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Lancet (London, England) Sep 2018In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial.
BACKGROUND
In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow-up of the UK participants in the original ASCOT trial.
METHODS
ASCOT was a multicentre randomised trial with a 2 × 2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15·7 years (IQR 9·7-16·4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressure-lowering treatment. Of these patients, those who had total cholesterol of 6·5 mmol/L or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death.
FINDINGS
Of 8580 UK-based patients in ASCOT, 3282 (38·3%) died, including 1640 (38·4%) of 4275 assigned to atenolol-based treatment and 1642 (38·1%) of 4305 assigned to amlodipine-based treatment. 1768 of the 4605 patients in the LLA died, including 903 (39·5%) of 2288 assigned placebo and 865 (37·3%) of 2317 assigned atorvastatin. Of all deaths, 1210 (36·9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in all-cause mortality between treatments (adjusted hazard ratio [HR] 0·90, 95% CI 0·81-1·01, p=0·0776]), although significantly fewer deaths from stroke (adjusted HR 0·71, 0·53-0·97, p=0·0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0·79, 0·67-0·93, p=0·0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p=0·022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0·85, 0·72-0·99, p=0·0395) occurred among patients assigned to statin than among those assigned placebo.
INTERPRETATION
Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes.
FUNDING
Pfizer.
Topics: Adult; Aged; Amlodipine; Anticholesteremic Agents; Antihypertensive Agents; Atenolol; Atorvastatin; Calcium Channel Blockers; Cardiovascular Diseases; Cause of Death; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Risk Factors; United Kingdom
PubMed: 30158072
DOI: 10.1016/S0140-6736(18)31776-8 -
Journal of the American Heart... Sep 2023Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and... (Observational Study)
Observational Study
Intensive Statin Therapy Versus Upfront Combination Therapy of Statin and Ezetimibe in Patients With Acute Coronary Syndrome: A Propensity Score Matching Analysis Based on the PL-ACS Data.
Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and Results The study included consecutive patients with ACS included in the PL-ACS (Polish Registry of Acute Coronary Syndromes), which is a national, multicenter, ongoing, prospective observational registry that is mandatory for patients with ACS hospitalized in Poland. Data were matched using the Mahalanobis distance within propensity score matching calipers. Multivariable stepwise logistic regression analysis, including all variables, was next used in propensity score matching analysis. Finally, 38 023 consecutive patients with ACS who were discharged alive were included in the analysis. After propensity score matching, 2 groups were analyzed: statin monotherapy (atorvastatin or rosuvastatin; n=768) and upfront combination therapy of statin and ezetimibe (n=768 patients). The difference in mortality between groups was significant during the follow-up and was present at 1 (5.9% versus 3.5%; =0.041), 2 (7.8% versus 4.3%; =0.019), and 3 (10.2% versus 5.5%; =0.024) years of follow-up in favor of the upfront combination therapy, as well as for the overall period. For the treatment, rosuvastatin significantly improved prognosis compared with atorvastatin (odds ratio [OR], 0.790 [95% CI, 0.732-0.853]). Upfront combination therapy was associated with a significant reduction of all-cause mortality in comparison with statin monotherapy (OR, 0.526 [95% CI, 0.378-0.733]), with absolute risk reduction of 4.7% after 3 years (number needed to treat=21). Conclusions The upfront combination lipid-lowering therapy is superior to statin monotherapy for all-cause mortality in patients with ACS. These results suggest that in high-risk patients, such an approach, rather than a stepwise therapy approach, should be recommended.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Acute Coronary Syndrome; Ezetimibe; Propensity Score
PubMed: 37671618
DOI: 10.1161/JAHA.123.030414 -
International Journal of Molecular... Oct 2021Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is...
Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is eventually affected by the organization of actin fibers. Atorvastatin is a statin known to influence both the cholesterol content and the organization of actin. This work analyzes the effects of the latter on the efficacy of electroporation of cancer cells. In addition, herein, electroporation was combined with calcium chloride (CaEP) to assess as well the effects of the statin on the efficacy of electrochemotherapy. Cholesterol-rich cell lines MDA-MB231, DU 145, and A375 underwent (1) 48 h preincubation or (2) direct treatment with 50 nM atorvastatin. We studied the impact of the statin on cholesterol and actin fiber organization and analyzed the cells' membrane permeability. The viability of cells subjected to PEF (pulsed electric field) treatments and CaEP with 5 mM CaCl was examined. Finally, to assess the safety of the therapy, we analyzed the N-and E-cadherin localization using confocal laser microscopy. The results of our investigation revealed that depending on the cell line, atorvastatin preincubation decreases the total cholesterol in the steroidogenic cells and induces reorganization of actin nearby the cell membrane. Under low voltage PEFs, actin reorganization is responsible for the increase in the electroporation threshold. However, when subject to high voltage PEF, the lipid composition of the cell membrane becomes the regulatory factor. Namely, preincubation with atorvastatin reduces the cytotoxic effect of low voltage pulses and enhances the cytotoxicity and cellular changes induced by high voltage pulses. The study confirms that the surface tension regulates of membrane permeability under low voltage PEF treatment. Accordingly, to reduce the unfavorable effects of preincubation with atorvastatin, electroporation of steroidogenic cells should be performed at high voltage and combined with a calcium supply.
Topics: Anticholesteremic Agents; Antineoplastic Agents; Apoptosis; Atorvastatin; Calcium; Cell Membrane; Cell Membrane Permeability; Cell Proliferation; Cholesterol; Electrochemotherapy; Electroporation; Humans; Neoplasms; Tumor Cells, Cultured
PubMed: 34681903
DOI: 10.3390/ijms222011245 -
Current Drug Delivery 2022Lung cancer is one of the main causes of mortality globally. This research paper aims a the development of inhaled nanotechnology for lung cancer to deliver an...
OBJECTIVE
Lung cancer is one of the main causes of mortality globally. This research paper aims a the development of inhaled nanotechnology for lung cancer to deliver an atorvastatin calcium compound, for lung cancer, capable of reaching the tumor site directly via inhalation.
METHODS
Atorvastatin calcium micellar nanoparticles (ATO-NPs) encapsulated with Pluronic F-127 and polyvinyl alcohol (PVA) were manufactured utilizing the solvent and anti-solvent precipitation technique. The physicochemical features of the formulation were evaluated in terms of their physicochemical characteristics using Fourier transform infrared spectroscopy, differential scanning calorimetry, and dynamic light scattering. Additionally, the Andersen Cascade impactor was used at 15 L/minutes to assist in the aerosols performances of the formulation. The ATO-NPs formula's cell viability was tested in vitro using the A549 non-small cell lung cancer cell type.
RESULTS
Transmission electron microscopy was utilized to determine the ATO-NPs particle morphology, demonstrating a spherical shape with a smooth surface. The fine particle fraction of the aerosol produced was 62.70 ± 1.18%. This finding suggests that atorvastatin micellar nanoparticles are suitable for medication administration by inhalation with a wide particle size dispersion. Moreover, it was found in vitro that concentrations of up to 21 μg/mL of the atorvastatin nanoparticles were safe and non-toxic in the cell model.
CONCLUSION
This study found that atorvastatin micellar nanoparticles for inhalation could potentially be used for lung cancer treatment.
Topics: Administration, Inhalation; Atorvastatin; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Nanoparticles; Particle Size; Respiratory Aerosols and Droplets
PubMed: 35473526
DOI: 10.2174/1567201819666220426091500 -
Molecular Pharmaceutics Sep 2021Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic...
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [F]Atorvastatin was synthesized via a previously optimized F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats ( = 7 for both groups), and for subsequent biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [F]atorvastatin kinetics in the liver. A strong correlation (R > 0.93) between quantitative (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of for monitoring [F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.
Topics: Animals; Atorvastatin; Female; Fluorine Radioisotopes; Hepatobiliary Elimination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Molecular Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Wistar; Sex Factors; Tissue Distribution
PubMed: 34351158
DOI: 10.1021/acs.molpharmaceut.1c00305 -
Circulation. Genomic and Precision... Jun 2022Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the p.Val174Ala missense variant in and SAMS in simvastatin-treated subjects; however, evidence for genetic predictors of SAMS in atorvastatin- or rosuvastatin-treated subjects is currently lacking.
