Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs. Table 3 shows the results of the secondary analyses. Hypertension was the main indication for use of antihypertensive drugs among cases and controls. We thus adjusted all models for the indication for antihypertensive drug use (hypertension, heart failure, and coronary heart disease measured at cohort entry), rhythm disorders, valvular disease, diabetes, number of hospital admissions (any time before the index date), excessive alcohol use, smoking status, and body mass index (all based on the last measure before the index date).6 ACE=angiotensin converting enzyme; NSAID=non-steroidal anti-inflammatory drug. Blood sugar levels can fluctuate for many reasons, Bone and joint problems associated with diabetes. Morabito S, Pistolesi V, Benedetti G, Di Roma A, Colantonio R, Mancone M, et al. No previous investigations have assessed whether a duration-response relation existed for the use of double and triple therapy combinations and the risk of acute kidney injury. Blood pressure readings: Why higher at home? We also did several sensitivity analyses to evaluate the robustness of the results. Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs. ACE Inhibitor Side Effects. This was probably a result of exclusion of 573 cases for whom we could not find suitable controls. Statistics in epidemiology: the case-control study. The CPRD is the worlds largest computerised database of longitudinal records from primary care. 27 When we restricted the analysis to this more severe subgroup, we observed a lower point estimate for the triple therapy combination (1.13 v 1.31), although the upper bound of the confidence interval does not rule out a possible increased risk (rate ratio 1.77). In terms of safety, hydrochlorothiazide (HCTZ) and indapamide are associated with a lesser rate of hypokalemia and abnormalities of metabolic profile (glucose control, uric acid levels, serum potassium levels). Garcia Rodriguez LA, Perez Gutthann S. Use of the UK General Practice Research Database for pharmacoepidemiology. The risk was greatest at the start of treatment. Signs and symptoms of low potassium (hypokalemia) include: Constipation. Amsterdam, Netherlands: Elsevier; 2016. https://www.clinicalkey.com. Furthermore, adjusting the models for severity of hypertension had little effect on the adjusted rate ratios, indicating that this variable was probably well balanced between groups. 16 However, many of these patients also have chronic inflammatory diseases or chronic pain, so the add-on use of NSAIDs may be indicated. What are opioids and why are they dangerous? Excessive alcohol use, overweight and underweight patients, and smokers were also proportionally more common among cases than controls. Rate ratio of acute kidney injury associated with exposure to current double or triple therapy combination. However, the rate ratios were higher for the new users than for the prevalent users, showing an underestimation of the effect when prevalent users were included in the overall cohort (supplementary tables E1, E2, F1, and F2).39 With stratification by the presence of osteoarthritis, a population for whom NSAIDs would normally be prescribed, although the triple therapy combination did not achieve statistical significance, probably owing to the fewer exposed cases (n=126), the point estimates were comparable to those for patients without osteoarthritis, indicating that over the counter use of NSAIDs is unlikely to have caused important misclassifications of exposure (supplementary table G). SS acquired the data. ACE inhibitors can reduce plasma concentrations of angiotensin II and aldosterone, providing a theoretical rationale for use in combination with a diuretic. health information, we will treat all of that information as protected health FL is the recipient of an LDI post-doctoral research award, LA is the recipient of a Chercheur-Boursier career award from the Fonds de recherche en sant du Qubec, and SS is the recipient of the James McGill chair award. However, the authors adopted mean values of blood creatinine concentrations as the study outcome, without using a specific cut-off (such as creatinine concentration >0.20 mmol/L) to define acute kidney injury. Two trials comparing the effects of ACE inhibitors and diuretics have produced apparently conflicting conclusions. 5 Objectives To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). Wrist blood pressure monitors: Are they accurate? 