Physical activity and PDE5 inhibitors in the treatment of erectile dysfunction: results of a randomized controlled study.

INTRODUCTION: Physical activity (PhA) has proven to be a protective factor for normal erectile function in numerous epidemiological studies. AIM: The aim of this study was to establish if PhA could have a therapeutic role in the treatment of erectile dysfunction (ED). METHODS: This was a randomized, open-label study. A total of 60 patients complaining of ED were studied. Patients were assessed at baseline and after 3 months of study treatment. At baseline, patients were randomized to receive phosphodiesterase type 5 inhibitor (PDE5i) alone (group A) or PDE5i plus regular (≥3 hours/week), aerobic, non-agonistic PhA (group B). MAIN OUTCOME MEASURES: All subjects completed the International Index of Erectile Function (IIEF-15) questionnaire and performed total testosterone (TT). RESULTS: Mean PhA was 3.4 hours/week in group B vs. 0.43 in group A; mean energy expenditure in group B was 1,868 kcal/ week or 22.8 metabolic equivalent (MET)/week. IIEF restoration of ED occurred in 77.8% (intervention group) vs. 39.3% (control) (P < 0.004). The IIEF-15 score resulted in statistical improvement in intervention group in all the domains but one (orgasm): erectile function 24.7 vs. 26.8 (P = 0.003); confidence (Q15) 3.53 vs. 4.07 (P = 0.006); sexual desire 6.46 vs. 7.18 (P = 0.028); intercourse satisfaction 9.85 vs. 11.25 (P = 0.001); total satisfaction 7.17 vs. 8.07 (P = 0.009); total score 56.2 vs. 61.07 (P = 0.007). TT was statistically similar in the two groups; separate analysis in each group showed statistical increase in group B 4.24 vs. 4.55 (P = 0.012). At multivariate logistic regression analysis, PhA was the only independent variable for normal erection (P = 0.010) (95% confidence interval [CI] 0.036-0.643), higher sexual satisfaction (P = 0.022) (95% CI 0.084-0.821) and normal total IIEF-15 score (P = 0.023) (95% CI 0.85-0.837). CONCLUSION: In this randomized controlled pilot study, PDE5i plus PhA was more effective than PDE5i alone in the treatment of ED.

An association between atherosclerosis and venous thrombosis.

BACKGROUND: In about a third of patients with venous thromboembolism, the cause of the disorder is unexplained. In patients with atherosclerosis, activation of both platelets and blood coagulation and an increase in fibrin turnover are detectable, which may lead to thrombotic complications. Whether atherosclerosis is associated with an increased risk of venous thrombosis is unknown. METHODS: We performed ultrasonography of the carotid arteries in 299 unselected patients who had deep venous thrombosis of the legs without symptomatic atherosclerosis and in 150 control subjects. Patients with spontaneous thrombosis, patients with secondary thrombosis from acquired risk factors, and control subjects were assessed for plaques. RESULTS: At least one carotid plaque was detected in 72 of the 153 patients with spontaneous thrombosis (47.1 percent; 95 percent confidence interval, 39.1 to 55.0), 40 of the 146 with secondary thrombosis (27.4 percent; 95 percent confidence interval, 20.2 to 34.6), and 48 of the 150 control subjects (32.0 percent; 95 percent confidence interval, 24.5 to 39.5). The odds ratios for carotid plaques in patients with spontaneous thrombosis, as compared with patients with secondary thrombosis and with controls, were 2.3 (95 percent confidence interval, 1.4 to 3.7) and 1.8 (95 percent confidence interval, 1.1 to 2.9), respectively. In a multivariate analysis that accounted for risk factors for atherosclerosis, the strength of this association did not change. CONCLUSIONS: There is an association between atherosclerotic disease and spontaneous venous thrombosis. Atherosclerosis may induce venous thrombosis, or the two conditions may share common risk factors.

Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTPH) is associated with considerable morbidity and mortality. Its incidence after pulmonary embolism and associated risk factors are not well documented. METHODS: We conducted a prospective, long-term, follow-up study to assess the incidence of symptomatic CTPH in consecutive patients with an acute episode of pulmonary embolism but without prior venous thromboembolism. Patients with unexplained persistent dyspnea during follow-up underwent transthoracic echocardiography and, if supportive findings were present, ventilation-perfusion lung scanning and pulmonary angiography. CTPH was considered to be present if systolic and mean pulmonary-artery pressures exceeded 40 mm Hg and 25 mm Hg, respectively; pulmonary-capillary wedge pressure was normal; and there was angiographic evidence of disease. RESULTS: The cumulative incidence of symptomatic CTPH was 1.0 percent (95 percent confidence interval, 0.0 to 2.4) at six months, 3.1 percent (95 percent confidence interval, 0.7 to 5.5) at one year, and 3.8 percent (95 percent confidence interval, 1.1 to 6.5) at two years. No cases occurred after two years among the patients with more than two years of follow-up data. The following increased the risk of CTPH: a previous pulmonary embolism (odds ratio, 19.0), younger age (odds ratio, 1.79 per decade), a larger perfusion defect (odds ratio, 2.22 per decile decrement in perfusion), and idiopathic pulmonary embolism at presentation (odds ratio, 5.70). CONCLUSIONS: CTPH is a relatively common, serious complication of pulmonary embolism. Diagnostic and therapeutic strategies for the early identification and prevention of CTPH are needed.

