Chapter III: Management of cardiovascular risk factors and medical therapy

Critical limb ischaemia (CLI) is a particularly severe manifestation of lower limb atherosclerosis posing a major threat to both limb and life of affected patients. Besides arterial revascularisation, risk-factor modification and administration of antiplatelet therapy is a major goal in the treatment of CLI patients. Key elements of cardiovascular risk management are smoking cessation and treatment of hyperlipidaemia with dietary modification or statins. Moreover, arterial hypertension and diabetes mellitus should be adequately treated. In CLI patients not suitable for arterial revascularisation or subsequent to unsuccessful revascularisation, parenteral prostanoids may be considered. CLI patients undergoing surgical revascularisation should be treated with beta blockers. At present, neither gene nor stem-cell therapy can be recommended outside clinical trials. Of note, walking exercise is contraindicated in CLI patients due to the risk of worsening pre-existing or causing new ischaemic wounds. CLI patients are oftentimes medically frail and exhibit significant comorbidities. Co-existing coronary heart and carotid as well as renal artery disease should be managed according to current guidelines. Considering the above-mentioned treatment goals, interdisciplinary treatment approaches for CLI patients are warranted. Aim of the present manuscript is to discuss currently existing evidence for both the management of cardiovascular risk factors and treatment of co-existing disease and to deduct specific treatment recommendations.

[Consensus recommendations for the assessment of fitness to drive in cognitively impaired patients]

Memory Clinics provide evidence based diagnosis and treatment of dementia. Whenever a diagnosis of dementia is made, it is important to inform the patients about the possible impact of dementia on driving. Patients and their next of kin require competent advice whenever this difficult question is addressed and the mobility desire and the risks related to driving need to be carefully weight up. The time of diagnosis does not necessarily equate to the time when a person with dementia becomes an unsafe driver. The cause and severity of dementia, comorbidities and the current medication need to be carefully taken into account for this decision. On behalf of the association of the Swiss Memory Clinics, a group of experts has developed recommendations to assess fitness to drive in cognitively impaired older adults.

Lipid profiles and outcome in patients treated by intravenous thrombolysis for cerebral ischemia

OBJECTIVE:To determine whether low low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) and triglyceride concentrations are associated with worse outcome in a large cohort of ischemic stroke patients treated with IV thrombolysis. METHODS:Observational multicenter post hoc analysis of prospectively collected data in stroke thrombolysis registries. Because of collinearity between total cholesterol (TC) and LDL-C, we used 2 different models with TC (model 1) and with LDL-C (model 2). RESULTS:Of the 2,485 consecutive patients, 1,847 (74%) had detailed lipid profiles available. Independent predictors of 3-month mortality were lower serum HDL-C (adjusted odds ratio [(adj)OR] 0.531, 95% confidence interval [CI] 0.321-0.877 in model 1; (adj)OR 0.570, 95% CI 0.348-0.933 in model 2), lower serum triglyceride levels ((adj)OR 0.549, 95% CI 0.341-0.883 in model 1; (adj)OR 0.560, 95% CI 0.353-0.888 in model 2), symptomatic ICH, and increasing NIH Stroke Scale score, age, C-reactive protein, and serum creatinine. TC, LDL-C, HDL-C, and triglycerides were not independently associated with symptomatic ICH. Increased HDL-C was associated with an excellent outcome (modified Rankin Scale score 0-1) in model 1 ((adj)OR 1.390, 95% CI 1.040-1.860). CONCLUSION:Lower HDL-C and triglycerides were independently associated with mortality. These findings were not due to an association of lipid concentrations with symptomatic ICH and may reflect differences in baseline comorbidities, nutritional state, or a protective effect of triglycerides and HDL-C on mortality following acute ischemic stroke.

Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

Complicated intra-abdominal infections in Europe: preliminary data from the first three months of the CIAO Study

The CIAO Study is a multicenter observational study currently underway in 66 European medical institutions over the course of a six-month study period (January-June 2012).This preliminary report overviews the findings of the first half of the study, which includes all data from the first three months of the six-month study period.Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study.912 patients with a mean age of 54.4 years (range 4-98) were enrolled in the study during the first three-month period. 47.7% of the patients were women and 52.3% were men. Among these patients, 83.3% were affected by community-acquired IAIs while the remaining 16.7% presented with healthcare-associated infections. Intraperitoneal specimens were collected from 64.2% of the enrolled patients, and from these samples, 825 microorganisms were collectively identified.The overall mortality rate was 6.4% (58/912). According to univariate statistical analysis of the data, critical clinical condition of the patient upon hospital admission (defined by severe sepsis and septic shock) as well as healthcare-associated infections, non-appendicular origin, generalized peritonitis, and serious comorbidities such as malignancy and severe cardiovascular disease were all significant risk factors for patient mortality.White Blood Cell counts (WBCs) greater than 12,000 or less than 4,000 and core body temperatures exceeding 38°C or less than 36°C by the third post-operative day were statistically significant indicators of patient mortality.

