Diagnostic accuracy of on-site coronary computed tomography-derived fractional flow reserve in the diagnosis of stable coronary artery disease.

PURPOSE: Invasive fractional flow reserve (FFR), the reference standard for identifying significant coronary artery disease (CAD), can be estimated non-invasively by computed tomography-derived fractional flow reserve (CT-FFR). Commercially available off-site CT-FFR showed improved diagnostic accuracy compared to coronary computed tomography angiography (CCTA) alone. However, the diagnostic performance of this lumped-parameter on-site method is unknown. The aim of this cross-sectional study was to determine the diagnostic accuracy of on-site CT-FFR in patients with suspected CAD. METHODS: A total of 61 patients underwent CCTA and invasive coronary angiography with FFR measured in 88 vessels. Significant CAD was defined as FFR and CT-FFR below 0.80. CCTA with stenosis above 50% was regarded as significant CAD. The diagnostic performance of both CT-FFR and CCTA was assessed using invasive FFR as the reference standard. RESULTS: Of the 88 vessels included in the analysis, 34 had an FFR of ≤ 0.80. On a per-vessel basis, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 91.2%, 81.4%, 93.6%, 75.6% and 85.2% for CT-FFR and were 94.1%, 68.5%, 94.9%, 65.3% and 78.4% for CCTA. The area under the receiver operating characteristic curve was 0.91 and 0.85 for CT-FFR and CCTA, respectively, on a per-vessel basis. CONCLUSION: On-site non-invasive FFR derived from CCTA improves diagnostic accuracy compared to CCTA without additional testing and has the potential to be integrated in the current clinical work-up for diagnosing stable CAD.

ICD implantation for secondary prevention in patients with ventricular arrhythmia in the setting of acute cardiac ischemia and a history of myocardial infarction.

INTRODUCTION: In patients with a prior myocardial infarction (MI) but preserved left ventricular (LV) function, sustained ventricular arrhythmias (VAs) may arise in the setting of an acute coronary syndrome (ACS). It is unknown whether an implantable cardioverter-defibrillator (ICD) is mandatory in these patients as VA might be triggered by a reversible cause. The purpose of this study is to analyze the benefit of ICD therapy in this patient population. METHODS: We conducted a retrospective observational study in ICD recipients implanted from 2008 to 2011. The study group consisted of patients with sustained VA in the setting of an ACS, with a history of MI, but with left ventricular ejection fraction (LVEF) greater than 35 (group A). The two control groups consisted of patients admitted with VA with a history of MI, but without ACS at presentation, either with LVEF greater than 35% (group B) or ≤35% (group C). The primary endpoint was the number of patients with appropriate ICD therapy (antitachycardia pacing or shock). RESULTS: A total of 291 patients were included with a mean follow-up of 5.3 years. Appropriate ICD therapy occurred in 45.6% of the patients in group A vs 51.6% and 60.4% in groups B and C (P = .11). In group A, 31.1% received an appropriate ICD shock vs 34.7% and 44.3% in control groups B and C (P = .12). CONCLUSION: On the basis of these data, ICD implantation seems warranted in patients with history of MI presenting with VA in the setting of an ACS, despite preserved LV function and adequate revascularization. Further trials, preferably randomizes, should be performed to address these findings.

Long-term follow-up after bypass surgery or coronary stenting in elderly with multivessel disease.