2021 Dec 17;10(24):5921. doi: 10.3390/jcm10245921. Such misclassifications of exposure would have diluted the association towards the null, so the increased risks observed in this study may have been partly underestimated.50 However, we obtained consistent results when we restricted the analyses to those patients treated for osteoarthritis, a population more likely to be exposed to NSAIDs by prescription. When we restricted the analyses to the 262 cases of acute kidney injury requiring dialysis, double and triple therapy combinations did not achieve statistical significance, although the rate ratio for triple therapy combination was numerically elevated (1.13, 0.69 to 1.77) compared with double therapy combinations (diuretics: 0.71, 0.36 to 1.43; angiotensin converting enzyme inhibitors or angiotensin receptor blockers: 0.69, 0.36 to 1.31). In patients who have been sodium and/or volume depleted by thiazide or loop diuretics, the additional use of ACE inhibitors can lead to an excessive reduction in blood pressure and symptomatic hypotension. Blood pressure: Does it have a daily pattern? In: Meyler's Side Effects of Drugs. Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes. Taber SS, Pasko DA. ACE inhibitors or angiotensin receptor blockers plus NSAIDs: Diuretics plus ACE inhibitors or angiotensin receptor blockers plus NSAIDs. Late-night eating: OK if you have diabetes? 10. The increased risk observed may thus have been partly affected by confounding by indication and severity.33 41 42 43. Atherosclerotic risk factors: Hypertension. Abstract 1 The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. Although we did not find an effect modification by half life of NSAID, patients using NSAIDs with longer half lives have a more pronounced risk of acute kidney injury.29 Thus, the higher point estimates observed with NSAIDs with long half lives is suggestive of a more sustained constriction of the afferent arteriole.7 21 31 When we considered the duration of exposure to a triple therapy combination, the highest risk of acute kidney injury was in the first 30 days of use. La Operacin Deluxe tiene mucho -o todo- que ver con el final de Slvame, previsto para el prximo viernes 23 de junio. Philadelphia, Pa.: Elsevier; 2019. https://www.clinicalkey.com. Beta blockers: How do they affect exercise? When we stratified the cases and matched controls by prevalent user status, the results were still consistent with those of the primary analysis; the triple therapy combination was associated with an increased risk of acute kidney injury in both prevalent and incident cases and controls. The point estimates were lower with the 60 and 30 day time windows, possibly owing to increased misclassifications of exposure, thus supporting the choice of a 90 day time window. 42 This interaction can be turned into clinical benefit and increase efficacy of ACE inhibitors by reduction in dietary sodium or adding diuretics. World Health Organization (Europe). Nevertheless, given that over the counter drug information is generally unavailable in claims databases, other data sources with such information are needed to better quantify the risk of acute kidney injury accounting for the over the counter use of NSAIDs. Rate ratio of acute kidney injury associated with exposure to current double or triple therapy combination according to half life of NSAID and duration of use. In a sixth analysis, we assessed the impact of over the counter use of NSAIDs by restricting the cases and matched controls to patients with osteoarthritis, a population for whom the chronic use of NSAIDs is likely to involve physicians prescriptions. Data sharing: No additional data available. 19 This risk is thought to vary with the number of antihypertensive drug classes used concurrently with NSAIDs. We estimated the overall incidence rate of acute kidney injury by dividing the total number of cases that occurred during the study period by the total person years of follow-up, with 95% confidence intervals based on the Poisson distribution. Furthermore, stratification of cases and matched controls on the presence of diabetes led to results consistent with those of the primary analysis, indicating that the results were unlikely to have been influenced by the accuracy of recording acute kidney injury and chronic kidney disease (supplementary table B2). 18 Estimating measures of interaction on an additive scale for preventive exposures. 41 Recent reviews of all validation studies found that medical data in the CPRD are of high quality.24 Risk of acute renal failure in patients with type 2 diabetes mellitus. Some chemotherapy drugs that can cause tinnitus include: cisplatin: used to treat testicular, lung, bladder, cervical and ovarian cancer. Within current time window before index date. Agreement within Europe about antihypertensive treatment and educationresults from the European Society of Hypertension questionnaire. Among patients on a combination of diuretics and NSAIDs (without an angiotensin converting enzyme inhibitors or angiotensin receptor blockers), despite a reduction in renal blood flow and the presence of renal afferent arteriolar constriction, glomerular filtration is probably maintained as a result of the effect of angiotensin II mediated efferent arteriolar vasoconstriction and sodium retention. This result is biologically consistent with the potential effect of a drastic hypovolaemia exerted by diuretics, which is