ABSTRACT
Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry.Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013-2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described.Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7-5.5) in the eribulin group and 3.2 months (95% CI: 2.0-4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49-1.38). Median OS was 5.9 months (95% CI: 4.6-11.0) and 5.2 months (95% CI: 4.6-9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38-1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin.Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.
Subject(s)
Breast Neoplasms/drug therapy , Furans/therapeutic use , Ketones/therapeutic use , Adult , Aged , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Multivariate Analysis , Netherlands/epidemiology , Registries , Survival Rate , Treatment OutcomeABSTRACT
PURPOSE: The INTENS study was designed to determine whether delivering neoadjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600-T 100 mg/m2) or six cycles of TAC as triplet chemotherapy (75/50/500 mg/m2) every 3 weeks. The primary outcome was the pathologic complete response (pCR), with disease-free and overall survival as secondary endpoints. RESULTS: In total, 201 patients were included. The pCR rates were 28% for patients treated with AC-T and 19% for patients treated with TAC, with an odds ratio of 1.60 (95% CI 0.90-3.21). With a median follow-up of 6 years (range 0.04-8.41 years), the five-year disease-free survival was 81% for patients treated with sequentially AC-T and 71% for patients treated with concurrent triplet TAC chemotherapy with a stratified hazard ratio (HR) of 0.50 (95% CI 0.29-0.86). Five-year overall survival was 84% versus 76%, respectively, with a stratified HR of 0.55 (95% CI 0.29-1.03). CONCLUSIONS: No differences were observed between the two treatment arms with respect to pCR rate, but the sequentially delivered chemotherapy outperformed the triplet combination chemotherapy in terms of survival, despite a lower cumulative dose per agent. GOV nr NCT00314977.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. METHODS: A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. RESULTS: In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of 56,213 and 52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of 155,261 per QALY gained. In the trial scenario, the ICER amounted to 278,711 per QALY gained. CONCLUSION: According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/economics , Bevacizumab/administration & dosage , Bevacizumab/economics , Breast Neoplasms/economics , Bridged-Ring Compounds/economics , Cost-Benefit Analysis , Disease Progression , Docetaxel , Female , Health Resources/economics , Health Resources/statistics & numerical data , Humans , Kaplan-Meier Estimate , Netherlands , Paclitaxel/administration & dosage , Paclitaxel/economics , Quality-Adjusted Life Years , Receptor, ErbB-2/metabolism , Taxoids/administration & dosage , Taxoids/economicsABSTRACT
BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Palliative Care/methods , Aged , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Metastasis/pathology , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Treatment OutcomeABSTRACT
BACKGROUND: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients. METHODS: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy. RESULTS: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy. CONCLUSION: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.
Subject(s)
Breast Neoplasms/mortality , Neoplasm Recurrence, Local/mortality , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Prognosis , Survival RateABSTRACT
BACKGROUND: Prostate cancer truly is an age-associated disease. Due to the increased life expectancy and more sensitive diagnostic techniques in the Western world, prostate cancer is diagnosed more frequently and with rapidly increasing incidence and prevalence rates. However, age above 65 or 70 years has been an exclusion criterion in clinical trials for decades and the knowledge about chemotherapy tolerance in elderly is limited. METHODS: We performed a retrospective analysis of data acquired from the recently published Netherlands Prostate Study (NePro) to evaluate the influence of advanced age on docetaxel therapy in elderly men (>70 years) with castration resistant prostate cancer (CRPC) and bone metastases. Statistical analyses were performed stratified for age into four categories: <70 (n=315), 70-74 (n=150), 75-79 (n=85), and ≥80 years old (n=18). RESULTS: We analysed 568 patients (median age 68.1 years, range 46-89 years, 44.5% aged ≥70 years). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, time to progression (TTP), overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity and were five times less likely to complete the first three treatment cycles at the intended dose (Odds ratio (OR) 5.34, p=0.0052) and showed decreased overall survival (15.3 months versus 24.5 months in <80 years group, p=0.020). CONCLUSION: In CRPC patients up to the age of 80 years, docetaxel chemotherapy is well tolerated, with toxicity levels and TTP comparable to those of younger patients. For chemotherapeutic treatment of patients above the age of 80 years an individual assessment should be made.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Taxoids/therapeutic use , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Docetaxel , Etidronic Acid/administration & dosage , Etidronic Acid/adverse effects , Etidronic Acid/analogs & derivatives , Humans , Male , Middle Aged , Multicenter Studies as Topic , Netherlands , Prednisone/administration & dosage , Prednisone/adverse effects , Randomized Controlled Trials as Topic , Retrospective Studies , Risedronic Acid , Survival Analysis , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
