,patients with hypoglycemia used a higher number ofdrugs, had a longer length of stay and had a greaterprevalence of hypoglycemia as admission problem.Finally, although not signi®cant, liver and renal dis-eases were more frequent among patients with hy-poglycemia (Tables 1±3).

In the multivariate logistic regression analysis,contemporary use of insulin and sulfonylureas, liverdisease and length of stay were signi®cantly associ-ated with hypoglycemia (goodness of ®t 3343.694).Moreover, use of sulfonamides or antianginal drugs,renal disease and hypoglycemia as admission prob-lem showed an increase in risk of hypoglycemia,without reaching statistical signi®cance. None of theantihypertensive drugs showed a signi®cant associa-tion with the occurrence of hypoglycemia duringhospital stay. However, although not signi®cant, useof calcium channel blockers showed an increase inrisk, while use of ACE-inhibitors, diuretics or com-bination of antihypertensives showed a decrease inrisk of hypoglycemia (Table 4). Finally, we per-formed multivariate logistic regression analysis usingthe dichotomous variable for use±no use of antihy-pertensive drugs instead of the multi-level variable foruse of di�erent classes of antihypertensives, and wefound that use of any antihypertensive drugs was notsigni®cantly associated to hypoglycemia (OR: 0.71;95% CI: 0.45±1.11; p-value 0.134).

Discussion

This study indicates that antihypertensive therapywas not associated with an increased risk of hypo-glycemia during hospital stay. Our ®ndings do notcon®rm recent studies [9, 10], in which an increasedrisk of hypoglycemia was found in ACE-inhibitorsusers. On the other hand, Shorr et al. [16] failed to®nd any association between antihypertensive drugsexposure and hypoglycemia in elderly diabetics usinginsulin or sulfonylureas, while Moore et al. [17] foundthat ACE-inhibitor-associated hypoglycemia seemsto be related to concomitant use of antidiabeticdrugs.

Although some clinical studies indicate that ACE-inhibitors use can be associated with an improvedinsulin sensitivity [5, 6], several authors did not ®ndany e�ect of ACE-inhibitors on glucose metabolism

895

[11±15], thus further studies are needed to betterclarify the possible relationship between ACE-inhib-itors use and insulin sensitivity.

We included in our analysis variables re¯ecting thetype of diabetes treatment and use of other poten-tially interacting drugs because the associationbetween ACE-inhibitors use and hypoglycemia couldbe biased if ACE-inhibitors were preferentially pre-scribed to patients already at an increased risk ofhypoglycemia, and we also analyzed the use of thecombination of insulin with oral antidiabetic agents.Patients treated with both insulin and sulfonylureasshowed a greater risk of hypoglycemia, and use ofsulfonamides tended to be associated with hypogly-cemia in univariate analysis. The concomitant use ofinsulin and sulfonylureas was not extensively evalu-ated in previous studies [9, 10, 16], and recently re-ported ®ndings indicate that combined hypoglycemictherapy is a potential confounder in the assessment of

the risk of hypoglycemia [31]. Furthermore, hypo-glycemia resulting from the combination of antidia-betic drugs and sulfonamides is a known druginteraction [32, 33], thus this variable should beconsidered as a potential confounder.

In the Herings et al. study [9], no adjustment wasmade for the presence of congestive heart failure,diabetes with chronic complications, liver disease orrenal dysfunction, while in the Morris et al. study[10], diabetes duration, glycemic control and serumcreatinine were not associated to hypoglycemia inunivariate analysis. On the other hand, since heartfailure and renal dysfunction may independently in-crease the risk of hypoglycemia by reducing insulinclearance, and liver disease could be associated withreduced albuminemia and increased oral antidiabeticdrugs bioavailability, it is reasonable to speculate thatthese coexistent conditions are potential confoundersin the assessment of risk of hypoglycemia. Moreover,

Table 1. Characteristics of patients divided according to occurrence of hypoglycemia during hospital stay

No hypoglycemiaduring hospital stay

(n = 3391)