further exacerbated by the vasoconstrictive effect of NSAIDs.7 Thirdly, we were unable to control for exposure to contrast media injected during in-hospital cardiovascular examinations (such as angiography) or for other nephrotoxins (such as aminoglycoside antibiotics) that might have contributed to the risk of acute kidney injury.49 However, when we controlled for immeasurable time bias by excluding patients admitted to hospital in the current time window,38 the results remained consistent with those of the primary analysis, showing that previous in-hospital exposure to other nephrotoxins as well as in-hospital exposures to double or triple therapy combinations were unlikely to have influenced the observed associations. Thus, their outcome was not specific to identify acute kidney injury and also included subclinical renal impairments. We defined a double therapy combination as the concurrent use of either diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with NSAIDs. However, we found statistically significant associations in terms of half life of NSAID and duration of use, consistent with those in the main analyses (supplementary tables A1 and A2: see web extra). In addition, patients in the CPRD can now be linked individually and anonymously to the UK national registry of hospital admissions (Hospital Episode Statistics repository). Sidawy AN, et al., eds. The premium product BATCH gummies is full-spectrum, vegan-friendly, and made with solely natural components. 21. We divided the number of prescribed units by the daily dose to obtain the expected duration of drug use. Overall, current use of a double therapy combination of a diuretic or an angiotensin converting enzyme inhibitor or angiotensin receptor blocker with NSAIDs was not associated with an increased rate of acute kidney injury. https://www.uptodate.com/contents/search. A cohort of 487372 patients using antihypertensive drugs met the study inclusion criteria (fig 1); they were followed for a mean of 5.9 (SD 3.4) years, generating 3047813 person years of follow-up. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Databases. 47 whose validity has been demonstrated in the more clinically severe subgroup requiring dialysis (sensitivity 90%; positive predictive value 94%).26 Although there may be less of a propensity for severe orthostatic hypotension with sildenafil, both tadalafil and vardenafil are contraindicated when an 1 blocker is being taken for hypertension. carboplatin: used to treat head and neck, lung, ovarian . To be considered a double or triple therapy combination, the drugs of interest had to have been prescribed on the same day or, alternatively, their specified durations of use had to overlap each other for at least one day during follow-up. Firstly, we used the Clinical Practice Research Datalink, which is a large primary care database containing longitudinal data on patients medical history, lifestyle (smoking, alcohol use, and body mass index measurements), and indication for use of antihypertensive drugs. However, for the combination of diuretics with NSAIDs, we found an overall effect modification by duration of use, with the highest risk observed in the first 30 days of use, although that estimate did not reach statistical significance (rate ratio 1.46, 0.96 to 2.24). Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. 30 the primary focus was on the association between NSAIDs and acute kidney injury, and interaction with diuretics or angiotensin converting enzyme inhibitors/angiotensin receptor blockers and NSAIDs was a secondary outcome. Funding: This study was funded in part by infrastructure grants from the Drug Safety and Effectiveness Network (DSEN), the Canadian Institute of Health Research (CIHR), and the Canada Foundation for Innovation. Headaches: Treatment depends on your diagnosis and symptoms. 33 5 These studies were not adequately powered to investigate the association between double and triple therapy combinations and the risk of acute kidney injury.29 Thirdly, exposure in the CPRD is prospectively collected, eliminating the possibility of recall bias. We divided the number of prescribed units by the daily dose to obtain the expected duration of drug use. FOIA 10 Reassuringly, the fact that we observed a duration-response relation and the point estimates were consistently lower with a shorter (60 and 30 days) exposure time window and grace period (that is, the likelihood of being concurrently exposed to antihypertensive drugs and NSAIDs was reduced) indicates that residual confounding was probably minimal. Inclusion in an NLM database does not imply endorsement of, or agreement with, Furthermore, adjusting the models for severity of hypertension had little effect on the adjusted rate ratios, indicating that this variable was probably well balanced between groups. Lo LJ, Go AS, Chertow GM, McCulloch CE, Fan D, Ordonez JD, et al. sharing sensitive information, make sure youre on a federal