Real-World Effectiveness of Preventive Pharmacological Therapy in Patients With Urolithiasis: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Data supporting the efficacy of preventive pharmacological therapy (PPT) to reduce urolithiasis recurrence are based on clinical trials with composite outcomes that incorporate imaging findings and have uncertain clinical significance. This study evaluated whether the use of PPT leads to fewer symptomatic stone events. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare enrollees with urolithiasis who completed 24-hour urine collections that revealed hypercalciuria, hypocitraturia, low urine pH, or hyperuricosuria. EXPOSURE: PPT (thiazide diuretics for hypercalciuria, alkali for hypocitraturia or low urine pH, or uric acid lowering drugs for hyperuricosuria) categorized as (1) adherent to guideline-concordant PPT, (2) nonadherent to guideline-concordant PPT, or (3) untreated. OUTCOME: Symptomatic stone event occurrence (emergency department [ED] visit or hospitalization for urolithiasis or stone-directed surgery). ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: Among 13,942 patients, 31.0% were prescribed PPT. Compared with no treatment, concordant/adherent PPT use was associated with a significantly lower hazard of symptomatic stone events for patients with hypercalciuria (HR, 0.736 [95% CI, 0.593-0.915]) and low urine pH (HR, 0.804 [95% CI, 0.650-0.996]) but not for patients with hypocitraturia or hyperuricosuria. These associations were largely driven by significantly lower rates of ED visits after initiating PPT among the concordant/adherent group versus untreated patients. Patients with hypercalciuria had adjusted 2-year predicted probabilities of a visit of 3.8% [95% CI, 2.5%-5.2%%] and 6.9% [95% CI, 6.0%-7.7%] for the concordant/adherent PPT and no-treatment groups, respectively. Among patients with low urine pH, these probabilities were 4.3% (95% CI, 2.9%-5.7%) and 7.3% (95% CI, 6.5%-8.0%) for the concordant/adherent PPT and no-treatment groups, respectively. LIMITATIONS: Potential bias from the possibility that patients prescribed PPT had more severe disease than untreated patients. CONCLUSIONS: Patients with urolithiasis and hypercalciuria who were adherent to treatment with thiazide diuretics as well as those with low urine pH adherent to prescribed alkali therapy had fewer symptomatic stone events than untreated patients. PLAIN-LANGUAGE SUMMARY: Despite multiple clinical trials demonstrating the efficacy of thiazide diuretics and alkali for secondary prevention of kidney stones, they are infrequently prescribed due in part to a lack of data about their effectiveness in real-world settings. We analyzed medical claims from older adults with kidney stones for whom urine chemistry data were available. We found that patients who took prescribed thiazide diuretics for elevated urine calcium levels or alkali for low urinary pH were less likely to experience symptomatic stone recurrences than untreated patients. This benefit was expressed as lower rates of emergency department visits after initiating therapy. Our findings should inform the prescription of and adherence to treatment with thiazide diuretics and alkali for the prevention of recurrent kidney stones.

Preventive Pharmacological Therapy and Risk of Recurrent Urinary Stone Disease.

BACKGROUND: Urinary stone disease is a prevalent condition associated with a high recurrence risk. Preventive pharmacological therapy has been proposed to reduce recurrent stone episodes. However, limited evidence exists regarding its effectiveness, contributing to its underutilization by physicians. This study aimed to evaluate the association between preventive pharmacological therapy (thiazide diuretics, alkali therapy, and uric acid-lowering medications) and clinically significant urinary stone disease recurrence. METHODS: Using data from the Veterans Health Administration, adults with an index episode of urinary stone disease from 2012 through 2019 and at least one urinary abnormality (hypercalciuria, hypocitraturia, or hyperuricosuria) on 24-hour urine collection were included. The primary outcome was a composite variable representing recurrent stone events that resulted in emergency department visits, hospitalizations, or surgery for urinary stone disease. Cox proportional hazards regression was performed to estimate the association between preventive pharmacological therapy use and recurrent urinary stone disease while adjusting for relevant baseline patient characteristics. RESULTS: Among the cohort of patients with urinary abnormalities ( n =5637), treatment with preventive pharmacological therapy was associated with a significant 19% lower risk of recurrent urinary stone disease during the 12-36-month period after the initial urine collection (hazard ratio, 0.81; 95% confidence interval, 0.65 to 1.00; P = 0.0496). However, the effectiveness of preventive pharmacological therapy diminished over longer follow-up periods (12-48 and 12-60 months after the urine collection) and did not reach statistical significance. When examining specific urinary abnormalities, only alkali therapy for hypocitraturia was associated with a significant 26% lower recurrence risk within the 12-36-month timeframe (hazard ratio, 0.74; 95% confidence interval, 0.56 to 0.97; P = 0.03). CONCLUSIONS: When considering all urinary abnormalities together, this study demonstrates that the use of preventive pharmacological therapy is associated with a lower risk of clinically significant recurrent episodes of urinary stone disease in the 12-36 month timeframe after urine collection, although only the association with the use of alkali therapy for hypocitraturia was significant when individual abnormalities were examined.