Hypoglycemiaduring hospital stay

(n = 86)

p-value

Age (years)a 71.4 � 0.2 71.1 � 1.4 0.835Sex (males)b 1509 (44.5%) 33 (38.4%) 0.273BMI (kg/m2)a, c 25.9 � 0.1 25.4 � 0.6 0.394

Plasma glucose (mg/dl)a, d 197.8 � 2.2 194.2 � 19.8 0.830Plasma albumin (g/dl)a, e 3.66 � 0.02 3.55 � 0.12 0.338Creatinine clearance (ml/min)a, f 63.7 � 0.6 69.1 � 5.6 0.282

Type of wardb 0.663

Geriatric 1720 (50.7%) 46 (53.5%)Medicine or others 1671 (49.3%) 40 (46.5%)

Length of stay (days)a 17.4 � 0.3 25.1 � 2.3 0.001

a Mean � standard error of the mean (unpaired t-test).b Number of cases with percent in parentheses (Fisher's exact test).c No hypoglycemia during hospital stay (n = 2494); Hypoglycemia during hospital stay (n = 59).d No hypoglycemia during hospital stay (n = 2130); Hypoglycemia during hospital stay (n = 38).e No hypoglycemia during hospital stay (n = 1219); Hypoglycemia during hospital stay (n = 32).f No hypoglycemia during hospital stay (n = 2185); Hypoglycemia during hospital stay (n = 37).

Table 2. Discharge diagnoses, admission for hypoglycemia and Charlson index in the patients divided according tooccurrence of hypoglycemia during hospital stay

No hypoglycemiaduring hospital stay

(n = 3391)

Hypoglycemiaduring hospital stay

(n = 86)

p-value

Discharge diagnosesa

Congestive heart failure 358 (10.6%) 9 (10.5%) 1.000Diabetes with chronic complications 182 (5.4%) 6 (7.0%) 0.467

Liver disease 267 (7.9%) 11 (12.8%) 0.105Renal disease 189 (5.6%) 8 (9.3%) 0.151

Hypoglycemia as admission problema 84 (2.5%) 5 (5.8%) 0.068Charlson comorbidity scoreb 2.0 � 0.03 1.9 � 0.14 0.293

aNumber of cases with percent in parentheses (Fisher's exact test).bMean � standard error of the mean (unpaired t-test).

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ACE-inhibitors could be more frequently prescribedto patients with chronic complications from diabetesto slow disease progression. In our study the diag-noses of congestive heart failure, diabetes withchronic complications, liver or renal disease wereconsidered as potential confounders, and since in theunivariate analysis only the presence of liver or renaldisease showed a trend for association with hypo-glycemia, these variables were entered in the multi-variate analysis. In this way we found an increasedrisk of hypoglycemia in patients with liver or renaldisease, which was statistically signi®cant for liverdisease. Moreover, although not signi®cant, the ad-mission for hypoglycemia was associated to an in-creased risk of hypoglycemia during hospital stay,thus indicating that it may be a relevant confounderin the assessment of risk of hypoglycemia.

Finally, we also detected a signi®cant associationof length of stay with hypoglycemia. This ®nding maybe explained by a longer exposure to the risk, andthus, a greater probability to experience an adverseevent. In fact, a previous GIFA report showed thatthe length of hospital stay may represent a risk factorfor any ADR [22]. Alternatively, the hypoglycemiamay have resulted in an increase in length of stay.

Interestingly, although not signi®cant, calciumchannel blockers tended to be associated to an

increased risk of hypoglycemia, while ACE-inhibi-tors, diuretics and combined antihypertensives tendedto be associated to a decrease in risk. However, thewide con®dence intervals for these variables probablyindicate a reduced statistical power due to the smallsample size.

Our study has some limitations. Though the pres-ent study did not con®rm previous ®ndings, an in-creased risk of hypoglycemia cannot be ruled out. Asstated above, the sample studied was relatively smalland a type II error may have occurred. However, thesmall number of events could be partially explainedby the fact that, due to our methodology, only clin-ically relevant events were reported. Furthermore,some variables could have been changed widely in thetime span considered (e.g. the prevalence of the use ofACE inhibitors) and the sample studied could beheterogeneous. Anyway, since we did not performany comparison between patients enrolled in di�erentsurvey periods, it is unlikely that the hetereogeneityof patients may a�ect the results.