BACKGROUND: This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. PATIENTS AND METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100 mg/m(2)) or six cycles of TAC (75/50/500 mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast. RESULTS: In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%). CONCLUSIONS: With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Docetaxel , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Humans , Middle Aged , Neoadjuvant Therapy , Survival Rate , Taxoids/administration & dosage , Taxoids/adverse effects , Young AdultABSTRACT
A 1-year complete remission could be achieved with high-dose systemic chemotherapy in a 33-year-old patient with relapsed germ cell tumor presenting with leptomeningeal carcinomatosis (LC). Although LC in general has a very poor prognosis for patients with chemosensitive malignancies, systemic chemotherapy should be considered.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Meningeal Neoplasms/drug therapy , Neoplasms, Germ Cell and Embryonal/drug therapy , Salvage Therapy , Testicular Neoplasms/drug therapy , Adult , Carcinoma/complications , Humans , Male , Meningeal Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Neoplasms, Germ Cell and Embryonal/etiology , Remission InductionABSTRACT
BACKGROUND: Smoking cessation rapidly reduces cardiovascular risk. The pathophysiological mechanisms involved are still being debated. We measured structural and functional arterial wall properties of the femoral and carotid arteries after smoking cessation to investigate their possible role in cardiovascular risk reduction. METHODS: Out of 127 smokers, 33 proved to stop smoking for two years. They were compared with 50 nonsmokers and 55 persistent smokers in a prospective study. Cross-sectional compliance and distensibility coefficients as well as intima-media thickness of both carotid arteries and of the right common femoral artery were measured ultrasonographically at baseline and 3, 6, 12 and 24 months after smoking cessation. The nonsmoking and persistent smokers group were measured twice at an interval of 24 months. RESULTS: Persistent smoking and two years of smoking cessation did not affect cross-sectional compliance and distensibility coefficients. Although at baseline intimal-medial layers were thicker in smokers, the change over time in intima-media thickness did not differ significantly between all three groups. CONCLUSION: Two years of smoking cessation was not accompanied by a slower progression or a regression in intima-media thickness nor by an improved cross-sectional compliance or distensiblity coefficient. Nevertheless, smoking cessation should be recommended as it reduces cardiovascular risk rapidly after smoking cessation.
Subject(s)
Carotid Arteries/pathology , Femoral Artery/pathology , Smoking Cessation , Smoking/physiopathology , Tunica Intima/pathology , Tunica Media/pathology , Adult , Carotid Arteries/diagnostic imaging , Cross-Sectional Studies , Disease Progression , Female , Femoral Artery/diagnostic imaging , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Risk Reduction Behavior , Smoking/adverse effects , Smoking Prevention , Surveys and Questionnaires , Tunica Intima/diagnostic imaging , Tunica Media/diagnostic imaging , UltrasonographyABSTRACT
BACKGROUND: Toll-like receptor-4 (TLR4) is a major receptor for inflammatory stimuli potentially involved in the pathogenesis of atherosclerosis, such as lipopolysaccharide (LPS) and heat-shock proteins. The Asp299Gly polymorphism of the TLR4 gene has been associated with a reduced intima-media thickness (IMT) of the common carotid artery in healthy individuals. We have investigated whether the presence of the Asp299Gly polymorphism in patients with familial hypercholesterolaemia (FH) has a similar protective effect, and whether it influences the effects of HMG-CoA reductase treatment. MATERIALS AND METHODS: A cohort of 293 FH patients and 200 healthy volunteers were genotyped for the presence of the Asp299Gly allele using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Intima-media thickness measurements, inflammatory parameters and the effect of HMG-CoA reductase inhibitors were compared between the patients with and without Asp299Gly allele. RESULTS: The Asp299Gly allele was present in 10.6% of the FH patients and 11.0% of the healthy individuals. Whereas the FH patients carrying the Asp299Gly allele displayed a reduced absolute IMT value compared with the FH patients carrying the wild-type allelle, the difference did not reach statistical significance. In addition, the effect of treatment with HMG-CoA reductase inhibitors was not influenced by the presence of Asp299Gly allele. CONCLUSION: The presence of the Asp299Gly allele of the TLR4 gene does not seem to exert a major influence on the progression of atherosclerosis in patients with FH.