BACKGROUND: We sought to compare long-term follow-up of coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) in elderly patients with left main or multivessel disease, hypothesising that completeness of revascularisation and severity of coronary artery disease are predictors of adverse outcomes. METHODS: Patients aged ≥75 years with multivessel disease or left main disease who underwent PCI or CABG between 2012-2016 were included in this retrospective cohort study. Baseline characteristics from the index procedure were collected. Severity of coronary artery disease and completeness of revascularisation were assessed. Primary outcome was all-cause mortality, in addition we captured major adverse cardiac and cerebral events, bleedings, recurrent angina and new onset atrial fibrillation. RESULTS: A total of 597 patients were included. Median follow-up was 4 years (interquartile range 2.8-5.3 years). At baseline, patients in the PCI group more often had a previous medical history of CABG and more frequently underwent an urgent procedure compared with patients in the CABG group. Mortality at 5­year follow-up was significantly higher in patients who underwent PCI compared with CABG (39.9% vs 25.4%, p < 0.001). Furthermore, acute coronary syndrome (ACS), repeat revascularisation and recurrent angina occurred more frequently after PCI, while occurrence of bleedings and new onset atrial fibrillation were more frequent after CABG. Neither completeness of revascularisation nor severity of coronary artery disease was a predictor for any of the outcomes. CONCLUSION: Long-term mortality was higher in elderly patients with multivessel disease undergoing PCI compared with CABG. In addition, patients undergoing PCI had a higher risk of ACS, repeat revascularisation and recurrent angina.

Bosentan or Macitentan Therapy in Chronic Thromboembolic Pulmonary Hypertension?

OBJECTIVE: Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH. METHODS: All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation. RESULTS: In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56-6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962-4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up. CONCLUSION: CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.

Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis.

BACKGROUND: Many patients who have surgery for acute cholecystitis receive postoperative antibiotic prophylaxis, with the intent to reduce infectious complications. There is, however, no evidence that extending antibiotics beyond a single perioperative dose is advantageous. This study aimed to determine the effect of extended antibiotic prophylaxis on infectious complications in patients with mild acute cholecystitis undergoing cholecystectomy. METHODS: For this randomized controlled non-inferiority trial, adult patients with mild acute calculous cholecystitis undergoing cholecystectomy at six major teaching hospitals in the Netherlands, between April 2012 and September 2014, were assessed for eligibility. Patients were randomized to either a single preoperative dose of cefazolin (2000 mg), or antibiotic prophylaxis for 3 days after surgery (intravenous cefuroxime 750 mg plus metronidazole 500 mg, three times daily), in addition to the single dose. The primary endpoint was rate of infectious complications within 30 days after operation. RESULTS: In the intention-to-treat analysis, three of 77 patients (4 per cent) in the extended antibiotic group and three of 73 (4 per cent) in the standard prophylaxis group developed postoperative infectious complications (absolute difference 0·2 (95 per cent c.i. -8·2 to 8·9) per cent). Based on a margin of 5 per cent, non-inferiority of standard prophylaxis compared with extended prophylaxis was not proven. Median length of hospital stay was 3 days in the extended antibiotic group and 1 day in the standard prophylaxis group. CONCLUSION: Standard single-dose antibiotic prophylaxis did not lead to an increase in postoperative infectious complications in patients with mild acute cholecystitis undergoing cholecystectomy. Registration number: NTR3089 (www.trialregister.nl).

Development of new extra-glandular manifestations or associated auto-immune diseases after establishing the diagnosis of primary Sjögren's syndrome : A long-term study of the Antonius Nieuwegein Sjögren (ANS) cohort.

To investigate in a long-term study, the development of new extra-glandular manifestations (EGM) or associated auto-immune diseases (AID) from 1 year after establishing the diagnosis of primary Sjögren's syndrome (pSS). The primary goal was to examine the frequency and type of these manifestations and to find out which demographic, clinical and serological profile was most at risk. All outpatients diagnosed with primary Sjögren's syndrome were included in a retrospective study, with at least one check-up per year, from June 1991 until August 2015. Patients also fulfilling the criteria for concomitant connective tissue disorders were excluded. Data were collected with respect to the cumulative prevalence of a new EGM or associated AID. 140 patients were included in the final analysis. After 10 years of follow-up, the cumulative incidence of a new EGM or associated AID was 30.7%. The most frequent events were polyneuropathy, interstitial lung disease, (poly)arthritis, discoid lupus erythematosus (LE)/subacute cutaneous LE and Hashimoto's disease. Non-Hodgkin lymphoma was not diagnosed during the follow-up. Patients without chronic benign pain syndrome (CBP) (HR 2.13; 95% CI [0.94-4.76]; p = 0.061), but in particular those with cryoglobulins (HR 2.87; 95% CI [1.20-6.86]; p = 0.013), developed more events. Age at diagnosis, gender, the presence of ANA, anti-Ro/SSA, anti-La/SSB, IgM-RF, decreased levels of C3 or C4, or hypergammaglobulinaemia did not show any statistically significant differences. The burden of disease in pSS is higher than expected due to the development of EGM or associated AID. Therefore, we recommend long-term follow-up of all pSS patients, particularly those with cryoglobulinaemia.