Thiazide Diuretics and Risk of Colorectal Cancer: A Population-Based Cohort Study.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood. Objective: To determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up. Design, Setting, and Participants: This prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at least 1 other coronary heart disease risk factor for up to 23 years, from February 23, 1994, to December 31, 2017. Trial participants were linked with administrative databases for posttrial mortality (N = 32 804) and morbidity outcomes (n = 22 754). Statistical analysis was performed from January 2022 to October 2023. Interventions: Participants were randomly assigned to receive a thiazide-type diuretic (n = 15 002), a CCB (n = 8898), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of approximately 4 to 8 years and posttrial passive follow-up for up to 23 years. Main Outcomes and Measures: The primary end point was mortality due to cardiovascular disease (CVD). Secondary outcomes included all-cause mortality, combined fatal and nonfatal (morbidity) CVD, and both mortality and morbidity for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer. Results: A total of 32 804 participants (mean [SD] age, 66.9 [7.7] years; 17 411 men [53.1%]; and 11 772 Black participants [35.9%]) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean [SD] age, 68.7 [7.2] years; 12 772 women [56.1%]; and 8199 Black participants [36.0%]) were followed up for fatal or nonfatal CVD through 2017 (mean [SD] follow-up, 13.7 [6.7] years; maximum follow-up, 23.9 years). Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 [95% CI, 0.89-1.05] for CCB vs diuretic; AHR, 1.06 [95% CI, 0.97-1.15] for ACE inhibitor vs diuretic). The long-term risks of most secondary outcomes were similar among the 3 groups. Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19 [95% CI, 1.03-1.37]) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11 [95% CI, 1.03-1.20]). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial in an adult population with hypertension and coronary heart disease risk factors, CVD mortality was similar between all 3 groups. ACE inhibitors increased the risk of stroke outcomes by 11% compared with diuretics, and this effect persisted well beyond the trial period. Trial Registration: ClinicalTrials.gov Identifier: NCT00000542.

Thiazide diuretics and primary hyperparathyroidism.

Thiazide diuretics exert a natriuretic and diuretic effect by inhibiting sodium reabsorption in the distal convoluted tubule. Furthermore, thiazide diuretics affect renal calcium handling by increasing calcium reabsorption, leading to hypocalciuria. The effect that thiazide diuretics exert on parathyroid hormone secretion is controversial. Some studies found parathyroid hormone levels were suppressed with the use of thiazide diuretics, while others found that thiazides were associated with initial parathyroid hormone suppression followed by raised parathyroid hormone levels. This makes the relationship between thiazide diuretics and primary hyperparathyroidism interesting. If a patient is taking thiazide diuretics, this may make it harder to establish the aetiology of hypercalcaemia and may unmask normocalcaemic or mild primary hyperparathyroidism. Thiazide diuretics may have a beneficial role in the diagnosis of patients with concomitant hyperparathyroidism and hypercalciuria by distinguishing secondary hyperparathyroidism caused by hypercalciuria from normocalcaemic primary hyperparathyroidism. In addition, thiazide diuretics may have a role in managing patients with primary hyperparathyroidism who have an indication for parathyroidectomy in view of significant hypercalciuria, but are unfit for surgery.