Moreover, signi®cant results in the ®nal logisticregression summary are probably borderline signi®-cant. In fact, although odds ratios for use of combi-nation of insulin and sulfonylureas and liver diseasesuggest a doubling of risk for hypoglycemia, the95% lower con®dence limit is only 1.05 and 1.0,

Table 3. Use and number of drugs during hospital stay in the patients divided according to occurrence of hypoglycemiaduring hospital stay

No hypoglycemia

during hospital stay(n = 3391)

Hypoglycemia

during hospital stay(n = 86)

p-value

Hypoglycemic therapya 0.039Sulfonylureas 1414 (41.7%) 27 (31.4%)

Insulin 1546 (45.6%) 41 (47.7%)Insulin + sulfonylureas 431 (12.7%) 18 (20.9%)

Use of any antihypertensive drugsa 0.277No users 1729 (51.0%) 49 (57.0%)

Users 1662 (49.0%) 37 (43.0%)

Use of di�erent classes of antihypertensive drugsa 0.287

No use 1729 (51.0%) 49 (57.0%)Ca-channel blockers 271 (8.0%) 11 (12.8%)Diuretics 585 (17.3%) 13 (15.1%)

Ace-inhibitors 262 (7.7%) 4 (4.7%)b-blockers or others 38 (1.1%) 1 (1.2%)Associations of antihypertensives 506 (14.9%) 8 (9.3%)

Number of drugsb 6.3 � 0.1 7.7 � 0.6 0.014

Potentially interacting drugsa

Allopurinol 172 (5.1%) 5 (5.8%) 0.624H2-receptor antagonists 764 (22.5%) 20 (23.3%) 0.896Anti-anginal drugs 913 (26.9%) 29 (33.7%) 0.176Digitalis glycosides 989 (29.2%) 30 (34.9%) 0.280

Salycilates 294 (8.7%) 5 (5.8%) 0.439Sulfonamides 50 (1.5%) 4 (4.7%) 0.043

aNumber of cases with percent in parentheses (Fisher's exact test).bMean � standard error of the mean (unpaired t-test).

897

respectively (i.e. small increase in risk of 5% and0%). Similarly, the association between length of stayand hypoglycemia should probably be considered amodest clinically important ®nding (average increasein risk of 5% per 5 days period).

Our database did not allow us to evaluate the di-abetes and drugs exposure duration, thus our ®ndingsare referred to the actual drug consumption and abias could occur because patients had di�erent drugsexposure times. Finally, although we failed to ®ndany association between the use of b-blocking agentsand risk of hypoglycemia, the use of these drugs wasrare in our study. In fact, it is generally believed thatb-blockers blunt hypoglycemic awareness, thus pro-longing hypoglycemia. However, although b-blockersreduce heart rate and blood pressure responses dur-ing hypoglycemia, other warning symptoms, such asdiaphoresis, are una�ected [34] or accentuated [35].Furthermore, b-blocking agents are potentially usefuldrugs in diabetic patients with hypertension or heartdisease [36], and it should be kept in mind that theclinical relevance of the above contraindication hasnot been clearly assessed, and the risk of symptomsmasking probably does not outweigh the potentialbene®ts of these drugs in the treatment of diabeticpatients with myocardial infarction [3, 4].

Our results suggest that antihypertensive drugs useis not associated to an increased risk of hypoglycemia

in elderly hospitalized diabetic patients. Althoughfurther studies are needed to better evaluate the risk ofhypoglycemia associated with use of antihypertensiveagents, this risk probably does not outweigh thebene®ts of these drugs in diabetic patients withchronic complications.

Appendix

List of the GIFA investigators

Coordinating center

Principal investigator: P.U. CarboninInvestigators: Marco Pahor, Luciana Carosella, AntonioSgadari, Giuseppe ZuccalaÁ , Claudio Pedone, RobertoBernabei.

