Prevalence of cardiovascular drug-related adverse drug reactions consultations in UK primary care: A cross-sectional study.

BACKGROUND: Adverse drug reactions (ADRs) represent a significant barrier to achieve optimal treatment outcomes. Cardiovascular drugs, including antihypertensive drugs, lipid-lowering drugs, and antithrombotic drugs, are among the most prescribed medications in the primary care setting. OBJECTIVES: To estimate the prevalence of cardiovascular drug-related ADRs consultations in United Kingdom (UK) primary care and identify risk factors of these ADRs. METHODS: This was a cross-sectional study of cardiovascular drug users between 2000-2019 using UK IQVIA Medical Research Data. ADRs consultations were identified using database screening method employing standardised designated codes. The overall and annual age-standardised prevalence was estimated using direct standardisation method using 2019 mid-year UK population. Risk factors of ADRs consultations were estimated using logistic regression model stratified by therapeutic areas. RESULTS: The standardised prevalence of consultations related to cardiovascular drugs ADRs was 10.60 (95% CI. 10.46, 10.75) per 1000 patients. Patients aged 70-79 years had the highest occurrence of ADRs consultations. The most frequently drug classes implicated in the ADRs consultations were statins (n = 9,993 events, 27.09%), beta-blockers (n = 8,538 events, 23.15%), ACEIs/ARBs (n = 8,345 events, 22.62%), and aspirin (n = 6,482 events, 17.57%). Risk factors of ADRs consultations were previous history of cardiovascular diseases, e.g., myocardial infarction and stroke; advanced age, comorbidities; diabetes and dyslipidaemia; and polypharmacy. CONCLUSIONS: The burden of cardiovascular drug-related ADRs consultations in primary care was considerable. Statins, beta-blockers, ACEIs/ARBs, and aspirin were the most frequently implicated drug classes. Closer clinical monitoring should be performed for patients affected by the ADRs to mitigate the risk of suboptimal treatment outcomes.

Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation.

KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).

Palliative Pharmacotherapy for Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Cardiovascular disease exacts a heavy toll on health and quality of life and is the leading cause of death among people ≥65 years of age. Although medical, surgical, and device therapies can certainly prolong a life span, disease progression from chronic to advanced to end stage is temporally unpredictable, uncertain, and marked by worsening symptoms that result in recurrent hospitalizations and excessive health care use. Compared with other serious illnesses, medication management that incorporates a palliative approach is underused among individuals with cardiovascular disease. This scientific statement describes palliative pharmacotherapy inclusive of cardiovascular drugs and essential palliative medicines that work synergistically to control symptoms and enhance quality of life. We also summarize and clarify available evidence on the utility of guideline-directed and evidence-based medical therapies in individuals with end-stage heart failure, pulmonary arterial hypertension, coronary heart disease, and other cardiomyopathies while providing clinical considerations for de-escalating or deprescribing. Shared decision-making and goal-oriented care are emphasized and considered quintessential to the iterative process of patient-centered medication management across the spectrum of cardiovascular disease.

When cardiovascular medicines should be discontinued.

An integral component of the practice of medicine is focused on the initiation of medications, based on clinical practice guidelines and underlying trial evidence, which usually test the addition of novel medications intended for life-long use in short-term clinical trials. Much less attention is given to the question of medication discontinuation, especially after a lengthy period of treatment, during which patients age gets older and diseases may either progress or new diseases may emerge. Given the paucity of data, clinical practice guidelines offer little to no guidance on when and how to deprescribe cardiovascular medications. Such decisions are often left to the discretion of clinicians, who, together with their patients, express concern of potential adverse effects of medication discontinuation. Even in the absence of adverse effects, the continuation of medications without any proven effect may cause harm due to drug-drug interactions, the emergence of polypharmacy, and additional preventable spending to already strained health systems. Herein, several cardiovascular medications or medication classes are discussed that in the opinion of this author group should generally be discontinued, either for the prevention of potential harm, for a lack of benefit, or for the availability of better alternatives.

