Abstract
Treatment with ACE inhibitors has shown to be effective in the prophylaxis of migraine attacks. The aim of this study was to explore whether among hospitalized hypertensive patients use of ACE inhibitors may reduce the risk of headache caused by nitrates. To this end, we used the GIFA database, that includes patients admitted to academic medical centres throughout Italy. We studied 1537 patients (mean age 75 ± 10 years) receiving treatment with nitrates during a hospital stay and diagnosed with hypertension. Headaches that had a probable or definite causal relation with nitrates use based on the Naranjo algorithm were considered for this analysis. Of the total enrolled sample, 762 patients (50%) used ACE inhibitors during hospital stay. Headache caused by nitrates was recorded in 12/762 (1.6%) ACE inhibitor users and in 24/775 (3.2%) other participants (P = 0.049). After adjusting for potential confounders, ACE inhibitors use was associated with a significantly lower risk of headache (OR 0.43; 95% Confidence Intervals: 0.20-0.90). This result was confirmed if ACE inhibitors use was compared with use of other antihypertensive agents (OR 0.44; 95% CI 0.20-0.95). In conclusion, this study suggests that among hypertensive subjects use of ACE inhibitors is associated with a reduced risk of headache caused by nitrates.
Introduction
Headache is a prominent adverse effect of nitrate therapy and in the most severe cases, it limits the use of such medication (1). It has been hypothesized that nitrates may determine this effect through conversion to nitric oxide (NO), a molecule which has also been shown to be involved in headache in healthy individuals and in migraine attacks (2).
Angiotensin Converting Enzyme (ACE) inhibitors are medications commonly used to treat hypertension (3, 4) and it has been suggested that these agents may exert drug-specific effects that are independent of blood pressure control (5, 6). A recent study showed that the ACE inhibitor lisinopril is effective in the prophylactic treatment of migraine attacks (7). This finding is consistent with the evidence of a close interaction between Angiotensin II and NO production (8). Therefore, the aim of this study was to explore whether among hypertensive patients treatment with ACE inhibitors may reduce the risk of nitrates-induced headache.
Methods
GIFA database
The GIFA is a group of investigators operating in community and university-based hospitals throughout Italy. The GIFA periodically surveys drug use, occurrence of adverse drug reactions, and quality indicators of hospital care.
The methods of the GIFA study have been described in detail elsewhere (3, 9). Briefly, all patients admitted to 81 acute geriatric and general internal medicine wards participating in the study were enrolled and followed until discharge. The study periods were the following: May 1 to June 30 and September 1 to December 31, 1988; May 15 to June 15, 1991; and May 1 to June 30 and September 1 to October 31 in 1993, 1995, 1997. For each participant, a questionnaire was completed at admission and updated daily by a study physician who received specific training.
Medications
The drug product names, dosage form and strength of medications taken during hospital stay were gathered from the medical and nursing records. Drugs were coded according to the Anatomical Therapeutic and Chemical codes (10).
Likewise, specific nitrate ingredients, strength and dosage form were also identified from the ATC codes. Analytic variables were created for all nitrates, as well as for transdermal, oral, sublingual and intravenous nitrates. Consumption of nitrates on a ‘as needed’ basis was not considered in this analysis. New users of nitrates were considered those who had nitrates prescribed during the hospital stay and had not been taking them for at least 2 weeks before admission.
Analytical variables were created for the in-hospital use of ACE inhibitors, beta-blockers, calcium channel blockers (CCB), thiazides, clonidine, Angiotensin II receptor antagonists, alpha-blockers, Non Steroidal Anti-inflammatory Drugs (NSAIDs), Acetylsalicylic Acid (ASA) and antidepressants. Users of other antihypertensive drugs were defined as consumers of beta-blockers or CCB or thiazides or alpha-blockers, but not ACE inhibitors during hospital stay. For analytic purpose the median daily dose for each ACE inhibitor was calculated (fosinopril, 20 mg; captopril, 50 mg; lisinopril, 10 mg; enalapril, 20 mg; ramipril, 5 mg; benazepril, 10 mg; quinapril, 20 mg) and a variable was computed based on the use of a dose below and equal-or-above the median.