METHODS
ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; n=18 924) was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of alirocumab (a PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor) in acute coronary syndrome patients receiving high-intensity statin therapy. The goal of this pharmacogenomic analysis was to identify genetic variants associated with atorvastatin- and rosuvastatin-mediated SAMS among ODYSSEY OUTCOMES subjects who consented to participate in the genetic study (n=11 880). We performed multi-ancestry exome-wide and genome-wide association studies and gene burden analysis across 2 phenotypes (clinical SAMS [n=10 617] and creatine kinase levels [n=9630]).
RESULTS
A novel genome-wide significant association for an intronic variant (rs6667912) located within (odds ratio [95% CI], 1.39 [1.24-1.55]; =3.71×10) for patients with clinical SAMS (cases=894, controls=9723) was identified. This variant is located ≈30 kb upstream of , a locus associated with severe SAMS. We replicated 2 loci, at and , previously associated with creatine kinase levels during statin treatment. No association was observed between p.Val174Ala (rs4149056) in and SAMS (odds ratio [95% CI], 1.03 [0.90-1.18]; =0.69).
CONCLUSIONS
This study comprises the largest discovery exome-wide and genome-wide association study for atorvastatin- or rosuvastatin-mediated SAMS to date. These novel genetic findings may provide biological/mechanistic insight into this drug-induced toxicity, and help identify at-risk patients before selection of lipid-lowering therapies.
Topics: Acute Coronary Syndrome; Antigens, CD; Atorvastatin; Cholesterol, LDL; Creatine Kinase; Genome-Wide Association Study; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Membrane Proteins; Muscles; PCSK9 Inhibitors; Pharmacogenomic Testing; Receptors, Immunologic; Rosuvastatin Calcium
PubMed: 35543701
DOI: 10.1161/CIRCGEN.121.003503 -
Andrologia Jul 2022Atorvastatin may be an effective treatment for erectile dysfunction (ED). The purpose of this meta-analysis was to determine whether atorvastatin therapy is effective in... (Meta-Analysis)
Meta-Analysis Review
Atorvastatin may be an effective treatment for erectile dysfunction (ED). The purpose of this meta-analysis was to determine whether atorvastatin therapy is effective in the treatment of ED. All published research on atorvastatin in the treatment of ED patients in EMBASE, PubMed, Web of Science and Cochrane were investigated till 30 October 2021. A meta-analysis of randomized controlled trials (RCTs) was done to investigate the efficacy of atorvastatin and placebo in the treatment of ED. Moreover, we also performed a meta-analysis based on single-arm trials (SATs) to explore the atorvastatin treatment on the efficacy of ED. In a meta-analysis based on RCTs, the weighted mean difference of the change of International Index for Erectile Function-5 (IIEF-5) score in the atorvastatin treatment group with or without treatment was 4.53 (95 per cent confidence interval [CI] of 3.28-5.79) higher than in the control group. In an SAT-based meta-analysis, the ES of the change in IIEF-5 score in the atorvastatin treatment group before and after treatment was 3.22 (95 per cent CI of 1.32-5.12). Atorvastatin is an effective therapeutic drug for patients with ED. However, we expect that more multicentre clinical trials will be conducted to support this assertion.
Topics: Atorvastatin; Erectile Dysfunction; Humans; Male; Penile Erection; Treatment Outcome
PubMed: 35224753
DOI: 10.1111/and.14408 -
International Journal of Clinical... Feb 2022To describe a case of angioedema associated with increasing the dose of HMG-CoA reductase inhibitor (atorvastatin) from 20 to 40 mg daily in a patient previously stable...
PURPOSE
To describe a case of angioedema associated with increasing the dose of HMG-CoA reductase inhibitor (atorvastatin) from 20 to 40 mg daily in a patient previously stable on angiotensin II receptor blocker (losartan) and calcium channel blocker (amlodipine) as antihypertensive agents.