Risk factors for hypokalemia and its association with postoperative recovery in patients scheduled for radical gastrectomy: a retrospective study.

BACKGROUND: Hypokalemia is common in patients of various operations, especially gastrointestinal surgery, which seriously affects the safety and enhanced recovery after surgery. Our study aims to explore the risk factors of preoperative hypokalemia of radical gastrectomy for gastric cancer and analyze its impact on postoperative recovery. METHODS: A total of 122 patients scheduled for radical gastrectomy from September, 2022 to December, 2022 were retrospectively analyzed. According to the serum potassium level before skin incision, patients were divided into hypokalemia group (n = 64) and normokalemia group (n = 58). Factors including age, gender, BMI, ASA classification, glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), creatinine, blood urea nitrogen (BUN), albumin, hypertension history, whether taking calcium channel blockers, ß-receptor blockers, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor antagonist (ARB), thiazide diuretics and other drugs, anemia history, diabetes mellitus history, inability to eat or intestinal obstruction, vomiting, diarrhea, hypokalemia on admission and whether under cooperation with clinical nurse specialist were compared between groups. Univariate logistic regression analysis was used to determine risk factors for hypokalemia with p < 0.2 included as a cutoff. Multivariate logistic regression was used to analyze the influencing factors of preoperative hypokalemia for the indicators with differences. A receiver operating characteristic (ROC) curve was used to evaluate the efficacy of the regression model. Primary exhaust time and defecation time after surgery were compared between the two groups. RESULTS: The use of ACEI or ARB [OR 0.08, 95% CI (0.01 to 0.58), p = 0.012] and thiazide diuretics [OR 8.31, 95% CI (1.31 to 52.68), p = 0.025], inability to eat for more than 3 days or intestinal obstruction [OR 17.96, 95% CI (2.16 to 149.43), p = 0.008], diarrhea for more than 48 h [OR 6.21, 95% CI (1.18 to 32.61), p = 0.031] and hypokalemia on admission [OR 8.97, 95% CI (1.05 to 77.04), p = 0.046] were independent influencing factors of hypokalemia before skin incision. Primary postoperative exhaust time and defecation time was significantly longer in the hypokalemia group than in the normokalemia group, no matter after laparoscopic radical gastrectomy (p = 0.044, p = 0.045, respectively) or open radical gastrectomy (p = 0.033, p = 0.019, respectively). CONCLUSION: Early attention and management of serum potassium in patients undergoing radical gastrectomy can better reduce perioperative adverse reactions and promote recovery of gastrointestinal function.

Comparison of the effects of angiotensin receptor-neprilysin inhibitors and thiazide diuretic/renin-angiotensin system inhibitor combination therapy in hypertensive patients: a retrospective cohort study.

Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m2 [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects.

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics.

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

NITROSOGENESIS OF SKIN (HUMAN) CANCER- THE HIDDEN TRUTH OF A NEVERENDING STORY: NITROSAMINE CONTAMINATION IN OLMESARTAN, VALSARTAN AND HCT AS MAIN RISK FACTOR FOR THE DEVELOPMENT OF KERATINOCYTE CANCER.