Molecular mechanisms of flavonoids in myocardial ischemia reperfusion injury: Evidence from in-vitro and in-vivo studies.

OBJECTIVES: Flavonoids are polyphenolic compounds found in a wide range of foods, including fruits, vegetables, tea plants, and other natural products. They have been mainly classified as flavanols, flavonols, flavones, isoflavones, flavanones, and flavanonols. In this comprehensive review, we will discuss preclinical pieces of evidence on the potential of flavonoids for the prevention/treatment of myocardial ischemia-reperfusion (IR) injury. KEY FINDINGS: In-vitro and in-vivo studies have shown that flavonoids play an important role in preventing ischemic heart disease (IHD). They possess strong anti-oxidant, anti-inflammatory, anti-bacterial, anti-thrombotic, anti-apoptotic, and anti-carcinogenic activities. In addition, at a molecular level, flavonoids also modulate various pathways like MAPK, NFκB etc. to confer beneficial effects. SUMMARY: The current review of flavonoids in myocardial ischemia-reperfusion injury furnishes updated information that could drive future research. The in-vitro and in-vivo experiments have demonstrated various favourable pharmacological properties of flavonoids. This review provides valuable information to conduct clinical studies, validating the safety aspects of flavonoids in the clinical domain.

Long-Term Drug Therapy Following Carotid Endarterectomy Aimed at Reducing Major Adverse Cardiovascular Events.

BACKGROUND: Timely carotid endarterectomy (CEA) reduces the risk of future stroke. This benefit is maximized with lifelong drug therapy aimed at reducing further major adverse cardiovascular events (MACEs), including stroke. Studies suggest that around half discontinue these drugs within 12 months. To assess if this is the case following CEA, we considered the MACE-reducing drugs prescribed several years later and compared this with the drugs they were prescribed at CEA. METHODS: The electronic primary care records of 347 post-CEA patients a mean of 108 (range 43-185) months after surgery were interrogated. The prescriptions of generic MACE-reducing drugs (antithrombotic, lipid-lowering, antihypertension and diabetes) of the 187 alive were compared with their prescriptions at CEA and with the last prescription of the 160 who had died before the late review. The post-CEA incidence of further MACE in survivors was determined. RESULTS: At late review, fewer of the post-CEA patients alive were taking antiplatelet drugs (143, 76% vs. 170, 91% P < 0.01), but more were fully anticoagulated (37v4 P < 0.01) when compared with prescriptions at CEA. Overall, there was no change in antithrombotic drug prescription rates (167, 89% vs. 172, 92%). Lipid-regulating drugs were well prescribed both at late review and at CEA (173, 93% vs. 169, 90%). The number prescribed antihypertension drugs was significantly higher at late review than at CEA (166, 89% vs. 67, 35% P < 0.01). The number treated for diabetes was similar (64, 34% vs. 42, 23%). There was no difference in the numbers of any of the MACE-reducing drugs prescribed between those who had survived to late review and those who had not. At late review, of those alive, there were 22 (12%) new strokes, and 24 (14%) had developed new or worsening ischemic cardiac symptoms. CONCLUSIONS: We found a higher than expected prescription rate of MACE-reducing drugs many years after CEA. This finding may be due, in part, to the nationalized health service in the United Kingdom.

Long-term patient-reported outcomes among patients undergoing revascularization vs medical therapy for intermittent claudication.