SUMMARY
A 79-year-old woman with no known drug allergies and a history of multiple clinical conditions presented to the emergency department with facial and periorbital swelling, edema of the lower extremities, shortness of breath, and generalized itching and skin rash, that started 2 days after increasing her atorvastatin dose from 20 to 40 mg daily. She was concurrently on losartan 50 mg and amlodipine 5 mg daily for the management of hypertension. Atorvastatin was discontinued, and the symptoms resolved during hospitalization.
CONCLUSION
While atorvastatin use is not commonly associated with angioedema, the prescriber should be mindful of this possible adverse effect, especially when increasing the dose, or when prescribing together with medications known to cause angioedema (e.g., angiotensin II receptor blockers and calcium channel blockers), which may increase the risk of this adverse event.
Topics: Aged; Amlodipine; Angioedema; Antihypertensive Agents; Atorvastatin; Calcium Channel Blockers; Female; Humans; Hypertension; Losartan
PubMed: 34779391
DOI: 10.5414/CP204025 -
Medical Oncology (Northwood, London,... Dec 2022Cancer is one of the most challenging diseases to manage. A sizeable number of researches are done each year to find better diagnostic and therapeutic strategies. At the... (Review)
Review
Cancer is one of the most challenging diseases to manage. A sizeable number of researches are done each year to find better diagnostic and therapeutic strategies. At the present time, a package of chemotherapy, targeted therapy, radiotherapy, and immunotherapy is available to cope with cancer cells. Regarding chemo-radiation therapy, low effectiveness and normal tissue toxicity are like barriers against optimal response. To remedy the situation, some agents have been proposed as adjuvants to improve tumor responses. Statins, the known substances for reducing lipid, have shown a considerable capability for cancer treatment. Among them, atorvastatin as a reductase (HMG-CoA) inhibitor might affect proliferation, migration, and survival of cancer cells. Since finding an appropriate adjutant is of great importance, numerous studies have been conducted to precisely unveil antitumor effects of atorvastatin and its associated pathways. In this review, we aim to comprehensively review the most highlighted studies which focus on the use of atorvastatin in cancer therapy.
Topics: Humans; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunotherapy; Radiation Oncology; Adjuvants, Immunologic; Neoplasms
PubMed: 36459301
DOI: 10.1007/s12032-022-01892-9 -
Clinical Hemorheology and... 2023To investigate if there is a correlation between lipid-lowering treatment with statins and the occurrence, number, and location of cerebral microbleeds (CMBs) among...
OBJECTIVE
To investigate if there is a correlation between lipid-lowering treatment with statins and the occurrence, number, and location of cerebral microbleeds (CMBs) among patients with ischemic cerebrovascular disease (ICVD), and also to compare treatment with atorvastatin and rosuvastatin in terms of the occurrence of CMBs and their differences.
METHODS
In this retrospective study, we included patients who were diagnosed with ICVD and underwent susceptibility weighted imaging (SWI) in a grade A tertiary hospital from October 1, 2014 to October 1, 2022. We collected information on previous statin use, past medical history, clinical test indicators, and imaging data.
RESULTS
We found that out of 522 patients, 310 patients (59.4%) had no CMB and 212 patients (40.6%) had CMBs. There was no statistically significant correlation between prior statin use, the occurrence, and number of CMBs in patients diagnosed with ICVD (P < 0.05). As for the location of CMB, there was a statistically significant correlation between prior statin use and lobar CMBs (P < 0.048). However, there was no statistically significant correlation between the use of atorvastatin and rosuvastatin and the occurrence of CMBs (P > 0.05).
CONCLUSION
There was no independent correlation between previous statin use, and the occurrence, and number of CMBs in patients with ICVD. As for CMBs in different locations, there was a correlation between previous use of statin and lobar CMBs. There was no significant difference between atorvastatin and rosuvastatin in the occurrence of CMBs in patients with ICVD.
Topics: Humans; Cerebral Hemorrhage; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Retrospective Studies; Atorvastatin; Rosuvastatin Calcium; Magnetic Resonance Imaging; Risk Factors
PubMed: 37355888
DOI: 10.3233/CH-231833