Conceived and designed the experiments: JPF MLM AS JLM. Performed the experiments: JPF MLM AS JLM. Analyzed the data: JPF MLM AS JLM. Wrote the paper: JPF MLM AS JD JCP JLM.
The authors have declared that no competing interests exist.
Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs) and Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blocker (ARBs) or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs.
We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs) and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing.
General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3–86.6). The more commonly prescribed NSAIDs were ibuprofen (20%), ketoprofen (15%), diclofenac (15%) and piroxicam (12%). Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5–11.8) in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescribers were cardiologists or anesthesiologists.
Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.
Because Non Steroidal Anti-Inflammatory Drugs (NSAIDs) inhibit cyclooxigenase enzymes (COX) and prevent prostaglandin synthesis, their drug-drug interactions (DDIs) with antihypertensive drugs can lead to adverse drug reactions
In France, two drug interaction compendia are available. The main one is provided by the
All the French population is covered by a publicly funded health system. The French Health Insurance Reimbursement Database gathers information concerning these patients. Four kinds of data are computerized in this database: demographic characteristics of users, characteristics of health professionals, data concerning health facilities and reimbursement data (drug, laboratory, radiology, medical acts)
We extracted a random sample of patients (sample rate: 5%, as provided by the French Health Insurance System Database), living in the Midi-Pyrénées area (2,600,000 inhabitants) between 1 April 2005 and 1 April 2006, receiving at least two prescriptions of the same antihypertensive drug and not receiving any NSAID (including topical, injectable and oral forms) during this period. Inclusion in the study was on 1 April 2006 for all patients and the maximal follow-up was 4 years (until 31 March 2010, because of database size limitations). Patients were considered lost-to-follow-up if having no drug dispensing for more than 3 months. All data were anonymous in conformity with the French Law of Privacy (8).
The following oral and injectable NSAIDS marketed in France during the period of study were extracted: arylcarboxylic acids (aceclofenac, alminoprofen, diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, nabumetone, tiaprofenic acid), oxicams (meloxicam, piroxicam, tenoxicam), coxibs (celecoxib), acetylsalicylic acid (excluding anti-platelet doses) and others (indometacin, sulindac, phenylbutazone, nimesulide, mefenamic acid, morniflumate, niflumic acid).
Antihypertensive drugs included beta-blocking agents, ACEI, ARBs, diuretics (except eplerenone), calcium channel blockers (except bepridil), alpha-blocking agents or other drugs (centrally acting antihypertensive drugs, minoxidil and dihydralazine). Renin inhibitors were not available in France during the period of study and thus were not included in the analysis. We took into account fixed combinations of antihypertensive drugs as separate drugs. The level of renal failure and hyperkalemia risk caused by NSAID/antihypertensive DDIs was graduated in risk levels, as showed in
Risk group | Antihypertensive classes |
No risk | Beta-blocking agents |
Calcium channel blockers | |
Alpha-Blocking agents | |
Other antihypertensives | |
At risk of DDI |
|
«one drug» | Diuretics or ACEI or ARB |
«two drugs and more» | Diuretics + ACEI/ARB |
DDI, Drug-Drug Interaction; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers.
At risk of renal failure/hyperkalemia caused by Drug-Drug Interactions (DDIs) between NSAIDs and antihypertensives.
For chronically used drugs, data were extracted between 6 months before and 6 months after the first NSAID dispensing. Patients were considered exposed between the first and the last dispensing of these drugs in this one-year time frame.
Laboratory monitoring of serum creatinine and potassium were considered relevant if occurring within 3 weeks after the start of NSAID. This time frame is pharmacologically relevant and already used in monitoring of initiation or intensification of Renin Angiotensin System Inhibitors (RASIs)
We performed an observational study on anonymous data. Thus, considering the French legislation, it does not need to be approved by an ethic committee.