The pathogenesis of skin cancer remains shrouded in mystery. Nevertheless, a substantial amount of new data is now available to provide a logical explanation regarding the possible link between 1) the occurrence of single or multiple acquired/somatic mutations and 2) the generation and progression of skin cancer, as well as 3) the potential association of the above two facts with the availability of nitrosamines in drugs for hypertension, diabetes, gastritis, acne, tuberculosis, various other antibiotics, etc. The nitrosogenesis of skin cancer is slowly but surely being established as a significant concept that could not be ignored for longer periods of time. It should only be analysed in detail with a view to future prevention for the benefit of public health. The nitrosogenesis of skin cancer is slowly but surely being established as a significant concept that cannot be ignored for longer periods of time. It should only be analysed in detail with a view to future prevention for the benefit of public health. Although this information has been known for decades (but in relation to the development of other cancers), there is still no comparative analysis of the mutations that occur after ingestion of a particular mutagen, also known as nitrosamine. This analysis could to some extent highlight/support or reject to some extent the thesis of the role of nitrosamines and genetic instability leading to the subsequent generation of a malignant cell clone. The notion of skin cancer nitrosogenesis should become a priority concept very soon, but it should also become an evidential memory, a byword, and an equivalent of the ignorance with which modern civilization has treated its own health for decades within the processes of globalization. It is these processes that include nitrosamines as a major component of the "medicinal and nutritional menu" of patients. It remains unclear at present why regulatory authorities are making endless attempts to legalise the availability of a number of mutagens/human carcinogens in the most commonly distributed medicines worldwide. And to persuade "others" that there is no risk from their permanent, controlled and long-term intake. The newly introduced regulatory norms in practice concern the potential/permissive availability of nitrosamines in a serious number of drugs: drugs with radically different mechanisms of action such as: ranitidine, metformin, ACE inhibitors, beta blockers, thiazide diuretics, sartans, rifampicin, but also probably a number of others. However, the occurrence of identical, similar patterns of cancers (skin cancers) following their administration (after ingestion of different classes of drugs) makes the ubiquitous permissive availability of nitrosamines (in each class of these drugs) the most potent and most likely pathogenetic inducer of cancer. These comparative patterns of skin tumor occurrence should have even stronger evidentiary value than even so-called prospective follow-ups. Nitrosamines are and remain one of the best studied mutagens/carcinogens that can alter/modify the human genome. A fact underlined repeatedly over the years (also based on in vivo data, repeatedly ignored) and a fact that, according to the literature, concerns mainly tire industry workers (British rubber workers). It is in this category of patients and after exposure to high doses of nitrosamines (potential inhalation intake) that high mortality has been found in bladder, lung, stomach, oesophageal cancer, multiple myeloma, leukaemia, prostate cancer, pancreatic cancer, and liver cancer. Similar international observations (in vivo/Sweden) concerning intensive human exposure (Swedish rubber workers) to high doses of nitrosamines in a working atmosphere (inhalation type of carcinogen uptake) emphasize the resulting direct subsequent risk of other alarming symptoms such as: nasal bleeds, eye and throat symptoms, hoarseness, cough, nausea, headache, and altered levels of eosinophils and total immunoglobulin G (IgG), compared with unexposed patients. The neglect of these important observations over the years has led to the ubiquitous and currently difficult to counteract and unpunished prevalence of nitrosamines in even the most commonly distributed drugs worldwide (except in the food industry). It is precisely because of this fact that it should come as no surprise to anyone that there is new evidence of an avalanche in the number of new cancers after ingestion of potentially nitrosamine-contaminated preparations. Skin cancer could be seen in the near future precisely as a model of a side reaction after application or long-term contact with mutagens called nitrosamines. Based on the above, and wishing to add to the worldwide data on the heterogeneous cancers that occur after contact with nitrosamines, we draw the attention of the scientific community to the risk of developing keratinocytic cancer after ingestion of nitrosamine-contaminated drugs: sartans and thiazide diuretics. We believe that the role of the generic substance in these drugs could also contribute to some extent to the progression of an already present tumour branch, but this influence is rather minor and without significant clinical relevance. We present a patient who had been taking 2 sartans (valsartan/ olmesartan) over the years as monotherapy and in combination with hydrochlorothiazide, who developed over time and within this intake two forms of keratinocytic cancer: verrucous carcinoma and basal cell carcinoma. The focus of discussion concerns a newly introduced medical concept: nitrosogenesis of skin cancer. The detailed study of nitrosogenesis should be a major, primary task for regulators, researchers, clinicians, and pharmaceutical companies.

THE NITROSAMINE CONTAMINATION IN BETA BLOCKERS (BISOPROLOL/METOPROLOL), ACE INHIBITORS (LISINOPRIL/PERINDOPRIL), THIAZIDES DIURETICS (HCT), CALCIUM CHANNEL BLOCKERS (AMLODIPINE/FELODIPINE), SARTANS (CANDESARTAN) AND ТHE SUBSEQUENT SKIN CANCER DEVELOPMENT AND PROGRESSION: APOCALYPSE NOW.