The predictive value of conventional surgical risk scores for periprocedural mortality in percutaneous mitral valve repair.

BACKGROUND: Surgical risk scores are used to identify high-risk patients for surgical mitral valve repair. There is no scoring system to estimate the mortality risk for patients undergoing percutaneous treatment. The aim of this analysis is to evaluate the predictive value of the EuroSCOREs and the Society of Thoracic Surgeons Predicted Risk of Mortality Score (STS) for periprocedural mortality in percutaneous edge-to-edge mitral valve repair. METHODS: From 2009 to 2013, 136 high-risk patients were included who underwent 143 procedures. Observed periprocedural mortality was compared with predicted mortality using the logistic EuroSCORE, EuroSCORE II and STS. The predictive value was analysed by receiver operating characteristic curves for each score. RESULTS: Observed periprocedural mortality was 3.5 %. The predicted surgical mortality risk was: 23.1 ± 15.7 % for the logistic EuroSCORE, 9.6 ± 7.7 % for the EuroSCORE II and 13.2 ± 8.2 % for the STS. The predictive value estimated by the area under the curve was: 0.55, 0.54 and 0.65 for the logistic EuroSCORE, EuroSCORE II and STS respectively. Severe pulmonary hypertension and acute procedural success were significant predictive parameters in univariate analysis. CONCLUSION: Contemporary surgical scores do not adequately predict periprocedural mortality for high-risk patients undergoing edge-to-edge mitral valve repair, but they can be used to help decision-making in the selection process for this procedure.

Long-term bleeding events after mechanical aortic valve replacement in patients under the age of 60.

BACKGROUND: Although younger patients are supposed to be less susceptible to bleeding complications of mechanical aortic valve replacement (mAVR) than older patients, there is a relative paucity of data on this subject. Therefore, it remains uncertain whether younger patients are really at a lower risk of these complications than older patients. METHODS: Incidence rates of bleeding events during 15 years of follow-up after mAVR were compared between 163 patients under 60 (group I), 122 patients between 60 and 65 (group II), and 145 patients over 65 (group III) years of age at operation. The target international normalised ratio (INR) was 3.0-4.0. RESULTS: During 15 years of follow-up, the annual incidence rate of major bleeding events (excluding haemorrhagic stroke) was lower in the youngest as compared with the oldest group (3.0 versus 4.7 %, respectively; p = 0.030). However, the annual incidence rate of haemorrhagic stroke was as high in the youngest as in the two older groups (0.6 versus 0.7 % and 0.7 %, respectively; p = 0.928). CONCLUSIONS: With a target INR of 3.0-4.0, patients under 60 years of age are at equally high risk of haemorrhagic stroke after mAVR as older patients. This finding confirms the relevance of a lower target INR as used in international guidelines.

Lower prevalence of extra-glandular manifestations and anti-SSB antibodies in patients with primary Sjögren's syndrome and widespread pain: evidence for a relatively benign subset.