Participating centers

1. Acquaviva delle Fonti ± Ospedale Regionale `Miulli' ±

V. Aloia, G. Baldassarre, L. Venezia2. Agnone ± P. Occhionero, I. Masciotra, P. Pescetelli3. Ancona ± Centro di Patologia Cardiovascolare,

INRCA ± E. Paciaroni, A. Andreoni, P. Angelini,L. Gigli, C. Ferroni, P.F. Tomassini

4. Ancona ± Divisione di Medicina II, INRCA ± G. DeTommaso, M. Badiali, F. Guidi

5. Ancona ± Divisione di Geriatria, INRCA ± R. Gaetti,G. Cadeddu, F. Giovagnoli

Table 4. Relations of selected risk factors to hypoglycemia during hospital staya

ORs 95% CI p-value

Age (10-years increase) 0.98 0.81±1.18 0.807Sex (males) 0.74 0.47±1.17 0.194

Hypoglycemic therapy

Sulfonylureas 1.0Insulin 1.15 0.69±1.93 0.591Insulin + sulfonylureas 1.94 1.05±3.59 0.034

Antihypertensive drugs

No use 1.0Ca-channel blockers 1.54 0.78±3.05 0.211Diuretics 0.63 0.33±1.21 0.168Ace-inhibitors 0.55 0.19±1.55 0.259

b-blockers or others 0.95 0.13±7.20 0.963Associations of antihypertensives 0.46 0.21±1.02 0.060

Potentially interacting drugsAnti-anginal drugs 1.44 0.89±2.34 0.139

Sulfonamides 2.27 0.74±6.99 0.153

Number of drugs (1-drug increase) 1.02 0.99±1.05 0.224

Discharge diagnosesLiver disease 2.01 1.0±4.04 0.050Renal disease 1.79 0.82±3.89 0.143

Hypoglycemia as admission problem 2.38 0.92±6.12 0.073

Length of stay (5-days increase) 1.05 1.01±1.08 0.003

aOdds ratios (ORs) and 95% con®dence intervals were calculated by entering simultaneously all variables in the logisticregression model.

898

6. Appignano ± Divisione di Geriatria, INRCA ± S.Bonaiuto, L. Panichetti, P.F. Tomassini, E. Giannan-

drea7. Avellino ± Dipartimento di Geriatria, Ospedale

Ma�ucci ± M. Lingetti, F. Di Grezia, A. Marro,E. Piermatteo, P. Sorrentino,

8. Bari ± Cattedra di Gerontologia, UniversitaÁ di Bari ±A. Capurso, C. Capurso, D. Ciancia, N. Marella,G. A. Nardo', G. Nicoletti, F. Resta, Giovanni S.,

V. Solfrizzi, G. Triggiani, A. Venezia, E. Vespertino9. Bari ± Clinica Malattie Nervose e Mentali, UniversitaÁ

di Bari ± E. Ferrari and coworkers.

10. Bologna ± Centro Aterosclerosi, Policlinico S. Orsola-Malpighi ± A. Gaddi, B. Benassi, S. D'Addato, G. DeSimone, A. Dormi, C. Galetti, G. Magri, L. Marri,

D. Pomata, G. Volta11. Bologna ± Terza Divisione Geriatrica, Ospedale

Malpighi di Bologna ± D. Cucinotta, F. Cavazzuti,M. Corneli, R. Del Buono, P. Kalfus, R. Manopulo

12. Bologna ± Patologia Medica I, Policlinico S. Orsola ±G. Ravaglia, F. Boschi, M. Buttazzo, A. Cicognani,P. Forti, F. Maioli

13. Brindisi ± Divisione di Neurologia, Ospedale A.Di Summa ± G. Masi, C. Nozzoli, B. Passarella,C. Monetti

14. Cagliari ± Divisione di Geriatria, Ospedale SS. TrinitaÁ

± M. Jovine, P.F. Putzu, M.R. Frau15. Campobasso ± Divisione di Medicina Interna, Ospe-

dale Cardarelli ± L. Carile, O, Grassi, T. SanzoÁ

16. Campoli del Monte ± Divisione Cardiologica, CentroMedico di Riabilitazione ± F. Rengo, N. Ferrara,A. Nicolino

17. Castelfranco Veneto ± Divisione di Neurologia,Ospedale Civile ± V. Toso, L. Bartolomei

18. Chieti ± Istituto Clinica Geriatrica, UniversitaÁ `G.

D'Annunzio' ± G. Abate, M. D'Aviero, M. A. Cavoni,S. Capasso, C. Cervone, L. D'Andrea, F. Di Gi-angiacomo, A. Di Iorio, P. Lamanna, T. Palmerio,