The problem of contamination of the most commonly used medicines with nitrosamines is worsening worldwide. According to recent literature data, this "contamination" is the cause not only of skin cancer (keratinocytic/melanoma) but also of gastrointestinal neoplasms, brain tumours, neuroblastoma, rectal carcinoma, acute lymphoblastic leukaemia, and many others. It is these clinical manifestations that are associated with/ or already directly linked to the nitrosamine content of drugs and food products used by patients in previous periods. And it is this permissive availability/contamination that could prove to be the most likely, powerful inducer of acquired mutations underlying the worldwide cancer pandemic. Of further concern is the evidence of contamination of newer classes of medications by nitrosamines- namely: beta blockers, calcium antagonists and selective serotonin reuptake inhibitors (SSRIs). In practice, mankind faces the problem of certainly over 1 billion patients taking nitrosamine-contaminated drugs: 280 million patients with depression (antidepressants), over 1 billion patients with arterial hypertension (antihypertensive drugs), over half a billion patients with type 2 diabetes mellitus (oral antidiabetic drugs/metformin/ sitagliptin), over 4 billion patients with gastritis (ranitidine), over 5 million with tuberculosis (rifampicin), and probably a number of others. The calculations are apocalyptic, since even if only 20-30% of the groups were affected, the number of patients taking these drugs would, by a rough calculation, currently amount to over 1 billion. And there are certainly other classes of drugs yet to be announced. It is for this reason that we should not be surprised that the data on the development of keratinocyte cancer after intake of nitrosamine-contaminated preparations is growing at a breakneck pace. This data indirectly but strongly confirms the importance of a newly introduced concept in the medical science : Nitrosogenesis of skin cancer. A concept, until recently unknown, incomprehensible, but at the same time frightening and gradually accepted, imposing itself and which with each passing day is gaining more and more scientific significance and "visibility", "scientific tangibility, receptivity, and acceptability." This article presents, for the first time in the world literature, patients who developed single/multiple forms of keratinocytic cancer (partly in combination with melanoma precursors-dysplastic moles) after administration of two new classes of potentially nitrosamine-contaminated antihypertensive drugs: beta blockers (bisoprolol, metoprolol) and calcium antagonists (amlodipine, felodipine). For the first time in the scientific literature, the contributory pro-carcinogenic role of another potentially nitrosamine-contaminated ACE inhibitor- lisinopril , as well as that of candesartan: in the development of keratinocytic cancer is also discussed. For the first time in the world literature, the conclusion regarding the pathogenetic relationship between the intake of potentially contaminated drugs (from different drug groups) and cancer development is based on the model of the equivalent clinical manifestation of skin tumors (rather than on controlled long-term prospective analyses). Nitrosamine contamination in these drug groups appears to be the sole and major unifying factor or causative agent for these manifestations.

METATYPICAL BCCS OF THE NOSE TREATED SUCCESSFULLY VIA BILOBED TRANSPOSITION FLAP: NITROSAMINES IN ACES (ENALAPRIL), ARBS (LOSARTAN) AS POSSIBLE SKIN CANCER KEY TRIGGERING FACTOR.