Headache caused by nitrates
A study physician investigated each ADR detected during hospital stay, gathering information from the patients, the nurses and the attending physician, and reviewing charts and records. According to the World Health Organization definition an ADR was considered as any noxious, unintended, and undesired effect of a drug, excluding therapeutic failures, intentional and accidental poisoning, and abuse (11). For each suspected ADR, the study physician coded clinical description, severity and eventual evolution. In addition, he collected detailed information about the drug(s) identified as the potential culprit. The causality of the relation between drug use and ADR was assessed based upon the score of the Naranjo algorithm (12). Accordingly, ADR were classified as: definite (score, 9–12), probable (score, 5–8), possible (score 1–4) or doubtful (score, 0 or below).
In this study, we considered only headaches that had a probable or definite causal relation with nitrates use. Events detected at admission and related to nitrates consumption prior to admission were excluded from the present analysis.
Covariates
Cognitive performance was assessed using the Hodkinson Abbreviated Mental Test (AMT) and a score below 7 was used to identify patients as cognitively impaired (13, 14).
Discharge diagnoses were coded according to the International Classification of Diseases, Ninth Edition, Clinical Modification codes (15). Comorbidity was quantified using the Charlson comorbidity index by adding scores assigned to specific discharge diagnoses, as illustrated in the original publication (16). Diagnosis of hypertension was reported by the study physician based upon blood pressure measurements, previous medical history and clinical documentation. Data on blood pressure at hospital admission and discharge were gathered only in 1988, 1995 and 1997 surveys.
Study sample
From an initial sample of 28 411 participants, we selected patients with a diagnosis of hypertension and who received during hospital stay treatment with oral, sublingual or transdermal nitrates (n = 1555). Since intravenous nitrates are usually prescribed to critically ill patients that may unable to report headache, they were not considered for this study (17). Subjects experiencing headache that had possible or doubtful causal relation with nitrates use (n = 9) or that was caused by nitrates use prior to hospital admission (n = 5) and those receiving an Angiotensin II receptor antagonist during hospital stay (n = 4) were excluded from the analysis.
In the resulting sample of 1537 participants, differences between ACE inhibitors users and no ACE inhibitors users in categorical parameters were tested using the Chi-square test. Differences between continuous variables were assessed by ANOVA comparisons. To establish whether ACE inhibitors use was independently associated with nitrates-induced headache, an age and gender adjusted logistic regression model was performed. Other variables considered for adjustment were those associated with ACE inhibitors use at P ≤ 0.10 in the univariate analyses. A P-value < 0.05 (two tail) was considered statistically significant. All analyses were performed using SPSS for Windows version 10.0.
Results
The mean age of the 1537 patients entering the study was 75 ± 10 years, and 58% of the study population was female. Of the total enrolled, 762 patients (50%) used ACE inhibitors during a hospital stay. Enalapril was the most commonly prescribed ACE inhibitor (27% of the sample), followed by Captopril (11%), Lisinopril (7%) and Ramipril (3%). Characteristics of the study population according to ACE inhibitors use are summarized in Table 1. Compared with other participants, ACE inhibitors users presented a more severe Charlson comorbidity index and consumed a higher number of drugs but they had a shorter length of hospital stay. In addition, ACE inhibitors use progressively increased through years of survey and it was associated with a higher prevalence of congestive heart failure (CHF) and diabetes, with a higher use of ASA and with worse renal function.
Characteristics of the study population according to ACE inhibitors use
∗Abbreviated Mental Test < 7.
†Consumers of any amount of alcohol before hospital admission.
‡Three levels variables for number of drugs consumed during hospitalization and length of hospital stay were computed based on tertiles. NSAIDs, Non Steroidal Anti-inflammatory Drugs; ASA, Acetylsalicylic Acid.
Headache with a probable or definite causal relation with nitrates use was detected in 36 subjects (2.3% of the study population). Users of trans-dermal nitrates (n = 1118) had a slightly lower prevalence of headache compared with users of oral or sublingual forms (2.0% vs. 3.3%; P= 0.11). Other less frequent adverse reactions with a probable or definite causal relationship with nitrates use included cutaneous reactions (n = 10), hypotension (n = 6), gastrointestinal symptoms (n = 2), dizziness (n = 1) and palpitations (n = 1).
Nitrates-induced headache was observed in 12/762 (1.6%) ACE inhibitors users and in 24/775 (3.2%) other participants (P = 0.049). After adjusting for potential confounders, including age, gender, Charlson comorbidity index, prevalence of diabetes and CHF, number of drugs consumed during hospital stay, use of ASA, length of stay, creatinine level and year of survey, ACE inhibitors use was associated with a significantly lower risk of nitrates-induced headache (OR 0.43; 95% Confidence Intervals: 0.20–0.90). However, no dose–response relationship could be observed (data not shown). Limiting the analysis to users of transdermal nitrates, the inverse association between ACE inhibitors use and headache was confirmed (OR 0.36; 95% CI 0.14–0.93). Including in the analysis also participants presenting headache with possible or doubtful relation with nitrates use (n = 9) these results were unchanged (headache rate: ACE inhibitors users 2.0%, no ACE inhibitors users 3.8%, P= 0.028; OR 0.49, 95% CI 0.25–0.95).