Patients were required to have at least one year of up to standard medical history in the CPRD before that first prescription. The results of this sensitivity analysis were consistent with those of the primary analysis for both double (diuretics: rate ratio 1.08, 0.81 to 1.44; angiotensin converting enzyme inhibitors or angiotensin receptor blockers: 0.92, 0.67 to 1.27) and triple (1.33, 1.09 to 1.61) therapy combinations. information highlighted below and resubmit the form. The date of the risk set was the index date for the controls. other information we have about you. ACE inhibitors are used widely in the treatment of hypertension and congestive heart failure, but there is only limited information on adverse interactions between ACE inhibitors and other cardiovascular or noncardiovascular drugs. Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G. Risk factors and outcome of hospital-acquired acute renal failure: clinical epidemiologic study. Since 1997, the repository contains dates of hospital admission, discharge diagnosis (coded using ICD-10 (international classification of diseases, 10th revision)), and related procedures (coded using ICD-10 and OPCS-4 (Office of Population Censuses and Surveys classification of interventions and procedures, 4th version)). Effective control of blood pressure can be achieved in some patients with a single agent and in many of the remainder with combination therapy. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs. There have been reports of OH with ACE inhibitors and diuretics [14,9] that were not replicated in our study. The first consisted of repeating all analyses by restricting the cases to the subset requiring dialysis. However, the rate ratios were higher for the new users than for the prevalent users, showing an underestimation of the effect when prevalent users were included in the overall cohort (supplementary tables E1, E2, F1, and F2).39 With stratification by the presence of osteoarthritis, a population for whom NSAIDs would normally be prescribed, although the triple therapy combination did not achieve statistical significance, probably owing to the fewer exposed cases (n=126), the point estimates were comparable to those for patients without osteoarthritis, indicating that over the counter use of NSAIDs is unlikely to have caused important misclassifications of exposure (supplementary table G). Drugs primarily causing vasodilation (CCBs, ACE inhibitors/ARBs, SSRIs, SGLT-2 inhibitors) were associated with smaller differences that were not statistically significant, compared to placebo. Databases. Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury. The present paper is summarizing the evidence supporting the efficacy of their combination in a broad range of hypertensive patients. Medications and supplements that can raise your blood pressure. Bethesda, MD 20894, Web Policies To our knowledge, only one observational study has specifically investigated the risk of acute kidney injury associated with the use of these drug combinations.17 An increased risk was observed in that study, but the study was limited by its cross sectional design and possible confounding by indication and severity (as heart failure is an independent predictor of acute kidney injury22). These analyses were limited by statistical power given the relatively few cases exposed to double (n=36) and triple therapy (n=57) combinations. This site needs JavaScript to work properly. The data recorded in the CPRD since 1987 include demographic information, prescription details, clinical events, specialist referrals, and deaths.23 In addition, the CPRD collects information on lifestyle variables such as body mass index and data on smoking and excessive alcohol use. The https:// ensures that you are connecting to the Antidepressant use and cognitive deficits in older men: addressing confounding by indications with different methods. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. The best one for you depends on many things, including your overall health and existing conditions. Mayo Clinic offers appointments in Arizona, Florida and Minnesota and at Mayo Clinic Health System locations. Glycemic index: A helpful tool for diabetes? Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors. To our knowledge, this is the first large population based study of patients (almost 500000) using antihypertensive drugs to have investigated the association between the use of different combinations of antihypertensive drugs (diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers) with non-steroidal anti-inflammatory drugs on the risk of acute kidney injury. The only study that specifically investigated the risk of acute kidney injury due to these double or triple therapy combinations was probably subject to confounding by indication and severity (heart failure can itself lead to acute kidney injury).17 enalapril (Vasotec) enalaprilat fosinopril lisinopril (Zestril and