The pathogenesis of keratinocytic skin cancer has been well-studied over the years, with a main focus on the influence of UV radiation and the subsequent changes in the genome regulator p53, which affects the cell cycle and the programmed cell death, apoptosis. Alarming and relatively new trend is the link between nitrosamines in blood pressure medications (but not only) and the development of both melanocytic and keratinocytic skin tumors. In the recent past, high concentrations (above the so-called daily acceptable intake dose) of nitrosamines in ACE inhibitors and sartans became the reason for some of these medications to be officially withdrawn from the drug market. As of now, and according to the lawsuits filed, contamination with even or just one nitrosamine could be the cause of lawsuits for between 5 to 10 forms of cancer overall. Single case reports, but also large-scale retrospective international studies, find a connection between the intake of possibly nitrosamine contaminated ACE inhibitors/sartans with the subsequent development of basal cell carcinomas. The same studies also found a serious risk of developing melanomas and squamous cell carcinomas after taking ACE inhibitors, thiazide diuretics and sartans. This, in turn, leads clinicians to ponder the following dilemma: Is it possible that the key pathogenetic link concerning the development of skin cancer is due to their radically different mechanism of action (ACEs/ARBs/Thiazides)? Or, more likely, in all three antihypertensive drug classes, such as sartans, ACE inhibitors, and thiazide diuretics, there is another cancer-causing contaminant, the so-called nitrosamines? Systemic intake of potentially nitrosamine-contaminated sartans and ACE inhibitors would logically lead to the generation of relatively uniform skin tumors. Proceeding precisely from this thesis, we present two non-related cases of metatypical basal cell carcinomas in the nasal area, which occurred during the administration of ACE inhibitors/angiotensin receptor blockers and were successfully treated by transpositional reconstructive flap - bilobed flap. Possible contamination with nitrosamines as a pathogenetically significant factor is discussed.

Thiazide diuretics alone or combined with potassium-sparing diuretics to treat hypertension: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The magnitude of blood pressure (BP)-lowering effects and decrease of the adverse effects of thiazide diuretics provided by potassium-sparing diuretics remain uncertain. The aim of this study was to compare the BP-lowering efficacy and the incidence of adverse effects of high (T+) and low-dose (T-) thiazide diuretics, alone or combined with high (PS+) or low-dose (PS-) potassium-sparing diuretics in patients with primary hypertension. METHODS: A systematic literature search was performed in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, Scopus and LILACS. Randomized double-blind placebo or active-controlled trials (RCT) with 3 weeks to 1 year of follow-up were included. Sample size, mean and standard deviation from baseline, follow-up and change from baseline values were extracted by two independent reviewers. Pairwise random effect models and Bayesian network meta-analysis models were used to compare the effects of treatments. The risk of bias in individual studies was assessed using the Rob 1.0 tool. The primary outcome was the mean difference in office SBP. Secondary outcomes were the mean difference in biochemical parameters and the incidence of nonmelanoma skin cancer. RESULTS: Two hundred and seventy-six double-blind RCTs involving 58 807 participants (mean age: 55 years; 45% women) were included. All treatment groups were more effective than placebo in lowering BP, with mean differences (MDs) of change from baseline ranging from -7.66 mmHg [95% credible interval (95% CrI), -8.53 to -6.79] for T- to -12.77 mmHg (95% CrI, -15.22 to -10.31) for T+PS-. T+ alone or combined with potassium-sparing was more effective in reducing BP than T-. The surface under the cumulative ranking curve (SUCRA) estimated ranking showed that the best effectiveness in lowering SBP was found for T+PS- (0.69), T+PS+ (0.65) and T+ (0.54). Compared with placebo, all treatments (except T-PS-) were associated with more potassium reduction and T+ compared with all other treatments and T- when compared with T-PS-. Compared with placebo, all active treatments (except T+PS+) showed higher elevations of uric acid. The increase of plasma glucose promoted by thiazides alone was reduced by potassium-sparing agents. CONCLUSION: Thiazides with potassium-sparing diuretics are associated with increased BP-lowering efficacy compared with thiazides alone while minimizing hypokalaemia and hyperglycaemia. These findings demonstrate that thiazide and potassium-sparing diuretic combination is preferable to thiazide alone in treating hypertension.

Antihypertensive Use and the Risk of Cataract in Patients with Hypertension: A Nationwide Case-control Study.