Subject(s)
Carotid Artery Diseases/genetics , Hyperlipoproteinemia Type II/genetics , Membrane Glycoproteins/genetics , Polymorphism, Genetic , Receptors, Cell Surface/genetics , Adult , Aged , Carotid Artery Diseases/etiology , Cohort Studies , Disease Progression , Female , Genetic Predisposition to Disease , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/drug therapy , Inflammation Mediators/blood , Male , Middle Aged , Toll-Like Receptor 4 , Toll-Like ReceptorsABSTRACT
BACKGROUND: Raised plasma lipoprotein(a) (Lp(a)) is associated with increased risk of cardiovascular disease. It is unknown whether increased Lp(a) is an additional risk factor for coronary artery disease in familial hypercholesterolaemia (FH) or whether statin treatment can reduce Lp(a) concentrations in the long term. OBJECTIVE: To investigate Lp(a) concentrations in relation to statin treatment and the progression of atherosclerosis in a large cohort of FH patients. DESIGN: A two year, randomised, double blind trial (the ASAP trial). PATIENTS: 325 heterozygous FH patients. INTERVENTION: Treatment with 80 mg atorvastatin or 40 mg simvastatin. MAIN OUTCOME MEASURE: Change in Lp(a) concentrations and intima-media thickness of carotid artery segments at one year and two years. RESULTS: At baseline, median Lp(a) concentrations were 327 mg/l and 531 mg/l in the atorvastatin and simvastatin arms, respectively (p = 0.03). In the atorvastatin arm, Lp(a) concentrations decreased to 243 mg/l after one year (p < 0.001) and to 263 mg/l after two years (p < 0.001). In the simvastatin arm, Lp(a) concentrations decreased to 437 mg/l after one year (p < 0.001) and to 417 mg/l after two years (p < 0.001). The difference in Lp(a) reduction between the two treatment arms was significant after one year (p = 0.004), but not after two years (p = 0.086). Lp(a) concentrations at baseline were not related to cardiovascular events at baseline. There was no correlation between baseline Lp(a) concentrations and low density lipoprotein cholesterol concentrations or intima-media thickness at baseline. Change in Lp(a) concentrations was not correlated with change in intima-media thickness after one or two years. CONCLUSIONS: Long term statin treatment significantly lowers Lp(a) in FH patients. However, this reduction was unrelated to changes in intima-media thickness and casts doubt on the importance of Lp(a) in the progression of atherosclerotic disease in these patients.
Subject(s)
Arteriosclerosis/prevention & control , Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Lipoprotein(a)/blood , Pyrroles/therapeutic use , Simvastatin/therapeutic use , Atorvastatin , Carotid Arteries , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Double-Blind Method , Female , Humans , Hyperlipoproteinemia Type II/blood , Male , Middle AgedSubject(s)
Dyspnea/etiology , Pulmonary Artery/diagnostic imaging , Pulmonary Embolism/diagnostic imaging , Tomography, X-Ray Computed , Adult , Aerospace Medicine , Aged , Angiography , Diagnosis, Differential , Female , Humans , Lung/diagnostic imaging , Male , Netherlands , Practice Guidelines as Topic , Pulmonary Embolism/complications , Pulmonary Embolism/etiology , Tomography, X-Ray Computed/adverse effects , Tomography, X-Ray Computed/economics , Tomography, X-Ray Computed/methodsABSTRACT
Familial hypercholesterolemia is a hereditary metabolic disorder characterised by high low-density lipoprotein cholesterol levels and an extreme risk of premature cardiovascular disease. In patients with heterozygous familial hypercholesterolemia a substantial variation is seen in both the severity of the hypercholesterolemia and onset of atherosclerotic disease symptoms. We discuss the contribution of additional atherogenic risk factors of metabolic, environmental and genetic origin. Subclinical disease measurements, such as the intima media thickness (IMT), assessed by ultrasonography, may contribute to a better risk prediction of future cardiovascular disease in these patients.