Descriptive statistics were computed to characterize patients, drug dispensing, and laboratory monitoring. Factors associated with laboratory monitoring in univariate analysis (p<0.2) were assessed using logistic regression modeling. Characteristics considered in univariate models included age, gender, level of renal failure and hyperkalemia risk caused by DDIs with antihypertensive drugs, digoxin, potassium supplements, glucose lowering drugs, platelet anti-aggregating agents, hospitalizations in the three months previous first dispensing of NSAIDs. Statistical analyses were performed using Stata®, version 11.0 (StataCorp LP, College Station, TX).
Over the 6,633 patients of the cohort, 3,622 had a first dispensing of NSAIDs during the follow-up (incidence rate: 25.1/100 PY). Among them, 122 were not treated with antihypertensive drug anymore when the first dispensing of NSAIDs occurred and were thus excluded from the analysis (
Characteristics | NSAID (all) | Ibuprofen | Ketoprofen | Diclofenac | Piroxicam | Celecoxib | Acetylsalicylic Acid |
Number of patients, n (%) | 3,500 (100.0) | 722 (20.6) | 531 (15.2) | 526 (15.0) | 416 (11.9) | 124 (3.5) | 144 (4.1) |
DDD dispensed, n (m ± sd) | 13.5±7.8 | 7.5±3.9 | 18.4±8.1 | 17.3±6.2 | 13.8±5.2 | 28.1±6.9 | 5.8±3.0 |
Time since index date,d (med [IQR]) | 376 [170–718] | 418 [208–786] | 404 [174–828] | 444 [194–787] | 258 [128–480] | 476 [176–833] | 321 [169–622] |
Prescriber, n (%) | |||||||
General Practitioner | 2.992 (85.5) | 560 (77.6) | 464 (87.4) | 492 (93.5) | 403 (96.9) | 116 (93.5) | 139 (96.5) |
Dentist | 274 (7.8) | 143 (19.8) | 12 (2.3) | 4 (0.8) | 1 (0.2) | 0 (0.0) | 1 (0.7) |
Other prescribers | 230 (6.6) | 18 (2.5) | 55 (10.3) | 30 (5.7) | 12 (2.9) | 8 (6.4) | 4 (2.8) |
Surgeons | 76 (2.2) | 11 (1.5) | 31 (5.8) | 13 (2.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Rheumatologist | 57 (1.6) | 2 (0.3) | 12 (2.3) | 9 (1.7) | 6 (1.4) | 6 (4.8) | 1 (0.7) |
Anesthesiologist | 21 (0.6) | 0 (0.0) | 1 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Cardiologist | 13 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (1.4) |
Other | 67 (1.9) | 5 (0.7) | 10 (1.9) | 8 (1.5) | 6 (1.4) | 0 (0.0) | 0 (0.0) |
Missing | 4 (0.1) | 1 (0.1) | 1 (0.2) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 1 (0.7) |
Antihypertensive drug DDI risk, n (%) | |||||||
No risk | 804 (23.0) | 168 (23.3) | 122 (23.0) | 115 (21.9) | 95 (22.8) | 24 (19.3) | 33 (22.9) |
At risk of DDI |
2,696 (77.0) | 554 (76.7) | 409 (77.0) | 411 (78.1) | 321 (77.2) | 100 (80.6) | 111 (77.1) |
«one drug» | 1,460 (41.7) | 289 (40.0) | 219 (41.2) | 214 (40.7) | 190 (45.7) | 57 (46.0) | 59 (39.6) |
«two drugs and more » | 1,236 (35.3) | 265 (36.7) | 190 (35.8) | 197 (37.4) | 131 (31.5) | 43 (34.7) | 54 (37.5) |
n, number; m, mean; sd, standard deviation; d, days; med, median; IQR, interquartile range; DDI Drug-Drug interaction.
NSAIDs, non steroidal anti-inflammatory drugs; DDD, defined Daily Dose;
Acetylsalicylic Acid: excluding anti-platelet dose.