OBJECTIVES: To investigate in primary Sjögren's syndrome, the differences between patients with and without widespread pain (WSP) with respect to the cumulative prevalence of extra-glandular manifestations (EGMs) and systemic auto-antibodies. METHODS: All outpatients diagnosed with primary Sjögren's syndrome (2) were included in a prospective follow-up, with at least one check up each year, from June 1991 until November 2011. Patients who also fulfilled criteria for concomitant connective tissue disorders were excluded. Widespread pain was defined as the presence of long-lasting (>one year) diffuse pain in all four body quadrants. Data were collected with respect to the cumulative prevalence of systemic auto-antibodies (anti-nuclear antibodies [ANA], anti-Sjögren syndrome A antigen [anti-SSA], anti-Sjögren syndrome B antigen [anti-SSB] and immunoglobulin M-Rheumatoid factor [IgM-RF]) and EGMs related to primary Sjögren's syndrome. RESULTS: Eighty-three patients were included in the final analysis. Thirty-nine (34.9%) patients had widespread pain. Anti-SSB was found less frequently (p<0.05) in patients with WSP than in patients without WSP. The WSP-positive patients were more frequently negative for all four tested autoantibodies (p<0.05). The patients with WSP had fewer EGMs than the patients without WSP (p<0.01); more specifically, polyneuropathy occurred less frequently (p<0.05) in the patients with WSP. Cytopenia, uveitis, pericarditis, pleuritis, interstitial lung disease, vasculitis, monoclonal gammapathy of unknown significance and non-Hodgkin lymphoma only occurred in the patients without WSP. CONCLUSIONS: Primary Sjögren's patients with WSP form a benign subgroup, with a lower prevalence of anti-SSB and EGMs (in particular polyneuropathy). We suggest a shorter period of follow-up for this subset than for the WSP-negative patients.

Patients with left bundle branch block pattern and high cardiac risk myocardial SPECT: does the current management suffice?

INTRODUCTION: Myocardial perfusion SPECT (MPS) is frequently used for cardiovascular risk stratification. The significance of MPS in patients with abnormal electrical ventricular activation is often questionable. This review assesses the value of MPS for risk stratification of patients with intrinsic left bundle branch block or that due to right ventricular apical pacing. METHODS: We reviewed the literature by a search of the MEDLINE database (January 1980 to September 2010). The terms prognosis or prognostic value were combined with SPECT and LBBB or pacing or pacemakers. MPS was categorised as low and high risk according to the original definitions. RESULTS: We identified 11 studies suitable for review. A low-risk MPS is associated with a low risk of cardiac events whereas high-risk MPS carries a 4.8-fold increased risk, 95% CI [3.2 - 7.2] (p < 0.0001). Despite secondary prevention and an improved medical and interventional care, these figures have hardly changed over time. CONCLUSION AND CLINICAL IMPLICATIONS: A low-risk MPS permits a policy of watchful waiting whereas a high-risk MPS requires further analysis and treatment. The persistent high cardiac death and acute myocardial infarction rate after a high-risk MPS suggest that the current management of these patients does not suffice and needs reconsideration.

Predictive factors for Day 7 positive patch test readings at a secondary referral centre.

Background: Based on studies at tertiary centres it is known that patch test reading on Day (D) 7 may show additional positive reactions. Female gender, higher age and allergen groups of topicals and corticosteroids were identified as predictive factors. Objectives: The first aim was to study the value of reading patch tests on D2, D3 and D7 at a secondary referral centre. The second aim was to investigate the predictive potential of the factors sex, age, atopic dermatitis, body location, allergen group and clinical relevance for a positive reaction only on D7. Methods: Retrospective data from patients tested between 2013 and 2016 were evaluated. The factors sex, age, atopic dermatitis, body location, allergen group and clinical relevance were tested by regression analysis. Results: Two hundred and sixty-three out of a total of 396 patients had a positive reaction only on D2, D3 and D7 in 14 (2.5%), 152 (27.5%) and 61 (11.0%) occasions, observed in 10 (2.5%), 108 (27.3%) and 51 (12.9%) patients, respectively. These reactions were deemed relevant in 0 (0%), 12 (2.2%) and 9 (1.6%) occasions, observed 0 (0%), 11 (2.8%) and 9 (2.3%) patients, respectively. Higher age and allergen groups of metals, fragrances and resins were predictive for late positive reactions. Conclusions: D7 patch test reading should also be routinely adopted at secondary referral centres. D7 positive reactions were associated with higher age and sensitization to metals, fragrances and resins.