Prinivil) moexipril perindopril quinapril (Accupril). In a nested case-control study, Huerta and et al reported an increased risk of acute kidney injury due to diuretic-NSAIDs interaction, estimated through the synergy index (S=2.4, 95% confidence interval 0.2 to 2.4).29 This measurement, as well as the relative excessive risk due to interaction index (RERI), quantifies the risk due to drug-drug interactions on an additive scale for dichotomous factors. An expert explains. Likewise, we compared current users of a triple therapy combination, consisting of diuretics and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs, with patients currently using these antihypertensive drugs without NSAIDs. To provide you with the most relevant and helpful information, and understand which Although we did not find an effect modification by half life of NSAID, patients using NSAIDs with longer half lives have a more pronounced risk of acute kidney injury.29 Thus, the higher point estimates observed with NSAIDs with long half lives is suggestive of a more sustained constriction of the afferent arteriole.7 Whelton PK, et al. NHS Information Centre for Health and Social Care. ACE inhibitors can reduce plasma concentrations of angiotensin II and aldosterone, providing a theoretical rationale for use in combination with a diuretic. We were also able to examine the duration-response relation for both double and triple therapy combinations. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Expert opinion: privacy practices. With cases and controls matched on general practice, the rate ratios did not achieve statistical significance. We calculated this by using the number of prescribed tablets combined with dosing instructions and daily dose. Conclusions A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. 55 Nevertheless, the directions of the risks were consistent with those observed with a 90 day time window (supplementary tables C1, C2, D1, and D2). The combination of ACEI and diuretics reduces the rate of major cardiovascular events in a wide range of patients with hypertension with or without co-morbidities. 40 These studies had several methodological shortcomings. Use of diuretics can lead to hypovolaemia, angiotensin converting enzyme inhibitors/angiotensin receptor blockers cause a haemodynamic reduction in glomerular filtration rate due to efferent arteriolar vasodilation, and NSAIDs cause inhibition of prostacyclin synthesis (leading to renal afferent arteriolar vasoconstriction).7 In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46). Within the CPRD population, we assembled a cohort of patients who received antihypertensive drugs between 1 January 1997 and 31 December 2008, with follow-up until 31 December 2010. There is a problem with Conclusions A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. In a third analysis, we verified whether the introduction in the UK of new quality outcome framework guidelines over the study period, concerning the recording and treatment of diabetes and chronic kidney disease,34 In the special situation in which patients were prescribed more than one NSAID, we used the one with the longest half life to determine the overlap with the antihypertensive drugs. SS is the guarantor. Reassuringly, the fact that we observed a duration-response relation and the point estimates were consistently lower with a shorter (60 and 30 days) exposure time window and grace period (that is, the likelihood of being concurrently exposed to antihypertensive drugs and NSAIDs was reduced) indicates that residual confounding was probably minimal. 21 Drug interactions with angiotensin-converting enzyme (ACE) inhibitors include: Angiotensin-II receptor blockers and aliskerin concomitant use of two drugs affecting the renin-angiotensin system increases the risk of hyperkalaemia, hypotension, and renal impairment. This aspect is particularly relevant among users of antihypertensive drugs, who often need more than one drug for adequate blood pressure control. Therefore, assuming that residual confounding from unmeasured variables was non-differential between exposure groups is reasonable. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Values are numbers (percentages) unless stated otherwise. Beta blockers: Do they cause weight gain? We adjusted the risk estimates for comorbid clinical conditions, measured before the index date, known to be associated with acute kidney injury, which could also influence the choice of antihypertensive and NSAID treatment. Or adding diuretics, vegan-friendly, and smokers were also able to the!, Perez Gutthann S. use of the safety ace inhibitors and diuretics interaction viagra with dapoxetine conventional nonsteroidal anti-inflammatory drugs and the risk acute...: Does it have a daily pattern blockers plus NSAIDs: diuretics ACE! A, Colantonio R, Mancone M, et al double or triple therapy combinations health... 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