[Approach to prostate cancer in men older than 75 years: active or passive?]

Based on the exponential aging of the population and the increasing life expectancy in industrialized western countries, prostate cancer (PCa) in elderly men is becoming a disease of increasing significance. Consensus exists that men over the age of 75 years should not be screened for PCa; however, higher age as a single parameter should not exclude men from being diagnosed with prostate cancer and treated accordingly. It is well-known that overdiagnosis and overtreatment are frequent in this age group. Competing mortality risks of men older than 75 years may supersede the risk of dying from PCa several fold. Both the treating physician and the patient himself should therefore balance the possible risks and benefits of diagnosing and treating prostate cancer concerning the impact on quality of life. This is of special importance when taking into account that the complication rates of curative treatment modalities are higher in older patients than in younger men and that hormonal treatment might have negative effects especially in older men.Age, existing comorbidities, cognitive and physical status in combination with specific tumor parameters are useful tools for an individualized treatment.Therapy should be considered for healthy, active men aged 75 years or older who present with high-risk PCa and/or with a PSA doubling time <12 months. Elderly men who are unfit or have low to intermediate risk PCa will most likely not benefit from treatment.

Potential drug-drug interactions and adverse drug reactions in patients with liver cirrhosis

Patients with liver cirrhosis may be at risk for potential drug-drug interactions (pDDIs) and/or adverse drug reactions (ADRs) due to the severity of their disease and comorbidities associated with polypharmacy.

[Old and new interventional therapies in the treatment of symptomatic benign prostate hyperplasia (BPH)]

Benign Prostatic Hyperplasia is a common entity among the aging male population. Its prevalence is increasing with age and is around 80% in the over 80-years old. The androgen-estrogen ratio changes in favor of the estrogens, which leads to a growth of prostatic tissue, presenting histologically as hyperplasia. BPH can cause irritative or obstructive symptoms or both. Nowadays we speak of bladder storage or bladder voiding symptoms, summarised as LUTS (Lower Urinary Tract Symptoms). LUTS has a structural and a functional component, the structural being caused by the size of the adenoma itself the functional depending on the muscle tone of the bladder neck and the prostatic urethra. To investigate LUTS, we use validated symptom scores, sonography for residual urine and eventually a urodynamic evaluation. There are 3 grades of BPH. The indication for an interventional therapy is relative in BPH II, and absolute in BPH III. Prior to treatment, other diseases mimicking the same symptoms, have to be ruled out and adequatly treated. Electro-resection of the prostate (TUR-P) remains the standard therapy and the benchmark any new technology has to compete with. TUR-P has good short- and longterm results, but can be associated with a considerable perioperative morbidity, and the learning curve for the operator is long. The most promising of the newer techniques is the Holmium-Laser-Enucleation of the prostate (Laser-TUR-P), showing at least identical short- and median-term results, but a lower perioperative morbidity than TUR-P For several minimally-invasive techniques, indications are limited. TUMT TUNA, WIT and laser-coagulation all produce a coagulation necrosis of the prostatic tissue by thermic damage with secondary tissue shrinking. Urodynamic results however, are not comparable to TUR-P or Laser-TUR-P, and significantly more secondary interventions within 2 to 5 years are required. Minimal-invasive techniques present a favorable alternative for younger patients without complications of BPH, and for older patients with relevant comorbidities, and can usually be performed under local anaesthesia. The morbidity is low and further therapies remain possible later, if necessary.

Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial

PURPOSE: Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98. PATIENTS AND METHODS: Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms). RESULTS: Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)--an excess only partially attributable to prior hypercholesterolemia--and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events. CONCLUSION: The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.