Postoperative myocardial injury and platelet reactivity in patients undergoing vascular surgery: The platelet reactivity and postoperative myocardial injury after major vascular surgery (PROMISE) study.

BACKGROUND: Postoperative myocardial injury (PMI) after major vascular surgery, detected by elevated cardiac troponin (cTn), has been associated with morbidity and mortality. It is unclear whether the pathophysiology of PMI is determined by increased platelet activity. OBJECTIVE: To examine the relationship between platelet activation (P-selectin expression) and PMI in patients undergoing elective open abdominal aortic surgery. METHODS: This prospective, single-centre, observational, cohort study included 33 patients undergoing elective open abdominal aortic surgery between March 2018 and April 2021. Patients were routinely treated with aspirin. Unstimulated platelet activation was measured by platelet bound P-selectin expression (range 0-100 %). Explorative coagulation measurements were: stimulated platelet aggregation measured with the VerifyNow® assay (aspirin cartridge), with the Multiplate® analyzer (ASPI, ADP and TRAP) and stimulated coagulation status evaluated by the TEG® Hemostasis Analyzer System (global hemostasis cartridge). The primary outcome was cTn release assessed by the fifth generation high-sensitive cTn assay. Multivariable generalized linear mixed models were used to evaluate the association between platelet function and cTn concentrations over time. RESULTS: Ten patients (30.3 %) developed PMI. Increased P-selectin expression directly after surgery was associated with the cTn concentrations over 48 h (ß = 1.39 (1.1-1.75), P = 0.0064). No association was found between P-selectin measured later after surgery (at 24 h or 48 h) and cTn concentrations. Furthermore, there was no association between the explorative coagulation parameters and cTn release. CONCLUSION: Platelet reactivity, assessed by P-selectin expression measured directly after surgery is associated with PMI, assessed by elevated cTn concentrations in the early postoperative period in patients undergoing elective open abdominal aortic surgery.

Five-year results of a randomized clinical trial comparing endovenous laser ablation with cryostripping for great saphenous varicose veins.

BACKGROUND: This was the long-term follow-up of a previously reported randomized clinical trial comparing endovenous laser ablation (EVLA) with cryostripping for great saphenous varicose veins. METHODS: A total of 120 patients with great saphenous varicose veins were randomized 1:1 to EVLA or cryostripping. Principal outcome measures were freedom from incompetence or neovascularization on duplex imaging, and improvement in Venous Clinical Severity Score (VCSS) and Aberdeen Varicose Vein Severity Score (AVVSS) 5 years after treatment. RESULTS: Life-table analysis showed freedom from duplex-derived incompetence and neovascularization at 5 years in 62 (95 per cent confidence interval 50 to 76) per cent after EVLA and in 51 (39 to 66) per cent after cryostripping (P = 0.246). Neovascularization was more common after cryostripping, but incompetent tributaries were more common after EVLA. VCSS and AVVSS values improved significantly after treatment in both groups, and were maintained for 5 years, but with no significant difference between the groups. CONCLUSION: In this study, no significant difference was demonstrated in late outcome after EVLA or cryostripping in patients with great saphenous varicose veins.

Five-year results of a randomised clinical trial of endovenous laser ablation of the great saphenous vein with and without ligation of the saphenofemoral junction.