At risk of renal failure/hyperkalemia caused by Drug-Drug Interactions (DDIs) between NSAIDs and antihypertensives (see
Baseline complete monitoring was performed in 59.1% (95% CI: 57.3–61.0) of patients treated by ACEIs, ARBs or diuretics (“at risk” group). In only 10.7% (95% CI: 9.5–11.8) of these patients, a complete laboratory monitoring was recorded in the three weeks after NSAID initiation. This monitoring occurred by mean on the 8th day (8.5±6.1) after the first dispensing of NSAID.
Risk group, n | Laboratory monitoring before start of NSAID |
Laboratory monitoring after start of NSAID |
||||
Creatinine and potassium monitoring | Creatinine monitoring | Potassium monitoring | Creatinine and potassium monitoring | Creatinine monitoring | Potassium monitoring | |
(n = 1.942) | (n = 534) | (n = 374) | (n = 347) | (n = 532) | (n = 374) | |
No risk, 804 | 348 (43.3) | 511 (63.6) | 367 (45.6) | 59 (7.3) | 109 (13.6) | 66 (8.2) |
At risk of DDI |
||||||
«one drug», 1,460 | 833 (57.0) | 1,038 (71.1) | 870 (59.6) | 154 (10.5) | 225 (15.4) | 164 (11.2) |
«two drugs and more», 1,236 | 761 (61.6) | 880 (71.2) | 792 (64.1) | 134 (10.8) | 198 (16.0) | 142 (11.5) |
NSAIDs, non steroidal anti-inflammatory drugs.
in the year previous first NSAID dispensing.
in the 3 weeks after start of NSAID.
At risk of renal failure/hyperkalemia caused by Drug-Drug Interactions (DDIs) between NSAIDs and antihypertensives (see
Univariate analysis showed that all the characteristics selected were associated to serum creatinine and potassium monitoring (
NSAID Prescriber (n) | Laboratory monitoring after start of NSAID* [n (%)] | ||
Creatinine and potassium monitoring | Creatinine monitoring | Potassium monitoring | |
(n = 347) | (n = 532) | (n = 372) | |
General Practitioner (2,992) | 294 (9.8) | 459 (15.3) | 317 (10.6) |
Dentist (274) | 24 (8.8) | 35 (12.8) | 24 (8.8) |
Other prescribers (238) | 29 (12.2) | 38 (16.0) | 31 (13.0) |
Anesthesiologist (21) | 4 (19.0) | 7 (33.3) | 5 (23.8) |
Cardiologist (13) | 5 (38.5) | 5 (38.5) | 5 (38.5) |
Surgeons (76) | 9 (11.8) | 14 (18.4) | 9 (11.8) |
Rheumatologist (56) | 3 (5.4) | 4 (7.1) | 3 (5.4) |
Other (67) | 8 (12.5) | 8 (12.5) | 9 (14.1) |
NSAIDs, non steroidal anti-inflammatory drugs.