Determinants of reduced walking speed in people with musculoskeletal pain

OBJECTIVE: Maintenance of good walking speed is essential to independent living. People with musculoskeletal disease often have reduced walking speed. We investigated determinants of slower walking, other than musculoskeletal disease, that might provide valuable additional targets for therapy. METHODS: We analyzed data from the Somerset and Avon Survey of Health, a community based survey of people aged over 35 years. A total of 2703 participants who reported hip or knee pain at baseline (1994/1995) were studied, and reassessed in 2002-2003; 1696 were available for followup, and walking speed was tested in 1074. Walking speed (m/s) was used as outcome measure. Baseline characteristics, including comorbidities and socioeconomic factors, were tested for their ability to predict reduced walking speed using multiple linear regression analysis. RESULTS: Age, female sex, and immobility at baseline were predictive of slower walking speed. Other independent risk factors included the presence of cataract, low socioeconomic status, intermittent claudication, and other cardiovascular conditions. Having a cataract was associated with a decrease of 0.10 m/s (95% CI 0.03, 0.16). Those in social class V had a walking speed 0.22 m/s (95% CI 0.126, 0.31) slower than those in social class I. CONCLUSION: Comorbidities, age, female sex, and lower socioeconomic position determine walking speed in people with joint pain. Issues such as poor vision and social-economic disadvantage may add to the effect of musculoskeletal disease, suggesting the need for a holistic approach to management of these patients.

Molecular mechanisms of alcohol-mediated carcinogenesis

Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.

[Endovascular therapy of an abdominal aortic aneurysm in a renal transplant recipient]

INTRODUCTION: The indications for endovascular aortic aneurysm repair (EVAR) are mainly established in hostile abdomen, in patients with significant comorbidities which affect the general operability of the patient and, given the necessary infrastructure, also in ruptured aneurysm. Along to those, we present another possible indication in the presence of a kidney allograft in patients with aortic aneurysm. METHODS: Based on a case report of aorto-biiliac stent-graft repair of an infrarenal aortic aneurysm in a patient with renal allograft, a systematic review of the literature was performed of all similar cases concerning surgical therapy in this constellation. RESULTS: EVAR was performed using an aorto-biiliac system (Zenith) Trifab, COOK) in a 61-year-old male patient 11 years after heterotopic renal allotransplantation in the right iliac fossa. Preoperative renal function was normal. Because the donor renal artery was anastomosed to the recipient's external iliac artery the stent-graft was implanted from the left common femoral artery to minimize temporary allograft ischemia. The intra- and postoperative course was uneventful with a follow-up of presently 12 months. A primary type-II endoleak (retroleak from a lumbar artery) is being treated conservatively so far with embolization being a future option. At present there are 15 cases of EVAR in renal allograft patients that have been reported, all of them being successful. DISCUSSION: All data existing in the literature reported to date as well as our own experience justify the first choice of EVAR in morphologically suitable cases. One major advantage of EVAR in this constellation is the avoidance of aortic cross clamping which poses the graft at risk of ischemia. Long-term results will be most important for definite assessment of EVAR. However, contrast media application during the operation and for CT surveillance should be considered as a major disadvantage.

[Fixed-combination of losartan/hydrochlorothiazide 100 mg/25 mg. Tolerability and efficacy on blood pressure measured in the practice and for 24 hours]

BACKGROUND: A high proportion of patients with essential hypertension need a combination therapy to reach the therapeutic goal. In the present study, the tolerability and efficacy of a fixed, once daily combination of the AT1 blocker Losartan (100 mg) and the diuretic hydrochlorothiazide (HCTZ) (25 mg) for patients in the real-life situation was investigated. Special consideration was given to the results of ambulatory 24-hourblood pressure (ABP) measurements. METHODS: The open label, prospective non-interventional surveillance study took place from October 2005 to June 2006. A total of 1139 patients over 18 years in age were included whose blood pressures could not be adequately treated with HCTZ alone and for whom an individual dose titration for Losartan and HCTZ had already been performed. RESULTS: The average age (+/- standard deviation) of the patients was 61.2 +/- 11.6 years; 55.8% were men. Comorbidities were common. Specifically, left ventricular hypertrophy was present in 3.1% of the patients, coronary heart disease in 30.1%, chronic heart failure in 11.8% and status post myocardial infarction in 10.5%, respectively. In addition to the Losartan/HCTZ treatment, 61.0% of the patients received a second antihypertensive medicine. After an average treatment duration of 50.4 +/- 17.2 days, the base line systolic blood pressure of 160.8 +/- 16.3 mmHg decreased by 24.0 +/- 17.0 mmHg (-14.4%) and the diastolic blood pressure of 94.4 +/- 9.9 mmHg decreased by 11.8 +/- 10.2 mmHg (-11.8%). For the ABP measurements, the overall average systolic and diastolic blood pressures fell by 16.9 +/- 14.2 mmHg and 8.8 +/-10.3 mmHg, the day average by 17.3 +/- 14.8 mmHg and 9.0 +/- 10.2 mmHg and the night average by 15.1 +/- 17.6 mmHg and 7.8 +/- 11.7 mmHg, respectively. In twelve of the 1139 patients (1.1%), a total of 15 adverse events occurred. A causal connection with the medication was suspected in only in one case (one patient with three). CONCLUSION: The combination of Losartan/HCTZ 100/25 mg, as the exclusive therapy or in addition to other antihypertensive medicines, was for patients, many of whom who had comorbidities, in the real-life situation well tolerated and effective. The efficacy was demonstrated also during the night through ABP.