As shown in Fig. 1, ACE inhibitors users showed a lower rate of headache than users of any other antihypertensive drugs (no. of events = 20/603, 3.3%, P vs. ACE inhibitors users = 0.037). Compared with the latter group of patients, ACE inhibitors users presented a 56% reduced risk of headache (OR 0.44; 95% CI 0.20–0.95). These results were confirmed limiting the analysis to transdermal nitrates users (headache rate: 1.2% vs. 2.9%, P = 0.057; OR 0.38, 95% CI 0.14–1.04). In addition, among 926 subjects for whom data on blood pressure were gathered at hospital discharge, no significant difference on systolic and diastolic blood pressure among ACE inhibitors and other drugs users was observed (systolic blood pressure 142 ± 18 vs. 143 ± 18; P= 0.330; diastolic blood pressure 79 ± 10 vs. 80 ± 10; P = 0.412). Finally, entering in separate logistic regression models the variables for use of beta blockers (n = 96), thiazides (n = 195) and CCB (n = 870), these were not significantly associated with the outcome (beta blockers: OR 1.14, 95% CI 0.40–3.20; thiazides OR 1.86, 95% CI 0.76–4.55; CCB: OR 1.17, 95% CI 0.57–2.93).
Prevalence of headache caused by nitrates according to antihypertensive treatment. ∗P= 0.037; ∗∗P= 0.057 (both vs. ACE inhibitors use). □ no antihypertensive drug use; ▪ ACE inhibitor drug use; ▨ other antihypertensive drug use.
Discussion
The present study showed that among hypertensive hospitalized subjects, ACE inhibitors use was associated with a reduced rate of headache caused by nitrates. This effect was not observed for other antihypertensive agents and it could not be explained by differences in blood pressure control.
This is, to our knowledge, the first study to show an effect of ACE inhibitors on nitrates induced headache. In previous observations ACE inhibitors and Angiotensin II receptors antagonists were found to be effective at reducing the risk of migraine (7, 18). Reasons for these findings are not clear. A possible explanation is the close interaction between Angiotensin II and NO, a molecule which has shown to be involved in headaches caused by nitrates and in migraine attacks (8). In experimental studies, Angiotensin II increases NO release in many cells types, and these two substances show opposite effects in the central nervous system and in the modulation of the sympathetic tone (19–21). In addition, ACE inhibition inhibits free radical activity, increases prostacyclin synthesis and blocks the degradation of encephalin and substance P, all important mechanisms in the modulation of pain (22).
The low rate of headache showed in this study, may be explained by several factors. First, the use of the Naranjo algorithm led to the exclusion of all cases of headache with an unlikely or only possible causal relation with nitrates use, thus limiting the number of events (12). Second, the observation period of this study was short, since it was limited to hospital stay. Third, participants to this study were elderly patients and advanced age has been previously found to be inversely associated with the risk of nitrates-induced headache (23).
This study has some strengths. The relationship between nitrates exposure and headache has been studied using a dedicated database. In addition, hospital is an ideal setting to evaluate this association, since compliance with medication is not an issue. Finally, to describe the causal relationship between headache and drug exposure, we used an algorithm that is associated with 85% interobserver agreement (12).
An important limitation of this study relates to generalizability of the results. Our findings, which are based on an elderly hospitalized population, cannot be extrapolated to younger subjects living in the community. In addition, in consideration of the small number of events we were unable to examine separately the effects of different types of ACE inhibitors.
In conclusion this study suggests that among hypertensive subjects use of ACE inhibitors is associated with a reduced risk of nitrates-induced headache. In consideration of the effect of ACE inhibitors to also prevent tolerance to nitrates (24), if confirmed in clinical trials, this finding may suggest the systematic use of low dose ACE inhibitors associated to nitrates treatment among hypertensive subjects.
Footnotes
Acknowledgements
The GIFA study was partially supported by a grant from the Italian National Research Council (Grant n. 94000402) and by Neopharmed. The work of Dr Onder and Dr Pahor has been supported by Health Claude Pepper Older Americans Independence Center Grant ♯ 5P60 AG 10484–07.