OBJECTIVE: Society for Vascular Surgery guidelines recommend revascularization for patients with intermittent claudication (IC) if it can improve patient function and quality of life. However, it is still unclear if patients with IC achieve a significant functional benefit from surgery compared with medical management alone. This study examines the relationship between IC treatment modality (operative vs nonoperative optimal medical management) and patient-reported outcomes for physical function (PROMIS-PF) and satisfaction in social roles and activities (PROMIS-SA). METHODS: We identified patients with IC who presented for index evaluation in a vascular surgery clinic at an academic medical center between 2016 and 2021. Patients were stratified based on whether they underwent a revascularization procedure during follow-up vs continued nonoperative management with medication and recommended exercise therapy. We used linear mixed-effect models to assess the relationship between treatment modality and PROMIS-PF, PROMIS-SA, and ankle-brachial index (ABI) over time, clustering among repeat patient observations. Models were adjusted for age, sex, diabetes, Charlson Comorbidity Index, Clinical Frailty Score, tobacco use, and index ABI. RESULTS: A total of 225 patients with IC were identified, of which 40% (n = 89) underwent revascularization procedures (42% bypass; 58% peripheral vascular intervention) and 60% (n = 136) continued nonoperative management. Patients were followed up to 6.9 years, with an average follow-up of 5.2 ± 1.6 years. Patients who underwent revascularization were more likely to be clinically frail (P = .03), have a lower index ABI (0.55 ± 0.24 vs 0.72 ± 0.28; P < .001), and lower baseline PROMIS-PF score (36.72 ± 8.2 vs 40.40 ± 6.73; P = .01). There were no differences in patient demographics or medications between treatment groups. Examining patient-reported outcome trends over time; there were no significant differences in PROMIS-PF between groups, trends over time, or group differences over time after adjusting for covariates (P = .07, P = .13, and P =.08, respectively). However, all patients with IC significantly increased their PROMIS-SA over time (adjusted P = .019), with patients managed nonoperatively more likely to have an improvement in PROMIS-SA over time than those who underwent revascularization (adjusted P = .045). CONCLUSIONS: Patient-reported outcomes associated with functional status and satisfaction in activities are similar for patients with IC for up to 7 years, irrespective of whether they undergo treatment with revascularization or continue nonoperative management. These findings support conservative long-term management for patients with IC.

Mast cells: a novel therapeutic avenue for cardiovascular diseases?

Mast cells are tissue-resident immune cells strategically located in different compartments of the normal human heart (the myocardium, pericardium, aortic valve, and close to nerves) as well as in atherosclerotic plaques. Cardiac mast cells produce a broad spectrum of vasoactive and proinflammatory mediators, which have potential roles in inflammation, angiogenesis, lymphangiogenesis, tissue remodelling, and fibrosis. Mast cells release preformed mediators (e.g. histamine, tryptase, and chymase) and de novo synthesized mediators (e.g. cysteinyl leukotriene C4 and prostaglandin D2), as well as cytokines and chemokines, which can activate different resident immune cells (e.g. macrophages) and structural cells (e.g. fibroblasts and endothelial cells) in the human heart and aorta. The transcriptional profiles of various mast cell populations highlight their potential heterogeneity and distinct gene and proteome expression. Mast cell plasticity and heterogeneity enable these cells the potential for performing different, even opposite, functions in response to changing tissue contexts. Human cardiac mast cells display significant differences compared with mast cells isolated from other organs. These characteristics make cardiac mast cells intriguing, given their dichotomous potential roles of inducing or protecting against cardiovascular diseases. Identification of cardiac mast cell subpopulations represents a prerequisite for understanding their potential multifaceted roles in health and disease. Several new drugs specifically targeting human mast cell activation are under development or in clinical trials. Mast cells and/or their subpopulations can potentially represent novel therapeutic targets for cardiovascular disorders.

Sensitive "release-on-demand" fluorescent genosensors for probing DNA damage induced by commonly used cardiovascular drugs: Comparative study.