Influence of pulmonary status and diabetes mellitus on aortic neck dilatation following endovascular repair of abdominal aortic aneurysms: a EUROSTAR report

PURPOSE: To elucidate the association of impaired pulmonary status (IPS) and diabetes mellitus (DM) with clinical outcome and the incidences of aortic neck dilatation and type I endoleak after elective endovascular infrarenal aortic aneurysm repair (EVAR). METHODS: In 164 European institutions participating in the EUROSTAR registry, 6383 patients (5985 men; mean age 72.4+/-7.6 years) underwent EVAR. Patients were divided into patients without versus with IPS or with/without DM. Clinical assessment and contrast-enhanced computed tomography (CT) were performed at 1, 3, 6, 12, 18, and 24 months and annually thereafter. Cumulative endpoint analysis comprised death, aortic rupture, type I endoleak, endovascular reintervention, and surgical conversion. RESULTS: Prevalence of IPS was 2733/6383 (43%) and prevalence of DM was 810/6383 (13%). Mean follow-up was 21.1+/-18.4 months. Thirty-day mortality, AAA rupture, and conversion rates did not differ between patients with versus without IPS and between patients with versus without DM. All-cause and AAA-related mortality, respectively, were significantly higher in patients with IPS compared to patients with normal pulmonary status (31.0% versus 19.0%, p<0.0001 and 6.8% versus 3.3%, p = 0.0057) throughout follow-up. In multivariate analysis adjusted for smoking, age, gender, comorbidities, fitness for open repair, co-existing common iliac aneurysm, neck and aneurysm size, arterial angulations, aneurysm classification, endograft oversizing >or=15%, and type of stent-graft, the presence of IPS was not associated with significantly higher rates of aortic neck dilatation (30.6% versus 38.0%, p>0.05) and did not influence cumulative rates of type I endoleak, endovascular reintervention, or conversion to open surgery (p>0.05). Similarly, the presence of DM did not influence the above-mentioned study endpoints. CONCLUSION: In contrast to observations regarding the natural course of AAAs, impaired pulmonary status does not negatively influence aortic neck dilatation, while the presence of diabetes does not protect from these dismal events after EVAR.

Late presentation of HIV-infected individuals

Late presentation remains a major concern despite the dramatically improved prognosis realized by ART. We define a first presentation for HIV care during the course of HIV infection as 'late' if an AIDS-defining opportunistic disease is apparent, or if CD4+ T-cells are <200/microl. In the Western world, approximately 10 and 30% of HIV-infected individuals still present with CD4+ T-cells <50 and <200/microl, respectively; estimates are substantially higher for developing countries. Diagnosis and treatment of opportunistic diseases and intense supportive in-hospital care take precedence over ART. Benefits of starting ART without delay, that is, when opportunistic diseases are still active, include faster resolution of opportunistic diseases and a decreased risk of recurrence. The downside of starting ART without delay could include toxicity, drug interactions and immune reconstitution inflammatory syndrome (IRIS). Among asymptomatic or oligosymptomatic individuals presenting late, where ART and primary prophylaxis are initiated, approximately 10-20% will become symptomatic from drug toxicity or undiagnosed opportunistic complications, including IRIS, which require appropriate therapies. In this review we describe late presentation to HIV care, the scale of the problem, the evaluation of a late-presenting patient and challenges associated with initiation of potent antiretroviral therapy (ART) in the setting of acute opportunistic infections and other comorbidities.