F. Pennese, G. Maria Puddu, L. Savini, M. Zito19. Chieti ± Istituto di Clinica Medica, UniversitaÁ di Chieti

± S. Sensi, A. Blasioli20. Cortona ± UnitaÁ Operativa di Medicina Generale,

Ospedale Civile ± M. Ricca, F. Cosmi, M. Margioni.21. Cosenza ± Divisione Medicina Geriatrica, INRCA ±

F. Corsonello, E. Cundari, G. Gaudio, B. Mazzei,

L. Pranno, C. Zottola22. Cosenza ± Servizio di Neuroriabilitazione, USL 9 ±

L. Pugliese and coworkers

23. Eboli ± Divisione di Geriatria, Presidio OspedalieroEboli ± L. D'Alessandro, V. Butrico, M. R. Coccaro,D. Di Biase, R. Esposito, M. Mandia

24. Fano ± Divisione di Geriatria, Ospedale S. Croce ±

M. Cuzzupoli, P. Candelora25. Ferrara ± Istituto di Medicina Interna II, UniversitaÁ di

Ferrara ± R. Fellin, A. Passaro, F. Romagnoni, S. V.,

G. Zuliani26. Firenze ± Dipartimento di Farmacologia, Universita'

di Firenze ± A. Mugelli, E. Cecchi

27. Firenze ± Istituto di Geriatria, UniversitaÁ di Firenze ±G. Masotti, E. Biondi, S. Fumagalli, L. Magherini,N. Marchionni, M. Marini, L. Matteucci

28. Firenze ± Istituto di Clinica Medica ± Universita' diFirenze ± G. Gensini, E. Cangioli, S. Del Pace,S. Gioni, I. Simone, A. Crucitti

29. Foiano ± Divisione di Medicina, Ospedale di Foianodella Chiana ± C. Pedace, P. Corsi, S. Simonetti

30. Genova ± Gerontologia e Geriatria, Dipartimentodi Medicina Interna ± R. Balestreri, V. Aimale,M.G. Carli, P. Cavagnaro, U. Compagnoni,R. Pizzorno, P. Mosca

31. Isernia ± Divisione di Medicina Interna, Ospedale F.Veneziale ± E. Melaragno, E. Calabrese, I. Masciotra,G. Angelone, C. Disernia

32. Larino ± divisione di Medicina Generale, OspedaleCivile ± F. Por®lio, N. Frate, A. Potena

33. Loiano ± Divisione di Medicina Interna, Ospedale

`Simiani' ± A. Bernardini, R. Nardi, D. Panuccio,M.R. Trabatti

34. Messina ± Dipartimento di Medicina Interna, Scuola

Specializzazione in Geriatria ± D. Ceruso, A. Allegra,S. Bonanzinga, C. Bontempo, L. Castagna, F. Corica,A. Corsonello, G. Cucinotta, T. De Gregorio, I. GranaÁ ,M. Pensabene, F. Rubino, M.S. Giacobbe, S. Chi-

arenza, A. Artuso35. Messina ± I Clinica Neurologica, Policlinico Gazzi ±

R. Di Perri, P. La Spina, R. Mussolino

36. Milano ± Cattedra Medicina Interna II, UniversitaÁ diMilano ± P. M. Mannucci, P. Ferrazzi, D. Mari,M. Venturati

37. Milano ± Istituto Pio Albergo Trivulzio ± A.E. Tam-maro, A. Borghese, G. Campiglio, L. Laghi, C. NegriChinaglia, L. Palvarini, C. Albanese

38. Modena ± Cattedra di Geriatria e Gerontologia,

Universita' di Modena ± G. Salvioli, S. Ascari,C. Mussi

39. Napoli ± Dipartimento di Geriatria, UniversitaÁ di

Napoli ± M. Varricchio, L. Amato, S. Ammen-dola, V. Balbi, A. Gambardella, L. Pesce, M. R.Rizzo, M. R. Tagliamonte, R. Tortoriello, G.