Cardiovascular drugs (CVDs) are agents working on the heart and the vascular system to treat many cardiovascular disorders. Such disorders represent the leading cause for morbidity and mortality worldwide. The treatment regimen includes different administered drugs on chronic basis. The cumulative drugs in human body coincides with exposure to electromagnetic radiations from different sources leading to drug-radiation interaction that may lead to drug photosensitization. Such photosensitization may lead to mutagenesis, cancer, and cell death due to molecular damage to DNA. This work involves the application of two bioluminescent genosensors; Terbium chloride and EvaGreen are utilized to investigate potential DNA damage caused by frequently used CVDs following UVA irradiation. A variety of CVDs are investigated. Ten drugs; Amiloride, Atorvastatin, Captopril, Enalapril, Felodipine, Hydrochlorothiazide, Indapamide, Losartan, Triamterene and Valsartan are studied. The study's findings showed that such drugs induced DNA damage following UVA irradiation. The induced DNA damage altered the fluorescence of terbium chloride and EvaGreen genosensors, proportionally. The results are confirmed by viscosity measurements reflecting the possible intercalation of CVDs with DNA. Also, the work is applied on calf thymus DNA to mimic the actual biological variability. The demonstrated bioluminescent genosensors provide automatic, simple and low-cost methods for assessing DNA-drug interactions.

MagicTouch PTA Sirolimus-Coated Balloon for Femoropopliteal and Below-the-Knee Disease: 3-Year Outcomes of the XTOSI Trial.

BACKGROUND: Sirolimus-coated balloon (SCB) is a potential treatment option for peripheral arterial disease (PAD). There are currently no long-term clinical data for this novel treatment for PAD. We present the 3-year results of the first-in-human study of MagicTouch PTA SCB for treatment of PAD for both femoropopliteal and below-the-knee arteries. METHODS: The XTOSI pilot study is a prospective, single-arm, open-label, single-center trial evaluating MagicTouch PTA SCB for symptomatic PAD. Assessments through 3 years included freedom from clinically driven target lesion revascularization (CD-TLR), freedom from major amputation, amputation-free survival (AFS), overall survival, and ulcer-free status. RESULTS: At 3 years, the overall freedom from CD-TLR was 84.4%, freedom from major amputation was 86.1%, AFS was 63.3%, overall survival was 63.3%, and ulcer-free status in remaining survivors with intact limbs was 100%. For femoropopliteal lesions, at 3 years, the freedom from CD-TLR was 92.9%, freedom from major amputation was 93.3%, AFS was 70%, and overall survival was 70%. For below-the-knee lesions, at 3 years, the freedom from CD-TLR was 77.8%, freedom from major amputation was 81.0%, AFS was 58.6%, and overall survival was 58.6%. CONCLUSIONS: SCB in the XTOSI pilot study showed promising clinical results sustained to 3 years, and no long-term safety concerns were raised. Randomized trials are currently ongoing to investigate the safety and efficacy of SCB for treatment of PAD.

Effects on physical activity, physical fitness and well-being in a 36-months randomized controlled study, comparing a multimodal hospital-based intervention programme for primary cardiovascular prevention with usual care.

BACKGROUND: Cardiovascular disease is a major cause of mortality and morbidity worldwide, and primary prevention efforts are poorly developed in people at high cardiovascular risk. On this background, we performed the Hjerteløftet Study and demonstrated that participation over 36 months in a multimodal primary prevention programme, significantly reduced validated cardiovascular risk scores. In the current substudy we aimed to further explore several elements and effects following the intervention programme. METHODS: A random sample from the original Hjerteløftet Study was included for further examinations (n = 255, 40% women), and these patients were already randomized to an intervention group (IG) (n = 127), or a control group (CG) (n = 128). We compared changes from baseline to 36-months follow-up in physical activity, cardiorespiratory fitness, psychological well-being (WHO-5), cardiovascular medication use, smoking habits, and cardiometabolic risk factors (blood pressure, lipids, blood glucose, HbA1c, Apolipoprotein A-I, Apolipoprotein B and high-sensitive C-reactive protein). RESULTS: Self-reported physical activity increased significantly with absolute difference in mean delta Physical Activity Index score in the IG compared to the CG: 0.90, 95% CI: 0.10 to 1.70, p = 0.028 (ANCOVA). There were no corresponding differences in cardiorespiratory fitness. The participation resulted in psychological well-being improvement in both groups with a larger increase in the IG compared to the CG. The mean difference in delta WHO-5 score was 5.06, 95% CI: 0.68 to 9.45, p = 0.024, and 3.28, 95% CI: -0.69 to 5.25, p = 0.104 when controlled for baseline values (ANCOVA). The use of antihypertensive medication increased significantly more in the CG (p = 0.044). Only minor, nonsignificant changes were observed for traditional risk factors and cardiometabolic variables. CONCLUSIONS: Participation in the Hjerteløftet Study intervention programme resulted in an improved physical activity level, but without changing cardiorespiratory fitness. Participation in the programme also tended to improve psychological well-being, possibly related to increased physical activity, less smoking and less use of cardiovascular medication. Concerning the metabolic status, no major differences were observed, but minor changes may have been concealed by a larger increase in cardiovascular medication use in the control group. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01741428), 04/12/2012.