PURPOSE: This study aims to investigate the association between antihypertensive use and the risk of cataract in a matched case-control study. METHODS: We analysed the Korean National Health Insurance Service-Health Screening Cohort database from 2002 to 2013. We defined 'cases' as patients prescribed antihypertensives and underwent their first eye cataract surgery between 2010 and 2013. 'Controls' were patients prescribed antihypertensives and no history of cataract surgery or diagnosis between 2002 and 2013. Four controls were matched to each case by several variables. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for cataract risk using a conditional logistic regression model after adjustment. RESULTS: The analyses comprised 12,166 cases and 48,664 controls. The adjusted ORs for cataracts were 1.18 (95% CI: 1.12-1.24) in thiazide diuretics, 1.12 (95% CI: 1.07-1.18) in beta-blockers, 0.94 (95% CI: 0.90-1.00) in calcium channel blockers, 1.22 (95% CI: 1.14-1.30) in angiotensin-converting enzyme (ACE) inhibitors, and 0.97 (95% CI: 0.91-1.03) in angiotensin II receptor blockers compared to 'non-use' of each antihypertensive. CONCLUSION: In a nationwide case-control study, the use of thiazide diuretics, beta-blockers, or ACE inhibitors do not represent minimal clinical important difference in the risk of cataract and the use of calcium channel blockers or angiotensin II receptor blockers is not associated with an increased risk of cataracts compared to non-use of each antihypertensive. Given the benefits of treating hypertension, such as the reduction in further complications, we suggest there is no need to change current clinical practice for antihypertensives.

Antihypertensive treatment changes and related clinical outcomes in older hospitalized patients.

BACKGROUND: Hypertension management in older patients represents a challenge, particularly when hospitalized. OBJECTIVE: The objective of this study is to investigate the determinants and related outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients. METHODS: A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in-patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines [an angiotensin-converting-enzyme-inhibitor (ACE-I) or an angiotensin-receptor-blocker (ARB) with a calcium-channel-blocker (CCB) and/or a thiazide diuretic; if >80 years old, an ACE-I or ARB or CCB or thiazide diuretic]. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all-cause death, cardiovascular (CV) hospitalization/death, CV death, non-CV death, evaluated according to the presence of MT at discharge. RESULTS: Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all-cause death, all-cause death/hospitalization, CV death, CV death/hospitalization and non-CV death. CONCLUSIONS: Guidelines-suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in antihypertensive treatment still occur in a significant proportion of older hospitalized patients.

Dihydropyridine Calcium Channel Blockers and Risk of Pancreatic Cancer: A Population-Based Cohort Study.

Background Recent studies have reported that dihydropyridine calcium channel blockers (dCCBs) may increase the risk of pancreatic cancer, but these studies had methodological limitations. We thus aimed to determine whether dCCBs are associated with an increased risk of pancreatic cancer compared with thiazide diuretics, a clinically relevant comparator. Methods and Results We conducted a new user, active comparator, population-based cohort study using the UK Clinical Practice Research Datalink. We identified new users of dCCBs and new users of thiazide diuretics between 1990 and 2018, with follow-up until 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs for pancreatic cancer, comparing dCCBs with thiazide diuretics. Models were weighted using standardized morbidity ratio weights based on calendar time-specific propensity scores. We also conducted secondary analyses by cumulative duration of use, time since initiation, and individual drugs and assessed for the presence of effect modification by age, sex, smoking status, body mass index, history of chronic pancreatitis, and diabetes. The cohort included 344 480 initiators of dCCBs and 357 968 initiators of thiazide diuretics, generating 3 360 745 person-years of follow-up. After a median follow-up of 4.5 years, the weighted incidence rate per 100 000 person-years was 37.2 (95% CI, 34.1-40.4) for dCCBs and 39.4 (95% CI, 36.1-42.9) for thiazide diuretics. Overall, dCCBs were not associated with an increased risk of pancreatic cancer (weighted HR, 0.93; 95% CI, 0.80-1.09). Similar results were observed in secondary analyses. Conclusions In this large, population-based cohort study, dCCBs were not associated with an increased risk of pancreatic cancer compared with thiazide diuretics. These findings provide reassurance regarding the long-term pancreatic cancer safety of these drugs.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4-5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial.

BACKGROUND: The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4-5 KDIGO. METHODS: A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as 'bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study's registration number was NCT03923933. RESULTS: Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2-29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p < 0.001) and Day 30 (intervention: -3.05 vs. control: -0.15, p < 0.000). There was also a decrease in systolic blood pressure on Day 7 (intervention: -18 vs. control: -7.5, p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018). CONCLUSION: In CKD stage 4-5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.