Factors | Unadjusted odds ratio | p | Adjusted odds ratio |
p |
[95% confidence interval] | [95% confidence interval] | |||
Age, years (<50 years as reference) | ||||
50–60 | 1.70 [0.94–3.07] | 0.075 | 1.64 [0.91–2.95] | 0.147 |
60–70 | 1.89 [1.07–3.34] | 0.028 | 1.78 [1.00–3.15] | 0.049 |
70–80 | 2.51 [1.44–4.36] | 0.001 | 2.31 [1.32–4.04] | 0.003 |
>80 | 3.42 [1.94–6.03] | 0.000 | 3.36 [1.90–5.96] | 0.000 |
Gender (male as reference) | 1.18 [0.95–1.48] | 0.129 | 1.26 [1.00–1.59] | 0.044 |
Concomitant drugs |
||||
Potassium supplements | 2.88 [1.74–4.75] | 0.000 | 2.47 [1.49–4.12] | 0.001 |
Glucose lowering drugs | 1.58 [1.22–2.04] | 0.001 | 1.58 [1.22–2.06] | 0.001 |
Digoxin | 2.04 [1.17–3.54] | 0.012 | 1.60 [0.91–2.82] | 0.106 |
Platelet aggregation inhibitors | 1.49 [1.17–1.88] | 0.001 | 1.20 [0.93–1.54] | 0.153 |
Risk level of DDI |
||||
One drug | 1.49 [1.09–2.04] | 0.013 | 1.27 [0.92–1.75] | 0.139 |
Two drugs | 1.53 [1.11–2.11] | 0.009 | 1.28 [0.92–1.77] | 0.140 |
Hospitalizations |
2.68 [1.14–6.27] | 0.023 | 2.09 [0.87–5.00] | 0.097 |
NSAID prescriber | ||||
Cardiologist or Anesthesiologist |
3.33 [1.54–7.19] | 0.002 | 3.32 [1.53–7.26] | 0.003 |
Adjusted for age, gender, exposure to potassium supplements, glucose lowering drugs and NSAIDs prescriber.
according to ATC classification.
Risk level of renal failure/hyperkalemia caused by Drug-Drug Interactions (DDIs) between NSAIDs and antihypertensives (see
in the 6 months before inclusion.
Compared to other prescribers.
Our study was performed to evaluate the implementation of laboratory monitoring in patients treated with ACEI/ARB/Diuretic plus NSAID. Our results show that despite well-known potential biochemical disturbances, serum creatinine and potassium monitoring were recorded in less than 11% of patients at risk. Monitoring occurred at day 8 and was more frequently performed to women aged over 60, treated with potassium supplements or glucose lowering drugs, but not to patients treated with ACEI, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescriber was a cardiologist or anesthesiologist.
The characteristics of NSAID prescriptions are close to the ones found in a monthly prevalence descriptive study leaded in the same area in 2006
To our knowledge, this study is the first one describing monitoring of serum creatinine and potassium in patients at risk of renal failure or hyperkalemia caused by NSAID DDIs with ACEI, ARBs or diuretics. The rate found in our study (around 11%) is unsurprisingly low. Low monitoring rates have been found in previous study whether in RASIs initiation (34% of control in the first 3 weeks
This study underlines the important lack of implementation of guidelines for DDIs between NSAIDs and antihypertensives. This finding is quite ambiguous, as GP have previously reported their concerns about NSAIDs safety of use in daily practice and claimed a caution approach in NSAID prescription
Regarding GPs-related factors for the non-implementation of drug prescribing guidelines, GPs may consider guidelines as too stringent in general. They consider laboratory monitoring as time-consuming, especially when they are uncertain that monitoring was already performed by another provider
In the present study, cardiologists and anesthesiologists prescribed more frequently adequate monitoring. This phenomenon can be explained by an increased prescription of flurbiprofen within these two medical specialties. Flurbiprofen is marketed in France for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction, in patients for whom aspirin is not recommended
The use of the French Health Insurance Reimbursement Database in pharmacoepidemiological studies has already been fully described
Finally, the low prevalence of complete monitoring could have been underestimated. In our study, we only have access to ambulatory biochemical monitoring and thus could have missed the ones realized during hospitalizations. On the other hand, one could have underestimated the prevalence of ibuprofen and aspirin consumption, as these specific NSAIDs can be sold out-of-the-counter and thus not recorded in the French Health Insurance Reimbursement Database.
The low prevalence of serum creatinine and potassium monitoring shows a very poor implementation of guidelines. Further studies are required to correlate this low prevalence with a potential increased risk of severe adverse drug reactions. Moreover, intervention studies are required to improve the knowledge of this specific risk, especially among GPs.
(DOCX)
The authors thank Dr Robert Bourrel and Carole Suarez of the Health Insurance System of Midi-Pyrénées for their kind help during the data extraction.