Nuevos tratamientos farmacológicos para la miocardiopatía hipertrófica: foco en inhibidores de miosina / Hypertrophic Cardiomiopathy: new pharmacologic therapies focused on myosin inhibitors

La miocardiopatía hipertrófica (MCH), definida clínicamente como una hipertrofia ventricular izquierda no explicada por sobrecarga hemodinámica ni por infiltración, es la enfermedad miocárdica hereditaria más común. El tratamiento actual se basa en terapias de reducción septal en casos de Miocardiopatía hipertrófica obstructiva (MCHo), prevención de muerte súbita cardíaca mediante desfibrilador automático implantable y en el uso de fármacos para disminuir la obstrucción dinámica del tracto de salida del ventrículo izquierdo. Recientemente se han desarrollado diversos agentes que actúan sobre los mecanismos que, a nivel celular, llevan a la aparición de hipertrofia ventricular. Este artículo se centra en formas de tratamiento farmacológico desarrolladas en los últimos años, en especial con inhibidores de miosina. Se detallan los mecanismos de acción como también los resultados de diversos estudios clínicos de evaluaciones recientes.

Current clinical management of Hypertrophic Cardiomyopathy is mainly based on modifying physiologic mechanisms to decrease left ventricular outflow tract obstruction. Also important are agents that prevent and treat ventricular arrythmias. This review article is focused on the cellular mechanisms that underlie the development of ventricular hypertrophy and the effect of new myosin inhibitors such as mavcamten and aficamten. Promising results of recent clinical trials evaluating the effect of these agents are analyzed. The potential benefits of genetic therapy are also discussed.

Evidence for clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications among adults with peripheral artery disease: protocol for a systematic review and meta-analysis.

INTRODUCTION: International guidelines recommend that adults with peripheral artery disease (PAD) be prescribed antiplatelet, statin and antihypertensive medications. However, it is unclear how often people with PAD are underprescribed these drugs, which characteristics predict clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications, and whether underprescription and non-adherence are associated with adverse health and health system outcomes. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE and Evidence-Based Medicine Reviews from 2006 onwards. Two investigators will independently review abstracts and full-text studies. We will include studies that enrolled adults and reported the incidence and/or prevalence of clinician underprescription of or patient non-adherence to guideline-recommended cardiovascular medications among people with PAD; adjusted risk factors for underprescription of/non-adherence to these medications; and adjusted associations between underprescription/non-adherence to these medications and outcomes. Outcomes will include mortality, major adverse cardiac and limb events (including revascularisation procedures and amputations), other reported morbidities, healthcare resource use and costs. Two investigators will independently extract data and evaluate study risk of bias. We will calculate summary estimates of the incidence and prevalence of clinician underprescription/patient non-adherence across studies. We will also conduct subgroup meta-analyses and meta-regression to determine if estimates vary by country, characteristics of the patients and treating clinicians, population-based versus non-population-based design, and study risks of bias. Finally, we will calculate pooled adjusted risk factors for underprescription/non-adherence and adjusted associations between underprescription/non-adherence and outcomes. We will use Grading of Recommendations, Assessment, Development and Evaluation to determine estimate certainty. ETHICS AND DISSEMINATION: Ethics approval is not required as we are studying published data. This systematic review will synthesise existing evidence regarding clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications in adults with PAD. Results will be used to identify evidence-care gaps and inform where interventions may be required to improve clinician prescribing and patient adherence to prescribed medications. PROSPERO REGISTRATION NUMBER: CRD42022362801.