OBJECTIVE: To evaluate whether ligation of the saphenofemoral junction (SFL) improves the results of endovenous laser ablation (EVLA) of the great saphenous vein (GSV) in a 5-year randomised clinical trial (RCT). METHODS: Forty-three symptomatic patients (86 limbs) with bilateral incompetent GSVs were randomised so that one limb underwent EVLA without SFL and the other limb underwent EVLA with SFL. Eleven patients were lost to follow-up and two patients died, leaving 30 patients (60 limbs) for analysis. Duplex-confirmed groin varicose vein recurrence and venous clinical severity score (VCSS) were investigated at 6, 12, 24 and 60 months after treatment. RESULTS: Five-year life table analysis showed freedom from groin varicose vein recurrence in 79% of limbs (95% confidence interval (CI); 67-92%) in the EVLA without SFL group and in 65% of limbs (95%; CI; 51-82) in the EVLA with SFL group (P = 0.36). Groin varicose vein recurrence was due to neo-vascularisation (0%), re-canalisation (9%) and incompetent tributaries in 14% in the EVLA without SFL group, and to neo-vascularisation (33%), re-canalisation (0%) and incompetent tributaries (0%) in the EVLA with SFL group. The VCSS improved significantly and was comparable in both groups. CONCLUSION: The rate of varicose vein recurrence was similar in both study groups. There was less neo-vascularisation in the EVLA without SFL group, but more incompetent tributaries and early re-canalisation at 5-year follow-up than in the EVLA with SFL group. REGISTRATION NUMBER: ISRCTN60300873 (http://www.clinical-trials.com).

Added value of computed tomography fractional flow reserve in the diagnosis of coronary artery disease.

Multiple non-invasive tests are performed to diagnose coronary artery disease (CAD), but all are limited to either anatomical or functional assessments. Computed tomography derived Fractional Flow Reserve (CT-FFR) based on patient-specific lumped parameter models is a new test combining both characteristics simulating invasive FFR. This study aims to evaluate the added value of CT-FFR over other non-invasive tests to diagnose CAD. Patients with clinical suspicion of angina pectoris between 2010 and 2011 were included in this cross-sectional study. All underwent stress electrocardiography (X-ECG), SPECT, CT coronary angiography (CCTA) and CT-FFR. Invasive coronary angiography (ICA) and FFR were used as reference standard. Five models mimicking the clinical workflow were fitted and the area under receiver operating characteristic (AUROC) curve was used for comparison. 44% of the patients included in the analysis had a FFR of ≤ 0.80. The basic model including pre-test-likelihood and X-ECG had an AUROC of 0.79. The SPECT-strategy had an AUROC of 0.90 (p = 0.008), CCTA-strategy of 0.88 (p < 0.001), 0.93 when adding CT-FFR (p = 0.40) compared to 0.94 when combining CCTA and SPECT. This study shows adding on-site CT-FFR based on patient-specific lumped parameter models leads to an increased AUROC compared to the basic model. It improves the diagnostic work-up beyond SPECT or CCTA and is non-inferior to the combined strategy of SPECT and CCTA in the diagnosis of hemodynamically relevant CAD.

Clinical outcome of acute leg ischaemia due to thrombosed popliteal artery aneurysm: systematic review of 895 cases.

OBJECTIVES: A systematic review was performed to summarise outcomes of acute thrombosed popliteal artery aneurysms (PAAs) treated with thrombolysis or thrombectomy followed by bypass. METHODS: A systematic review was conducted of data on acute thrombosed PAAs dated 1 January 1990 through 30 June 2008 using the Cochrane Library, MEDLINE and EMBASE databases. Primary endpoint was limb salvage; secondary endpoints were mortality and patency of the bypasses. RESULTS: Eight prospective studies and 25 retrospective studies with 895 patients presenting with acute ischaemia were included. No randomised trials were included. The mortality rate after surgical repair was 3.2% (95% confidence interval (C.I.) 1.8-4.6). The amputation rate was 14.1% (95% C.I. 11.8-16.4). Thrombolysis before surgery did not result in a significant reduction of the number of amputations, compared with surgery (thrombectomy and bypass) alone. The mean primary patency rates of the bypasses at 1, 3 and 5 years were 79%, 77% and 74%, respectively, in the 'thrombolysis' group and 71% (P=0.026), 54% (P=0.164) and 45% (P=0.249) in the 'thrombectomy' group. No distinction could be made regarding secondary patency and limb-salvage rates between the groups owing to insufficient data. CONCLUSIONS: Preoperative and intra-operative thrombolyses result in a significant improvement in 1-year primary graft patency rates, but do not result in a significant reduction for amputations compared with surgery alone.