Subject(s)
Cardiovascular Diseases/etiology , Glycoproteins , Hyperlipoproteinemia Type II , Apolipoproteins B/genetics , Carrier Proteins/genetics , Cholesterol Ester Transfer Proteins , Genetic Carrier Screening , Genetic Predisposition to Disease/genetics , Genotype , Humans , Hyperhomocysteinemia/complications , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/genetics , Hyperlipoproteinemia Type II/metabolism , Inflammation , Lipoprotein Lipase/genetics , Lipoprotein(a)/genetics , Mutation/genetics , Phenotype , Predictive Value of Tests , Receptors, LDL/genetics , Risk FactorsABSTRACT
BACKGROUND: High LDL-cholesterol is a risk factor for atherosclerosis. We aimed to determine whether aggressive cholesterol lowering with statins was more effective than conventional statin treatment in this disease. We investigated the effect of high-dose atorvastatin on carotid atherosclerosis progression. METHOD: We did a randomised, double-blind clinical trial in 325 patients with familial hypercholesterolaemia. Patients were given either atorvastatin 80 mg (n=160) or simvastatin 40 mg (n=165) daily, on an intent-to-treat basis. The primary endpoint was the change of carotid intima media thickness (IMT), as measured by quantitative B-mode ultrasound, over 2 years. FINDINGS: The overall baseline IMT, combining the measurements of the common and internal carotid artery and the carotid bifurcation on both sides, was 0.93 mm (SD 0.22) and 0.92 mm (0.21) in the atorvastatin and simvastatin groups, respectively. After treatment with atorvastatin for 2 years, IMT decreased (-0.031 mm [95% CI -0.007 to -0.055]; p=0.0017), whereas in the simvastatin group it increased (0.036 [0.014-0.058]; p=0.0005). The change in thickness differed significantly between the two groups (p=0.0001). Atorvastatin showed greater reductions in cholesterol concentrations than did simvastatin. HDL-cholesterol concentrations increased in both groups. Both drugs were equally well tolerated. INTERPRETATION: Our results show that aggressive LDL-cholesterol reduction by atorvastatin was accompanied by regression of carotid intima media thickness in patients with familial hypercholesterolaemia, whereas conventional LDL lowering was not.
Subject(s)
Anticholesteremic Agents/therapeutic use , Heptanoic Acids/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Pyrroles/therapeutic use , Simvastatin/therapeutic use , Adult , Aged , Atorvastatin , Carotid Arteries/drug effects , Carotid Arteries/pathology , Double-Blind Method , Female , Humans , Middle Aged , Tunica Intima/drug effects , Tunica Intima/pathologyABSTRACT
We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu-1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate.
Subject(s)
Arteriosclerosis/genetics , Glutathione Transferase/genetics , Smoking/adverse effects , Arteriosclerosis/diagnostic imaging , Arteriosclerosis/pathology , Carotid Artery, Common/diagnostic imaging , Carotid Artery, Common/pathology , Disease Progression , Genotype , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Risk Factors , Smoking/genetics , Tunica Intima/pathology , Tunica Media/pathology , UltrasonographyABSTRACT
We studied the associations between the common carotid-intima-media thickness (IMT), as a marker of atherosclerosis, and smoking characteristics and antioxidant vitamins among 158 male life-long cardiovascular disease (CVD)-free smokers. An "increased" carotid IMT was defined as the upper 25%. The prevalence of increased IMT was 2.5 times (odds ratio (OR) = 2.5; 95% CI: 1.1, 5.6) higher among smokers inhaling smoke deeply into the lungs than among moderate and non-inhalers. This association decreased when adjusted for other CVD risk factors. Smokers with an increased carotid IMT did not differ significantly in mean antioxidant vitamin intake and status with the remaining group. However, classical CVD risk factors contributed importantly to increased carotid IMT. In our study, depth of inhalation was the only smoking characteristic associated with carotid IMT although attenuated after adjustment for traditional risk factors for CVD. Furthermore, in these life-long smokers not using any vitamin supplements, no associations were found for antioxidant vitamins.