The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies.

Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of non-carriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used.

Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism. A retrospective cohort study.

Recent data have shown a higher incidence of arterial events in patients with venous thromboembolism (VTE) of unknown origin than in those with the secondary form of disease. Whether patients with idiopathic VTE have a higher risk of subsequent arterial events than the general population is unknown. The aim was to evaluate the rates of subsequent arterial events in patients with idiopathic VTE and control subjects. In a retrospective cohort study we compared the rates of subsequent arterial events (i.e. acute myocardial infarction, ischemic stroke and peripheral arterial disease) in 151 consecutive patients with objectively confirmed spontaneous VTE and 151 control subjects randomly selected from the database of two family physicians. We collected information about cardiovascular risk-factors (hypertension, hypercholesterolemia, diabetes, obesity and smoke) at the time of VTE episode, or corresponding date for the controls, and considered the follow-up from this time. Patients and controls who had suffered from arterial events before the index date were excluded. During a mean follow-up of 43.1 (+/- 21.7) months there were 16 arterial events in the VTE patients and six in the control group (HR, 2.84;95% CI,1.11 to 7.27; p = 0.03). The difference remained significant after adjusting for age and other cardiovascular risk factors (HR 2.86;95% CI,1.07 to 7.62). Overall mortality was also higher in the VTE patients (12 vs.4 deaths). In conclusion, arterial events are more common in patients with previous idiopathic VTE than in the general population. These findings may have practical implications.

Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism.

BACKGROUND: Few reports have addressed the value of unfractionated heparin (UFH) or low-molecular-weight heparin in treating the full spectrum of patients with venous thromboembolism (VTE), including recurrent VTE and pulmonary embolism. METHODS: In an open, multicenter clinical trial, 720 consecutive patients with acute symptomatic VTE, including 119 noncritically ill patients (16.5%) with pulmonary embolism and 102 (14.2%) with recurrent VTE, were randomly assigned to treatment with subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm (preceded by an intravenous loading dose), or fixed-dose (adjusted only to body weight) subcutaneous nadroparin calcium. Oral anticoagulant therapy was started concomitantly and continued for at least 3 months. We recorded the incidence of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of follow-up. RESULTS: Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as compared with 14 (3.9%) of the 360 patients assigned to nadroparin (absolute difference between rates, 0.3%; 95% confidence interval, -2.5% to 3.1%). Four patients assigned to UFH (1.1%) and 3 patients assigned to nadroparin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence interval, -1.2% to 1.7%). Overall mortality was 3.3% in each group. CONCLUSIONS: Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed-dose nadroparin for the initial treatment of patients with VTE, including those with pulmonary embolism and recurrent VTE.

Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial.

BACKGROUND: Because only limited evidence suggests that elastic stockings prevent the post-thrombotic syndrome in patients with symptomatic deep venous thrombosis (DVT), these stockings are not widely used. OBJECTIVE: To evaluate the efficacy of compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal DVT. DESIGN: Randomized, controlled clinical trial. SETTING: University hospital. PATIENTS: 180 consecutive patients with a first episode of symptomatic proximal DVT who received conventional anticoagulant treatment. INTERVENTIONS: Before discharge, patients were randomly assigned to wear or not wear below-knee compression elastic stockings (30 to 40 mm Hg at the ankle) for 2 years. Follow-up was performed for up to 5 years. MEASUREMENTS: The presence and severity of the post-thrombotic syndrome were scored by using a standardized scale. RESULTS: Post-thrombotic sequelae developed in 44 of 90 controls (severe in 10) and in 23 of 90 patients wearing elastic stockings (severe in 3). All but 1 event developed in the first 2 years. The cumulative incidence of the post-thrombotic syndrome in the control group versus the elastic stockings group was 40.0% (95% CI, 29.9% to 50.1%) versus 21.1% (CI, 12.7% to 29.5%) after 6 months, 46.7% (CI, 36.4% to 57.0%) versus 22.2% (CI, 13.8% to 30.7%) after 1 year, and 49.1% (CI, 38.7% to 59.4%) versus 24.5% (CI, 15.6% to 33.4%) after 2 years. After adjustment for baseline characteristics, the hazard ratio for the post-thrombotic syndrome in the elastic stockings group compared with controls was 0.49 (CI, 0.29 to 0.84; P = 0.011). LIMITATIONS: This study lacked a double-blind design. CONCLUSIONS: Post-thrombotic sequelae develop in almost half of patients with proximal DVT. Below-knee compression elastic stockings reduce this rate by approximately 50%.

Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism.

BACKGROUND: The optimum duration of anticoagulant therapy after an episode of deep venous thrombosis (DVT) is controversial. Contributing to the controversy is uncertainty about whether residual venous thrombosis, as assessed by repeated ultrasonography over time, increases the risk for recurrent thromboembolism. OBJECTIVE: To determine the risk for recurrent thromboembolism in patients who have persistent residual thrombosis compared with patients who have early vein recanalization. DESIGN: Prospective cohort study. SETTING: A university hospital in Padua, Italy. PATIENTS: 313 consecutive symptomatic outpatients with proximal DVT who received conventional short-term anticoagulation. MEASUREMENTS: Ultrasonographic assessment of the common femoral and popliteal veins was performed 3 months after acute DVT in all patients and at 6, 12, 24, and 36 months in patients found to have residual venous thrombosis. Veins were considered recanalized if they were 2.0 mm or less in diameter on a single test or 3.0 mm or less in diameter on two consecutive tests. Recurrent thromboembolism was assessed during a 6-year period. RESULTS: The cumulative incidence of normal results on ultrasonography was 38.8% at 6 months, 58.1% at 12 months, 69.3% at 24 months, and 73.8% at 36 months. Of 58 recurrent episodes, 41 occurred while the patient had residual thrombosis. The hazard ratio for recurrent thromboembolism was 2.4 (95% CI, 1.3 to 4.4; P = 0.004) for patients with persistent residual thrombosis versus those with early vein recanalization. CONCLUSIONS: Residual venous thrombosis is an important risk factor for recurrent thromboembolism. Ultrasonographic assessment of residual venous thrombosis may help clinicians modify the duration of anticoagulation in patients with DVT.

Superficial vein thrombosis: risk factors, diagnosis, and treatment.

Superficial vein thrombosis (SVT) is a very common disease even though its incidence has never been assessed properly. Until recently, the literature on this topic has been relatively poor, old, and with numerous methodologic drawbacks, probably because this disease was considered benign and trivial. However, the recent recognition of a frequent association with concomitant venous thromboembolism (VTE) (deep vein thrombosis [DVT] and pulmonary embolism [PE]) and the risk of subsequent VTE complications in patients with isolated SVT has revived interest and has encouraged new clinical research. SVT and VTE share many common predisposing risk factors. Even if varicose veins represent the main cause of SVT, several underlying conditions (e.g., malignancy, thrombophilia, autoimmune diseases) should be sought, especially in idiopathic, migrant, or recurrent SVT of nonvaricose vein patients. The diagnosis is made in a clinical setting but ultrasonography is useful to identify concomitant asymptomatic DVT. Many medical and surgical treatments have been suggested to relieve local symptoms and signs, prevent recurrences, and limit the VTE risk of SVT, but the evidence coming from the limited number of prospective randomized studies does not allow strong recommendations on the optimal treatment of SVT.

High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study.

BACKGROUND AND OBJECTIVES: The optimal treatment of superficial thrombophlebitis of the leg is undefined. The main study objective was to assess the efficacy and safety of unmonitored high doses as compared to low doses of unfractionated heparin (UFH) for prevention of venous thromboembolic complications in patients with superficial thrombophlebitis of the thigh. DESIGN AND METHODS: Sixty consecutive patients with acute thrombophlebitis of the great saphenous vein, as assessed by ultrasonography, were randomized to subcutaneous injection twice daily of UFH in high unmonitored doses (12,500 IU for one week followed by 10,000 IU) or prophylactic doses (5,000 IU) for four weeks. The rate of asymptomatic involvement of the deep venous system and/or symptomatic thromboembolic events during a six-month follow-up period was assessed and compared between the two study groups. RESULTS: Six of the 30 patients (20.0 %; 95% CI, 7.7 to 38.6) randomized to low-dose UFH developed symptomatic or asymptomatic events as compared to 1 of the 30 patients (3.3%; 95% CI, 0.07 to 17.2) who received high-dose UFH (p=0.05 by one-sided Fisher's exact test). No patient experienced major bleeding complications in either group. INTERPRETATION AND CONCLUSIONS: The results of this study suggest that in patients with acute thrombophlebitis of the thigh unmonitored high doses of UFH are more effective than prophylactic doses of UFH for prevention of venous thromboembolic complications and do not enhance the risk of bleeding complications.

Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.

A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer. This prospective follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulative incidence of recurrent thromboembolism in cancer patients was 20.7% (95% CI, 15.6%-25.8%) versus 6.8% (95% CI, 3.9%- 9.7%) in patients without cancer, for a hazard ratio of 3.2 (95% CI, 1.9-5.4) The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI, 1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy. These risks correlate with the extent of cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed.