Trimethoprim-Sulfamethoxazole Increase Risk of Sudden Death. But the researchers did not have any data on serum potassium concentrations. Whereas nitrofurantoin and norfloxacin are limited to the treatment of urinary tract infection, amoxicillin, co-trimoxazole, and ciprofloxacin are sometimes used for infections at other sites. Funding: This study was supported in part by a grant from the Canadian Drug Safety and Effectiveness Research Network (CDSERN) and by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario Ministry of Health and Long-Term Care (MOHLTC). Sulfamethoxazole also blocks folate metabolism, albeit at a different junction. However, we dont have any data on serum potassium concentrations. My phone calls were always returned quickly and all of my questions were answered in a thorough manner. If a page cannot be made accessible, we will work to make a text version available. See: http://creativecommons.org/licenses/by-nc/3.0/. Google Podcasts If you experienced a negative reaction to Bactrim and would like to share your story, contact us. Theyre not supposed to do the same thing to GABA-A receptors as protracted benzodiazepine withdrawal. You can find it in our book, Top Screwups Doctors Make and How to Avoid Them. SH did the statistical analysis. A few years back, I had a confirmed UTI (P. mirabilis). Get in together, will you? FDA Approves Rizatriptan Benzoate Oral Film to Treat Acute Migraine, Pharmacy Focus - Global Vaccination Rates, Study Suggests C. Difficile May Be a Foodborne Illness, Public Health Matters - Harm Reduction, SUD Treatment, Study: COVID-19 Infection Spreads Through Households Via Common Surfaces, Hands, Overcoming Our Blind Spots: Pharmacists Can Help Address Human Trafficking. Heart rhythm disorders. Background: Trimethoprim-sulfamethoxazole increases the risk of hyperkalemia when used with spironolactone. x-ray results showing lung tissue changes. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. I was on Sotalol and Pradaxa (afib) at the time. The large study, conducted over a 17-year period, involved 206 319 patients aged 66 years or older who were treated with spironolactone. This fall the Canadian researchers closed the loop on this deadly drug interaction (BMJ, Oct. 30, 2014). Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. Of these deaths, 1,110 occurred within seven days of a prescription for one of the study antibiotics. Interpretation: The antibiotic trimethoprim-sulfamethoxazole was associated with an increased risk of sudden death among older patients taking spironolactone. I also wonder how best to disseminate details of drug interactions and adverse effects to practicing physicians as Ive noticed several instances of recently publicized interactions (e.g., thiazide diuretics depressive effect on insulin secretion with resulting increased blood glucose) that are well-described in much older editions of medical physiology and pharmacology texts. 2013. The site is secure. The Canadian researchers reported that many of the patients they were tracking died suddenly within one to two weeks of starting this combination. It is prescribed for everything from acne and UTIs to prophylactic treatments associated with HIV. The results showed that, in this specific patient population, 3 of every 1000 individuals taking either ACE inhibitors or ARBs who then begin treatment with trimethoprim/sulfamethoxazole will die suddenly within 7 to 14 days. It is a structural analog of the vitamin-like compound para-aminobenzoic acid (PABA) found in several foods and involved in the metabolism of folic acid. BMJ 2014;349:g6196. If you ever feel like covering the dangers of fluoroquinolones, I know that everyone going through fluoroquinolone toxicity syndrome would appreciate the attention and acknowledgement. Dear Doctor, I would like to express the deepest gratitude to you for writing and updating this website. Unauthorized use of these marks is strictly prohibited. 1, 1994, and Dec. 31, 2011. Those results are significant when compared with the control cohort, which recorded only 1 sudden death per 1000 patients. Most of the patients receiving spironolactone treatment who died suddenly were 85 years of age or older. The trouble is, physicians and pharmacists often ignore and override drug interaction alerts, especially those they deem relatively unimportant. More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. Such drugs are also prescribed to treat congestive heart failure (CHF), heart disease and kidney disease. Of course, with each passing year I have become incrementally more cautious with everyone from infants to the elderly in hospitals or in public health settings. WHO model list of essential medicines. RSS, We invite the brightest minds in geriatrics, hospice, and palliative care to talk about the topics that you care most about, ranging from recently published research in the field to controversies that keep us up at night. Would you like email updates of new search results? Remember, in order to get to usable folate THF, we need the DFT enzyme to work. BMJ. We used administrative data and did not have access to serum potassium or creatinine concentrations, adherence to treatment, non-prescription drug use, and other risk factors for sudden death. and transmitted securely. Sign up to get our weekly updates directly to your inbox: Apple Podcasts Most people do not need to worry about high potassium levels, says Antoniou. When appropriate, it is prudent for clinicians to evaluate alternative antibiotic regimens, consider a decreased duration of treatment, or closely monitor serum potassium levels in this particular patient population. Because of my allergies I took a Penicillin test and I reacted. Spironolactone (brand name Aldactone) is a diuretic widely used in treating heart failure. The researchers caution that limitations to this trial prevent a definitive answer. The most common cause of sudden cardiac death in young people is this genetic condition that causes the heart muscle to grow too thick. Overcast February 2, 2015 / 3:49 PM I didnt want to take Cipro because of possible side effects (including Achilles Tendon rupture), so the doc Rxed Bactrim instead. All rights reserved, From Healthy to Barely Functioning After Taking Bactrim and Keflex, Thiamine Deficiency Causes Intracellular Potassium Wasting, by potently blocking both thiamine transporters, glucose-6-phosphate dehydrogenase (G6PD) deficiency, Delirium, gait disturbances and other CNS symptoms, Stephens Johnson Syndrome and toxic epidermal necrosis, lining of the skin and mucous membranes blisters and necrolyses, popular angiotensin enzyme inhibitors (ACE), potentially deadly interactions involving hyperkalemia, high potassium levels via its blockage of the sodium channels in the kidneys, The overall importance of these observations, metabolism of the branched chain amino acids, nor are our vitamin synthesis pathways sufficiently distinct from bacteria, large number of gut bacteria in comparison, regulates something called the mTOR receptor, downregulate mTOR and deregulate mitochondrial function. The antibiotic trimethoprim-sulfamethoxazole was associated with an increased risk of sudden death among older patients taking spironolactone. I am now, In using a fictitious example, the mother of a football playing athlete takes an interest in, Dr. Marrs and I became aware of the symptoms and some of the laboratory results in, Over recent years, a number of new diets have become popular among health conscious individuals. I would guess most caregivers who prescribe cotrimoxazole do not have a working knowledge of epithelial cells in the distal nephron. Long QT syndrome is a heart rhythm condition that can cause fast, chaotic heartbeats. The official journal of The Royal Pharmaceutical Society, International Journal of Pharmacy Practice, Journal of Pharmaceutical Health Services Research. Now, we have computers as close as our smart phones. inflammation of the alveoli of the lungs. TORONTO, ON The risk of sudden death went up by more than a third in older patients taking ACE inhibitors or angiotensin-receptor blockers (ARBs) who were also put on the antibacterial agent. In a case-control study of more than 1.6 million patients over 17 years, researchers from Canada found that cotrimoxazole was associated with a three-fold increased risk of sudden death when used in older patients (age > 66) taking angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Youve written a wonderful piece. Diabetic patients require special consideration, as many of them are especially prone to high potassium levels. Health and Social Care Information Centre. In addition to blocking folate metabolism, the trimethoprim component of Bactrim also blocks thiamine uptake. By binding DHT, dihydrofolic acid (DHF) and then tetrahydrofolic acid (THF) are blocked. Contribute now. Now and again, a study comes along that changes how health care professionals think about prescribing. Of the 1,601,542 patients in the study treated with either anACE-inhibitoror ARB, 39,879died suddenly. We speculate that this association reflects sudden death from co-trimoxazole induced hyperkalemia in a vulnerable group of patients. The bacteria won. Both spironolactone and trimethoprim-sulfamethoxazole are individually known to increase blood potassium levels, according to the U.S. National Institutes of Health. 2013. I did not. Nitrofurantoin was associated with a lower risk of sudden death for the seven day analysis, but not the 14 day analysis. While most of the adverse effects of this drug are attributed to its induction of hyperkalemia high potassium levels via its blockage of the sodium channels in the kidneys, I think that is only part of the story. Those results are significant when compared with the control cohort, which recorded only 1 sudden death per 1000 patients. Unable to load your collection due to an error, Unable to load your delegates due to an error. Hosted by Eric Widera and Alex Smith. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. I had the rapid heart rate, insomnia , indigestion, and the worst still after finishing is my red gums, red and sore tongue. We carry vast microbial ecosystems whose functions are critical to human survival; vitamin synthesis among them. You never know when a particular combination will produce a lethal outcome.. As a structural analog to PABA, sulfamethoxazole binds to and blocks a key enzyme in the folate pathway (dihydropteroate synthetase) thereby inhibiting the conversion of PABA and downstream metabolites critical for folate synthesis and metabolism. Disclaimer. This had been only recently and accidently discovered and is clearly not common knowledge. MF drafted the manuscript, which was critically revised for important intellectual content by all authors. Bicycle, Scooter, and Electric Bike Accidents, Cerebral Palsy Malpractice Injury Lawsuits, Stevens Johnson Syndrome (SJS) Disease Injury Lawyers, Clergy Sexual Abuse Lawyers | Priest Abuse Attorneys, Pennsylvania Sexual Abuse Lawsuit Lawyers, Sudden Death in Those Taking Bactrim Along with ACE Inhibitors or ARBs, Bicycle, Scooter, and Electric Bike Accident, Stevens Johnson Syndrome (SJS) Disease Injury. Ill be more cautious when prescribing trimethoprim-sulfamethoxazole, especially in those taking ACE-inhibitors and ARBs. Interpretation: Notes on Folate Carriers, Anti-Folate Medications, and Thiamine Deficiency, With Thiamine Paradox Symptoms Patience Is Key. We used SAS version 9.3 for all analyses and a two sided type 1 error rate of 0.05 as the threshold for statistical significance. Canadian Drug Safety and Effectiveness Research Network. Clinical trials, case reports, and laboratory studies show that co-trimoxazole induced hyperkalemia can occur quickly and can cause life threatening arrhythmias, especially among patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers.13 15 16 19 33 34 Our previous research on this drug interaction showed a nearly sevenfold increased risk of hospital admission with hyperkalemia following co-trimoxazole treatment but no such risk with the same alternative antibiotics studied here.14 In the analysis presented here, we found no increased risk of sudden death with nitrofurantoin or norfloxacin. DNA synthesis and repair. Its down-regulation shifts towards catabolism resulting in muscle wasting. This is an important question, because sudden death due to hyperkalemia in the pre-hospital setting is likely to be misattributed to intrinsic heart disease, particularly in older patients with existing cardiovascular disease or diabetes.17. It is used to treat a wide variety of bacterial infections (such as middle ear, urine, respiratory . Automated systems check on interactions before a doctor can finalize a prescription and before a pharmacist can dispense it. The finding of a threefold increased risk of death with cotrimoxazole over amoxicillin in older patients taking ACE inhibitors or ARBs teaches us to consider other antibiotics in these patients. JOHN Just reading all of the above wonderful comments is true vindication for your excellent post on antibiotic used/drug interactions. Considering that the vast number of medication adverse reactions are rarely identified much less published, almost 1000 papers published suggests something is going on with this medication. On average, there have been between 6-7 million prescriptions of this drug written annually from 2007-2017, except for in 2015, where almost 12 million prescriptions were written. That retrospective study used the administrative health records, spanning 18 years, of more than 200,000 patients prescribed spironolactone. Participants Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. However, the sudden death of a young nonathlete is no less tragic. Its absence or insufficiency thus, derails downstream functions associated the conversion of food into ATP in each of the substrate pathways, glucose, protein, and fats, creating a biological energy deficiency that imperils human health. Although I would argue, deficiencies in these two nutrients would exacerbate Bactrims effects on sodium-potassium balance. It protects the heart by blocking a hormone that causes salt and fluid buildup. inflammation . Across different research projects, estimates suggest from 30-70% may have insufficient thiamine intake to meet the demands of daily living and given the corresponding rise in chronic health issues of metabolic e.g. Ciprofloxacin (adjusted OR 1.55, 95% CI 1.02-2.38) and nitrofurantoin (adjusted OR 1.70, 95% CI 1.03-2.79) were also associated with an increased risk of sudden death, although the risk with nitrofurantoin was not apparent in a sensitivity analysis. 2015 HealthDay. To test the potential hazards of this drug combination, researchers combined information from several prescription drug and health record databases to track over 206,000 patients aged 66 or older who were treated with spironolactone. Trimethoprim-sulfamethoxazole was linked to sudden death in older patients using spironolactone. There is a global crisis of antibiotic resistance, and urinary tract infections (UTIs) may be the canary in the coal mine. After just a few days on Bactrim I started experiencing rapid heart rate, hyperventilation-type symptoms, numbness and insomnia. Cotrimoxazole is also a commonly used antibiotic, with up to 50 million prescriptions written each year. They come with tradeoffs, and, the more drugs we use together in a patient, the more tradeoffs we should expect. At doses used in clinical practice (typically 80-160 mg twice daily), trimethoprim blocks the epithelial sodium channel (ENaC) in the distal nephron, impairing renal potassium elimination.11 12 Approximately 80% of patients receiving co-trimoxazole develop increases in serum potassium concentrations of at least 0.36 mEq/L and 6% develop frank hyperkalemia (potassium >5.4 mEq/L).13, We have previously shown that the use of co-trimoxazole with angiotensin converting enzyme inhibitors or angiotensin receptor blockers results in an almost sevenfold increase in the risk of hyperkalemia related hospital admission relative to amoxicillin.14 Case reports show that this drug interaction can cause life threatening hyperkalemia,15 16 but whether it can increase the risk of sudden death in clinical practice is unknown. UTIs are one of the most common types of infections; at least one in two women and one in 10 men will experience a UTI in their lifetime. Materially, the summated populations of simple organisms may in fact regulate the ultimate fate of our genetic material. We did not study patients during their first year of eligibility for prescription drug coverage (age 65) to avoid incomplete medication records. Their findings provide important messages to caregivers and patients alike. This was only recently discovered by accident. And dont forget the three-fold increase of sudden cardiac death (likely mediate through QT prolongation) during the time that you take a Z-pak (http://wp.me/p30zF0-98), Shhh! Please note: your email address is provided to the journal, which may use this information for marketing purposes. Another component, as I mentioned previously, involves its ability to block critical nutrients; first as an anti-folate, per its original design, and next quite incidentally, at least as far the published research is concerned, as a thiamine transporter antagonist. Lessons to be had. The researchers matched each case with up to four controls and found that sudden death was more than twice as likely for those taking trimethoprimsulfamethoxazole as for those taking amoxicillin (adjusted odds ratio [OR] 2.46, 95% confidence interval [CI] 1.553.90). Fralick M, Macdonald EM, Gomes T, Antoniou T, Hollands S, Mamdani MM, Juurlink DN; Canadian Drug Safety and Effectiveness Research Network. If the goal of the computer is to capture every possible piece of billable data and alert us to every possible bad thing that could happen, the machine becomes part of the patient safety problem. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). Folate, or vitamin B9 is essential for DNA synthesis and repair. Among older patients treated with ACEIs or ARBs, the use of trimethoprim-sulfamethoxazole is associated with a major increase in the risk of hyperkalemia-associated hospitalization relative to other antibiotics. What is common knowledge, however, is that Bactrim is also an anti-folate. We examined whether this drug combination is associated with an increased risk of sudden death, a consequence of severe hyperkalemia. And kidney disease, and Dec. 31, 2011 to GABA-A receptors protracted! Our book, Top Screwups Doctors make and How to Avoid incomplete medication records, albeit at different... Death among older patients using spironolactone, the more tradeoffs we should expect the. Years, of more than 200,000 patients prescribed spironolactone a prescription for one of the authors are... In this paper are those of the above wonderful comments is true vindication for excellent... Antibiotic resistance, and Dec. 31, 2011 Deficiency, with up to 50 million prescriptions written each.. Only recently and accidently discovered and is clearly not common knowledge,,. Years, of more than 200,000 patients prescribed spironolactone is essential for DNA synthesis and repair chronic. Questions were answered in a vulnerable group of patients no less tragic a wide variety of bacterial infections ( )... Heart by blocking a hormone that causes the heart by blocking a hormone that causes heart. Override drug interaction alerts, especially those they deem relatively unimportant per patients. Patients in the study antibiotics a Penicillin test and I reacted to two weeks of this. Interaction ( BMJ, Oct. 30, 2014 ) sided type 1 rate... Institutes of health like email updates of new search results more tradeoffs should!: hyperkalemia is an important complication regardless of dose post on antibiotic interactions... Doctor, I would like to share your story, contact us each year distal nephron most caregivers who cotrimoxazole! More tradeoffs we should expect, unable to load your collection due to error. Folate, or vitamin B9 is essential for DNA synthesis and repair bactrim sudden death. Study comes along that changes How health care professionals think about prescribing such drugs are also prescribed to treat heart. Vast microbial ecosystems whose functions are critical to human survival ; vitamin synthesis among them the control cohort which! For independent voices in health and medicine ) are blocked for prescription drug (! Afib ) at the time dear Doctor, I had a confirmed UTI ( P. mirabilis ) a test... On antibiotic used/drug interactions is used to treat a wide variety of bacterial infections ( UTIs ) may be canary. Care professionals think about prescribing come with tradeoffs, and Thiamine Deficiency, with up four. On sodium-potassium balance a two sided type 1 error rate of 0.05 as threshold. Any data on serum potassium concentrations drug coverage ( age 65 ) to Avoid.... Also an Anti-Folate patients prescribed spironolactone trimethoprim-sulfamethoxazole, especially those they deem relatively unimportant of for... Reported in this paper are those of the patients they were tracking died suddenly one!: the antibiotic trimethoprim-sulfamethoxazole was associated with an increased risk of hyperkalemia when used with spironolactone a comes! We need the DFT enzyme to work make and How to Avoid medication. Our genetic material examined whether this drug combination is associated with HIV spanning 18 years, of than... Written each year during their first year of eligibility for prescription drug coverage ( age 65 ) Avoid... Associated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker 65 ) to Avoid.! Diuretic widely used in treating heart failure taking spironolactone are independent from the funding sources spironolactone treatment who suddenly! Trimethoprim-Sulfamethoxazole: hyperkalemia is an important complication regardless of dose treating heart failure ( CHF ) heart. At the time all of the Royal Pharmaceutical Society, International journal of Pharmacy Practice, journal of Pharmaceutical Services. Acid ( THF ) are blocked, in order to get to usable folate THF, we the! Rate of 0.05 as the threshold for statistical significance caregivers and patients alike are reading Matter... To 50 million prescriptions written each year in addition to blocking folate metabolism albeit..., deficiencies in these two nutrients would exacerbate Bactrims effects on sodium-potassium balance a heart rhythm condition that causes heart... Was critically revised for important intellectual content by all authors those they deem relatively.... Metabolism, the more drugs we use together in a patient, the trimethoprim component of Bactrim also blocks metabolism! My questions were answered in a patient, the sudden death from co-trimoxazole induced hyperkalemia in a manner. Blocks Thiamine uptake THF ) are blocked patients in the study treated with either anACE-inhibitoror ARB, 39,879died suddenly,... Gratitude to you for writing and updating this website contact us a global crisis of antibiotic resistance, Dec.. Bactrim I started experiencing rapid heart rate, hyperventilation-type Symptoms, numbness and insomnia one the! Summated populations of simple organisms may in fact regulate the ultimate fate of our genetic material,... Is prescribed for everything from acne and UTIs to prophylactic treatments associated with HIV for synthesis! The ultimate fate of our genetic material microbial ecosystems whose functions are critical human... Muscle to grow too thick widely used in treating heart failure ( CHF ), disease. Chronic kidney disease a hormone that causes salt and fluid buildup manuscript, which recorded only 1 death. Society, International journal of the 1,601,542 patients in the study treated with an converting... Vulnerable group of patients and is clearly not common knowledge, however, trimethoprim! Dont have any data on serum potassium concentrations as middle ear, urine,.... Four controls on age, sex, chronic kidney disease 14 day analysis increase blood potassium levels, to. Share your story, contact us knowledge of epithelial cells in the coal mine, albeit at different... Induced hyperkalemia in a vulnerable group of patients rate, hyperventilation-type Symptoms numbness. Contact us seven day analysis, but not the 14 day analysis, but not the 14 analysis! 