Cennamo40. Napoli ± IV Divisione Medicina Interna, UniversitaÁ di

Napoli ± L. SaccaÁ , V. Coto

41. Napoli ± Istituto di Medicina Interna, Cattedra diGeriatria ± F. Rengo, P. Abete, P. Caccese, P. Landino

42. Napoli ± Divisione di Neurologia, Ospedale Cardarelli± L. Stella, A.M. Fasanaro, V. Pizza

43. Napoli ± Istituto di Scienze Neurologiche, I PoliclinicoUniversitario ± B. Bonavita, G. Tedeschi

44. Novara ± III Divisione di Medicina, Ospedale

Maggiore ± C. Franzini, M. Sartori, M. Ruzza,S. Andorno

45. Padova ± Chirurgia Geriatrica, UniversitaÁ di Padova ±

O. Terranova, M. Baldan, D. Celi46. Padova ± Terza Divisione Geriatria, Ospedale Geri-

atrico ± O. De Candia, V. Bernini, M. Fabbris47. Palermo ± Divisione Medicina Geriatrica, Ospedale

Villa So®a ± A. Pardo, M. C. Fuschi, M. Pagano,M. Russotto, M. Sapienza, A. Spagnuolo

48. Palermo ± Istituto di Medicina Interna e Geriatria,

UniversitaÁ di Palermo ± G. Barbagallo, M. Barba-gallo, G. Castiglione, G. Catania, G. Di Lorenzo,A. Di Sciacca, A. Geraci, M. Lo Bue, G. Lucania,

F. Raspanti49. Parma ± Cattedra di Geriatria, UniversitaÁ di Parma ±

G. Valenti, D. Magnani

50. Parma ± Istituto Clinica Medica, UniversitaÁ di Parma± M. Passeri, M. C. Baroni, E. Courlios, A. De Blasio,R. Delsignore, R. Fiorini, S. Vourna

899

51. Perugia ± Cattedra di Gerontologia e Geriatria,UniversitaÁ di Perugia ± U. Senin, S. Cesarini,

A. Cherubini, M. Freddio, A. Longo, P. Mecocci,B. Salatino

52. Pontremoli ± Divisione di Medicina, Ospedale S. An-tonio Abate ± A. Leone, P. Fabiano, A. Martelli

53. Prato ± Divisione di Geriatria, Ospedale di Prato ±A. Bavazzano, F. Boni, D. Calvani, R. Guarducci,M.P. Lunardelli, A. Mitidieri Costanza

54. Roma ± Cattedra di Geriatria, UniversitaÁ `La Sap-ienza' ± V. Marigliano, L. Capponi, P. Cicconetti,M. G. Di Bernardo, C. F. Di Gioacchino, L. Perse-

chino, F. Thau55. Roma ± Dipartimento di Medicina Clinica, UniversitaÁ

la Sapienza ± P. Serra, P. Carfagna, M. Gaglie',

V. Paravati, A. Paris56. Roma ± Divisione di Medicina, Ospedale Fate-

benefratelli ± E. Bologna, A.M. Sidoti, D. Terracina,M. Di Girolamo

57. Roma ± Divisione Geriatria e Sezione Cerebrovascol-are Ospedale Israelitico ± S.M. Zuccaro, M. Manor,C. Pitigliani

58. Roma ± Medicina Degenze Speciali, Ospedale MilitarePrincipale ± M. Anaclerio, A. Graco, P. Pisanti

59. Roma ± Divisione di Geriatria, Ospedale Addolorata ±

V. Lumia, G. Marangi, C. Carletta60. Roma ± Clinica Neurologica, II UniversitaÁ Tor Ve-

rgata ± G. Bernardi, C. Caltagirone, G. A. Carlesimo61. Roma ± Clinica Neurologica, Ospedale Fatebenefra-

telli ± P. Rossini, M.T. De Lisio62. Roma ± Divisione di Geriatria, UniversitaÁ Cattolica ±