Subject(s)
Antioxidants/therapeutic use , Carotid Arteries/pathology , Carotid Artery Diseases/epidemiology , Smoking/pathology , Tunica Intima/pathology , Tunica Media/pathology , Aged , Carotid Artery Diseases/pathology , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Risk FactorsABSTRACT
BACKGROUND: Early in the process of atherosclerosis, changes in vessel wall stiffness and thickness may occur. The present study evaluates the effect of cholesterol reduction on artery wall stiffness and intima media thickness in patients with familial hypercholesterolaemia (FH). MATERIALS AND METHODS: Forty-five patients with familial hypercholesterolaemia (mean age 46+/-10 years) with untreated LDL cholesterol concentration > 9 mmol L(-1), were studied before and after one year of cholesterol lowering therapy with statins (simvastatin, atorvastatin 40-80 mg day(-1). The distensibility (DC in 10-3 kPa(-1) and compliance (CC in mm2. kPa(-1) of the common carotid artery (CCA) (right and left side) and common femoral artery (CFA) (right side) were determined by a wall track system (Pie Medical). The intima media thickness (IMT) (both right and left) of the CCA, bulb (BUL), internal carotid artery (ICA) and CFA were measured in mm by high-resolution ultrasound (Biosound). RESULTS: The mean concentration of total cholesterol (TC), LDL-cholesterol (LDL-C) and triglycerides (TG) were reduced significantly by 43%, 51% and 25%, respectively, whereas HDL-cholesterol (HDL-C) increased by 13% (P<0.001). In the CFA, the DC and CC increased significantly (DC from 7.9+/-3.0 to 9.1+/-3.7 in 10(-3) kPa(-1); CC 0.5+/-0.2-0.6+/-0.3 in mm2. kPa(-1), whereas the DC and CC did not change in the CCA. In contrast, the IMT of the CCA decreased significantly in both men and women whereas an IMT decrease was also seen in the BUL and ICA in premenopausal women. A LDL-cholesterol reduction of 44.8% and 45.4% was necessary to induce significant decreases in IMT and increases in DC and CC. CONCLUSIONS: One year of cholesterol lowering therapy in FH decreases the wall stiffness in the CFA and the arterial wall thickness in the CCA.
Subject(s)
Anticholesteremic Agents/administration & dosage , Arteriosclerosis/drug therapy , Arteriosclerosis/pathology , Hypercholesterolemia/drug therapy , Hypercholesterolemia/pathology , Simvastatin/administration & dosage , Adult , Arteriosclerosis/genetics , Atorvastatin , Blood Pressure/drug effects , Carotid Arteries/pathology , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Elasticity , Family Health , Female , Femoral Artery/pathology , Heptanoic Acids/pharmacology , Humans , Hypercholesterolemia/genetics , Male , Middle Aged , Pyrroles/pharmacology , Triglycerides/blood , Tunica Intima/pathologyABSTRACT
BACKGROUND AND PURPOSE: Although it is known that smoking is associated with an increase in arterial wall thickness, most studies have been performed in heterogeneous groups of older age, already suffering from atherosclerotic diseases or having additional cardiovascular risk factors. The purpose of this study is to assess the effect on arterial wall thickness of the carotid and femoral artery in cigarette smokers. METHODS: In a cross-sectional study, intima-media thickness of the common and internal carotid artery, carotid bulb and common femoral artery was determined with the use of a B-mode ultrasound device, in 184 (44.3+/-9.0 years) cigarette smokers for whom smoking is the single cardiovascular risk factor. Comparisons were made with 56 non-smokers, matching in age and gender. RESULTS: The posterior walls of both carotid bulbs (right: P=0.0005; left: P=0.02) and of the internal carotid arteries (right: P=0.004; left: P=0.003) as well as the posterior wall of the right common carotid artery (P=0.02) and of the right common femoral artery (P<0.0001) were thicker in smokers. CONCLUSIONS: Cigarette smoking as the single cardiovascular risk factor causes wall thickening of the carotid and femoral arteries, which indicates that early atherosclerosis is already present in smokers entering middle age.