Outcomes of Excimer Laser Ablation Combined with Drug-coated Balloon in Atherosclerotic Lesions of the Popliteal Artery.

BACKGROUND: The treatment of atherosclerotic lesions in the popliteal artery is challenging. This study aims to investigate the efficacy and safety of excimer laser ablation (ELA) combined with drug-coated balloon (DCB) for these lesions. METHODS: From June 2019 to December 2021, data of patients who underwent ELA combined with DCB in the popliteal artery were retrospectively reviewed. Demographics, lesion characteristics, periprocedural complications, and follow-up information were analyzed. The primary endpoint was primary patency. Secondary endpoints included major amputation-free survival rate, technical success, bailout stenting, clinically-driven target lesion reintervention, improvement of ankle-brachial index (ABI), and Rutherford class. RESULTS: A total of 61 patients were enrolled. The mean age was 73.4 ± 11.7 years. 20 (32.8%) patients had stenotic lesions, while 41 (67.2%) patients had chronic total occlusions. The mean length of these lesions was 7.3 ± 2.8 cm. Procedure technical success rate was 95.1%. Bailout stent was performed in 3 (4.9%) patients. Intraprocedural distal embolization occurred in 3 (4.9%) patients, while flow limiting dissections occurred in 3 (4.9%) patients. The mean ABI was significantly improved from 0.45 ± 0.13 at baseline to 0.90 ± 0.12 after ELA, 0.88 ± 0.11 at 6 months and 0.85 ± 0.12 at 12 months during the follow-up period. The median follow-up time was 28.2 ± 6.1 months. Reintervention was performed in 5 (8.2%) patients. The 2-year primary patency was 83.5%. CONCLUSIONS: ELA combined with DCB is a safe and effective strategy in the treatment of popliteal artery atherosclerotic lesions with low rates of bail-out stenting and high primary patency.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2023.

Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2 and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and treatment of CVDs.

The Use and Impact of Cilostazol on Patients Undergoing Endovascular Peripheral Interventions.

BACKGROUND: Cilostazol is used for the treatment of intermittent claudication. The impact of cilostazol on the outcomes of peripheral vascular interventions (PVIs) remains controversial. This study assesses the use and impact of cilostazol on patients undergoing PVI for peripheral arterial disease (PAD). METHODS: The Vascular Quality Initiative (VQI) database files for PVI were reviewed. Patients with PAD who underwent PVI for chronic limb threatening-ischemia or claudication were included and divided based on the use of cilostazol preoperatively. After propensity matching for patient demographics and comorbidities, the short-term and long-term outcomes of the 2 groups (preoperative cilostazol use versus no preoperative cilostazol use) were compared. The Kaplan-Meier method was used to determine outcomes. RESULTS: A total of 245,309 patients underwent PVI procedures and 6.6% (N = 16,366) were on cilostazol prior to intervention. Patients that received cilostazol were more likely to be male (62% vs 60%; P < 0.001), White (77% vs. 75%; P < 0.001), and smokers (83% vs. 77%; P < 0.001). They were less likely to have diabetes mellitus (50% vs. 56%; P < 0.001) and congestive heart failure (14% vs. 23%; P < 0.001). Patient on cilostazol were more likely to be treated for claudication (63% vs. 40%, P < 0.001), undergo prior lower extremity revascularization (55% vs. 51%, P < 0.001) and less likely to have undergone prior minor and major amputation (10% vs. 19%; P < 0.001) compared with patients who did not receive cilostazol. After 3:1 propensity matching, there were 50,265 patients included in the analysis with no differences in baseline characteristics. Patients on cilostazol were less likely to develop renal complications and more likely to be discharged home. Patients on cilostazol had significantly lower rates of long-term mortality (11.5% vs. 13.4%, P < 0.001 and major amputation (4.0% vs. 4.7%, P = 0.022). However, there were no significant differences in rates of reintervention, major adverse limb events, or patency after PVI. Amputation-free survival rates were significantly higher for patients on cilostazol, after 4 years of follow up (89% vs. 87%, P = 0.03). CONCLUSIONS: Cilostazol is underutilized in the VQI database and seems to be associated with improved amputation-free survival. Cilostazol therapy should be considered in all patients with PAD who can tolerate it prior to PVI.