A. Cocchi, V. Cardone, L. Manigrasso, A. Manto,

F. Ardito, A. Russo, E. Gaetani, G. Di Niro,V. Venturiero, A. Baldaccini, G. Onder, G. Orsitto,S. Urgese

63. Roma ± Istituto di Medicina Interna e Geriatria,UniversitaÁ Cattolica ± G. Ciappi, S. Cardo, A. Carl-ucci, G. M. Corbo, G. Fumagalli, L. Fuso

64. Roma ± Istituto di Medicina Interna e Geriatria,UniveritaÁ Cattolica ± Carlo Barone and coworkers.

65. Roma ± Istituto di Medicina Interna e Geriatria,UniversitaÁ Cattolica ± Nicola Gentiloni and coworkers

66. Roma ± Ospedale S. Camillo, II Divisione `Bassi' ±G. Di Lascio, C. Bizzarri, S. De Maria, G. C. Nicotra,S. Pedace

67. Rovigo ± Divisione di Geriatria, Ospedale Civile ±P.L. Forte, A. Andriolli, C. Boscolo, E. Carbonin,S. Sparesato

68. S. Giovanni Rotondo ± Divisione di Geriatria, Ospe-dale Casa Sollievo della So�erenza ± M. Giuliani,C. Ritrovato, P. D'Ambrosio, A.M. Colusso,G. Maruzzi

69. S. Giovanni Rotondo ± Divisione di Medicina, Ospe-dale Casa Sollievo della So�erenza ± R. Lucentini,A. Greco

70. Sezze ± Divisione di Geriatria, Ospedale di SezzeRomano ± L. Bartorelli, G. Mazzella

71. Siena ± Cattedra di Geriatria ± M. Guerrini, S. Gori,

C. Iaccarino, P. Sani, M. Bicchi, C. De Matteis72. Siena ± Cattedra di Geriatria ± S. Forconi, C. De

Matteis, F. Leoncini

73. Taranto ± Medicina Generale, Ospedale S.S. Ann-unziata ± A. Marinosci, M.C. Bonanno, A. Di Gena,G. Lantone

74. Termoli ± Reparto di Medicina, Ospedale Civile ±M. Cariello, F. Baccari, V. Di Marco

75. Torino ± I Clinica Neurologica, UniversitaÁ di Torino ±L. Bergamini and coworkers

76. Trento ± Divisione di Geriatria, Centro S. Chiara ±G. Bertoluzza, B. Bagozzi, E. Battisti, R. Garuti,

G. Mansoldo, G. Tava77. Trieste ± Istituto di Clinica Medica, Universita' di

Trieste ± L. Cattin, F. Feruglio, C. Adamo, E. Grande,

R. La Verde, M. Fonda, A. Petrucco, D. Nadalut,D. Trento

78. Venafro ± Reparto di Medicina, Ospedale SS. Rosario

± A. Bucci, G. Farrocco, D. Santilli79. Venafro ± Sanitrix, INRCA ± P. Simonelli, R. Mar-

coni, A. Ricci

80. Verona ± I Divisione Medico Geriatrica, OspedaleCivile Borgo Trento ± G. Zavateri, C. Bellamoli,G. Beltrami, L. Bettili, M.P. Conti, C. Di Battisti,P. Garzotti, P. Peroli, G. Raschella', C. Ruggiano,

F. Pedrazzi81. Vicenza ± Divisione di Geriatria, Ospedale Civile ±

G. Valerio, F. Azzini, E. Bianchi, F. Gioia

The Gruppo Italiano di Farmacovigilanza nell'Anzia-no (GIFA) is a research group of the Italian Society ofGerontology and Geriatrics (SIGG) ± Fondazione

Italiana per la Ricerca sull'Invecchiamento (FIRI-ONLUS).

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Address for correspondence: Francesco Corica, Salita VillaContino, Compl. MessinaDue pal. 8 int. 6, I-98124 Messina,

ItalyPhone: 0039 090 221-2551, -2395, -2371; Fax: 0039 090 2935 162

E-mail: coricaf@www.unime.it

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