Subject(s)
Arteriosclerosis/pathology , Carotid Artery, Common/pathology , Carotid Artery, Internal/pathology , Femoral Artery/pathology , Smoking/adverse effects , Tunica Intima/pathology , Adult , Aged , Arteriosclerosis/diagnostic imaging , Arteriosclerosis/etiology , Carotid Artery, Common/diagnostic imaging , Carotid Artery, Internal/diagnostic imaging , Cross-Sectional Studies , Female , Femoral Artery/diagnostic imaging , Humans , Male , Middle Aged , Prognosis , Risk Factors , Surveys and Questionnaires , Tunica Intima/diagnostic imaging , UltrasonographyABSTRACT
BACKGROUND: Cranial irradiation for children with brain tumors frequently leads to neuroendocrine deficiencies. In this controlled study, the authors investigated risk factors for cardiovascular disease (CVD) for long term survivors of childhood brain cancer. They also tested whether the presence of these risk factors was related to endocrine status. METHODS: In 26 survivors of childhood brain cancer (mean age, 25.8 years; mean posttreatment interval, 16 years) and 29 healthy controls (mean age, 27.7 years), the blood pressure, smoking habits, body mass index (BMI), and waist/hip (W/H) ratio were determined. Lipids and lipoproteins were measured and endocrine function was assessed. Carotid intima-media thickness (IMT) measurements were performed by high resolution ultrasonography. RESULTS: In the survivors of childhood brain cancer, systolic blood pressure and W/H ratio were elevated compared with controls. The cholesterol/high density lipoprotein ratio (4.7 +/- 1.7 vs. 3.4 +/- 0.8 mmol/L, P = 0.0005), low density lipoprotein cholesterol level (3.3 +/- 0.9 vs. 2.8 +/- 0.6 mmol/L, P = 0.027), and apolipoprotein B level (P = 0.001) were higher in survivors of childhood brain cancer, whereas HDL cholesterol was lower (P = 0.005). The IMT was increased in the survivor group, but only in the carotid bulb (0.63 mm +/- 1.6 vs. 0.53 mm +/- 1.1, P = 0.02), not in the internal or common carotid artery. In the absolute growth hormone deficient (GHD) population (n = 9), LDL cholesterol and apolipoprotein B levels were elevated and the W/H ratio was particularly increased compared with the other survivors of childhood brain cancer. CONCLUSIONS: For long term survivors of brain cancer, the risk for CVD is strongly increased due to dyslipidemia, central obesity, and elevated systolic blood pressure, particularly for those with GHD. The first effects of this increased risk for CVD were observed in the carotic bulb, as assessed by IMT measurements. Efforts should be directed at CVD prevention by risk factor control.
Subject(s)
Brain Neoplasms/radiotherapy , Cardiovascular Diseases/etiology , Cranial Irradiation/adverse effects , Survivors , Adolescent , Adult , Apolipoproteins B/blood , Blood Pressure , Body Constitution , Body Mass Index , Carotid Arteries/diagnostic imaging , Child , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Endocrine System Diseases/etiology , Female , Follow-Up Studies , Human Growth Hormone/deficiency , Humans , Longitudinal Studies , Male , Neurosecretory Systems/radiation effects , Risk Factors , Smoking , Tunica Intima/diagnostic imaging , Tunica Media/diagnostic imaging , UltrasonographyABSTRACT
OBJECTIVE: Hypercholesterolaemia is strongly associated with increased vessel wall thickness as measured by ultrasound. The question is whether aggressive cholesterol lowering with high-dose atorvastatin can alter intima media thickening to a greater extent than conventional therapy in patients with familial hypercholesterolaemia (FH). The baseline characteristics of a double-blind, randomised trial are described to determine whether two active treatments (high-dose atorvastatin 80mg versus conventional dose simvastatin 40mg), administered over a period of 2 years, may retard the process of intima media thickening in the carotid and femoral arteries of patients with FH. DESIGN AND PATIENTS: 325 patients with FH were randomised. Patients entered an 8-week placebo period in which all lipid-lowering medication was discontinued. Thereafter, baseline measurements of lipoprotein parameters and intima media thickness (IMT) of carotid and femoral artery were performed. RESULTS: Baseline low density lipoprotein (LDL) cholesterol (±SD) levels were 8.11 ± 1.92 mmol/L (312 ± 73 mg/dl) in men and 8.22 ± 1.91 mmol/L (316 ± 73 mg/dl) in women, respectively. Mean posterior wall IMT in the left common carotid artery (CCA) was significantly greater in men (0.94 ± 0.29mm) compared with women (0.85 ± 0.20) [p < 0.05]. A similar difference was found for the internal carotid artery (ICA). In the carotid bifurcation, IMT was 1.20 ± 0.50mm in men and 1.1 ± 0.54mm in women. The IMT of the common femoral artery (CFA) was 2.03 ± 0.88mm in men with cardiovascular disease (CVD) and 1.63 ± 0.70mm in men without CVD (p < 0.05). Strikingly, plaques were present in all men and 95% of the women with CVD. The cholesterol-year score and HDL cholesterol levels partially explained the variation in IMT in the carotid bifurcation, whereas gender and smoking contributed to the variation in IMT in the CFA in this group of patients. CONCLUSION: The patients participating in the Atorvastatin and Simvastatin on Atherosclerosis Progression (ASAP) trial constitute the largest well-documented FH population exhibiting marked increases in IMT of both carotid and femoral arteries and a very high prevalence of plaques, indicating extreme CVD risk. Since lipid-lowering therapy provides the highest benefit in precisely such patients, the ASAP trial will help assess whether aggressive LDL cholesterol intervention leads to retardation of subclinical atherosclerosis progression, as estimated with ultrasonographically assessed IMT.