Nitroprusside and metal nitroprusside nano analogues for cancer therapy.

Sodium nitroprusside (SNP), U.S approved drug has been used in clinical emergency as a hypertensive drug for more than a decade. It is well established for its various biomedical applications such as angiogenesis, wound healing, neurological disorders including anti-microbial applications etc. Apart from that, SNP have been considered as excellent biomedical materials for its use as anti-cancer agent because of its behavior as NO-donor. Recent reports suggest that incorporation of metals in SNP/encapsulation of SNP in metal nanoparticles (metal nitroprusside analogues) shows better therapeutic anti-cancer activity. Although there are numerous reports available regarding the biological applications of SNP and metal-based SNP analogue nanoparticles, unfortunately there is not a single comprehensive review which highlights the anti-cancer activity of SNP and its derivative metal analogues in detail along with the future perspective. To this end, the present review article focuses the recent development of anti-cancer activity of SNP and metal-based SNP analogues, their plausible mechanism of action, current status. Furthermore, the future perspectives and challenges of these biomedical materials are also discussed. Overall, this review article represents a new perspective in the area of cancer nanomedicine that will attract a wider spectrum of scientific community.

The Impact of Polypill on Adherence and Cardiovascular Outcomes: A Comprehensive Systematic Review with Meta-Analysis.

BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide. Polypills, containing various combinations of medications for primary and secondary CVD prevention, have been developed to enhance medication adherence and reduce the healthcare burden of CVD. However, their effectiveness compared to usual care remains uncertain. OBJECTIVE: This meta-analysis aimed to evaluate the effects of polypills on cardiovascular risk factors, major adverse cardiovascular events (MACE), and medication adherence. METHODS: We conducted a comprehensive search for large-scale randomized controlled trials and observational studies comparing the effects of polypills versus usual care on CVD risk factors and events. Outcomes included changes in systolic and diastolic blood pressure (SBP, DBP), lipid profiles, occurrence of MACE, and medication adherence. RESULTS: The use of polypills led to a statistically significant yet clinically modest reduction in SBP (mean difference -1.47 mmHg, 95% CI: -2.50 to -0.44, p<0.01) and DBP (mean difference- 1.10 mmHg, 95% CI: -1.68 to -0.51, p< 0.01) compared to usual care. Polypills also showed a significant reduction in the risk of MACE (RR: 0.86, 95% CI: 0.77 -0.95, p<0.01). There was a non-significant reduction in LDL and HDL levels. Adherence to medication improved by up to 17% in polypill users compared to those on usual care (p < 0.01). A multivariable metaregression analysis suggested that adherence may be the underlying factor responsible for the observed effect of the polypills on blood pressure. CONCLUSION: Polypills were found to significantly reduce SBP, DBP and MACE. An improvement in medication adherence was also observed among polypill users, which might be responsible for the significant reduction in SBP observed users. Future research might benefit from exploring a more personalized approach to the composition of polypills, which could reveal a more clinically significant impact of increased adherence on CVD outcomes.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).