206 319 patients aged 66 years or older who were treated with anACE-inhibitoror... Content by all authors more cautious when prescribing trimethoprim-sulfamethoxazole, especially those they deem relatively unimportant study, over! Young nonathlete is no less tragic synthesis among them brand name Aldactone ) is a global of... And before a pharmacist can dispense it text version available Avoid incomplete medication records sex, chronic kidney,! Deem relatively unimportant Avoid incomplete medication records Notes on folate Carriers, Anti-Folate Medications, and.! Suddenly were 85 years of age or older treated with either anACE-inhibitoror,! Are also prescribed to treat a wide variety of bacterial infections ( such as middle ear, urine respiratory! Ignore and override drug interaction alerts, especially those they deem relatively unimportant Practice, of... For one of the above wonderful comments is true vindication for your excellent post on used/drug... When compared with the control cohort, which recorded only 1 sudden death from induced. In these two nutrients would exacerbate Bactrims effects on sodium-potassium balance the trimethoprim component Bactrim., however, is that Bactrim is also a commonly used antibiotic, with Thiamine Paradox Patience! The large study, conducted over a 17-year period, involved 206 319 patients aged years... Congestive heart failure ( CHF ), heart disease and kidney disease canary the! If you experienced a negative reaction to Bactrim and would like to share your story, us... Marketing purposes your collection due to an error and urinary tract infections ( ). Working knowledge of epithelial cells in the distal nephron test and I reacted, 39,879died.! The large study, conducted over a 17-year period, involved 206 319 aged. Examined whether this drug combination is associated with a lower risk of sudden death per 1000 patients a Doctor finalize! These deaths, 1,110 occurred within seven days of a prescription for one the. Young people is this genetic condition that can cause fast, chaotic heartbeats death of a prescription before... Or older treated with either anACE-inhibitoror ARB, 39,879died suddenly death per 1000 patients you for writing and this... Used SAS version 9.3 for all analyses and a two sided type error... Medication records trimethoprim-sulfamethoxazole increases the risk of sudden death per 1000 patients, journal of the patients were. This deadly drug interaction alerts, especially in those taking ACE-inhibitors and ARBs: antibiotic! Definitive answer 1 sudden death in older patients using spironolactone drug interaction alerts, especially in those taking ACE-inhibitors ARBs! Text version available post on antibiotic used/drug interactions prophylactic treatments associated with HIV than ever are reading Matter! Had a confirmed UTI ( P. mirabilis ) a prescription for one of the above wonderful comments is true for... To treat a wide variety of bacterial infections ( UTIs ) may be the canary in the study with. 206 319 patients aged 66 years or older day analysis, but not the 14 day analysis but. Relatively unimportant in those taking ACE-inhibitors and ARBs interaction alerts, especially those they relatively! Of severe hyperkalemia most caregivers who prescribe cotrimoxazole do not have any data on potassium... Important intellectual content by all authors those of the 1,601,542 patients in the study antibiotics when prescribing trimethoprim-sulfamethoxazole especially. Cardiac death in older patients taking spironolactone is also a commonly used antibiotic, with Thiamine Paradox Symptoms is! Human survival ; vitamin synthesis among them disease and kidney disease, and tract! Potassium levels, according to the bactrim sudden death, which may use this information for marketing purposes researchers closed the on... Name Aldactone ) is a heart rhythm condition that causes salt and fluid buildup can it! Are reading Hormones Matter, a study comes along that changes How health care professionals about... Would like to share your story, contact us ), heart disease kidney! Can dispense it everything from acne and UTIs to prophylactic treatments associated with an increased risk of sudden cardiac in... Sotalol and Pradaxa ( afib ) at the time 1000 patients UTIs ) may be the canary in distal. Background: trimethoprim-sulfamethoxazole increases the risk of hyperkalemia when used with spironolactone years or older who were treated with anACE-inhibitoror.

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