Does combination therapy work in chronic thromboembolic pulmonary hypertension?

OBJECTIVE: The current experience with combination therapy in chronic thromboembolic pulmonary hypertension (CTEPH) is limited. We present the first survival results up to 5 years for dual combination therapy versus monotherapy in CTEPH. METHODS: All consecutive, non-operated CTEPH or residual PH after pulmonary endarterectomy patients treated with PH-specific medical therapy between January 2002 and November 2019 were included. We report and compare survival between monotherapy and (upfront or sequential) dual combination therapy until five years after medication initiation. RESULTS: In total, 183 patients (mean age 65 ± 14 years, 60% female, 66% WHO FC III/IV, 86% non-operated) were included, of which 83 patients received monotherapy and 100 patients received dual combination therapy. At baseline, patients receiving combination therapy had a higher NT-proBNP (p = 0.02) mean pulmonary artery pressure (p = 0.0001) and pulmonary vascular resistance (p = 0.02), while cardiac index was lower (p = 0.03). Total follow-up duration was 3.3 ± 1.8 years, during which 31 (17%) patients died. Estimated 1-, 3- and 5-year survival for monotherapy were 99%, 92% and 79%, respectively. For combination therapy percentages were 98%, 89% and 70%, respectively. Survival did not significantly differ between both groups (p = 0.22). CONCLUSION: Survival up to 5 years for patients treated with combination therapy, regardless of the combination strategy, was similar as patients with monotherapy, despite worse clinical and haemodynamic baseline characteristics.

Pulmonary arteriovenous malformations associated with migraine with aura.

Migraine with aura (MA) is associated with cardiac right-to-left shunt. We prospectively studied the association between pulmonary arteriovenous malformations (PAVMs) and MA in hereditary haemorrhagic telangiectasia (HHT). All 220 consecutive HHT patients who underwent high-resolution chest computed tomography for PAVM screening were included prospectively. Prior to screening, a structured validated headache questionnaire was completed by 196 patients (57% female; mean+/-sd age 44.6+/-15.2 yrs). Two neurologists diagnosed migraine according to the International Headache Society Criteria. A PAVM was present in 70 (36%) patients. The prevalence of MA was 24% in the presence of a PAVM compared with 6% in the absence of a PAVM (OR 4.6, 95% CI 1.84-11.2; p = 0.001), and MA was an independent predictor for the presence of PAVM using multivariate analysis (OR 3.6, 95% CI 1.21-10.5; p = 0.02). A PAVM was present in 68% of the patients with MA compared with 32% in the non-migraine controls (OR 4.6, 95% CI 1.84-11.2; p = 0.001), and a PAVM was an independent predictor for MA using multivariate analysis (OR 3.0, 95% CI 1.00-9.20; p = 0.05). In conclusion, PAVMs are associated with MA in HHT patients.

Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor.

BACKGROUND: In assisted reproductive technology, human chorionic gonadotrophin (hCG) is administered subcutaneously for the induction of oocyte maturation and ovulation. Our efforts to develop orally bioavailable luteinizing hormone (LH) receptor agonists have led to the discovery of Org 43553, a low molecular weight (LMW) LH receptor (LH-R) agonist. METHODS: Org 43553 was tested in vitro and in vivo in pre-clinical pharmacological models to demonstrate efficacy and oral availability. RESULTS: Org 43553 is a potent stimulator of the human LH-R in vitro (EC(50) 3.7 nM). In primary mouse Leydig cells, Org 43553 stimulated testosterone production. Pharmacokinetic analyses showed high oral bioavailability in rats (79%) and dogs (44%) with a shorter half-life compared with hCG (3.4 versus 5.6 h in the rat). Ovulation induction by Org 43553 was demonstrated in immature mice as well as in cyclic rats after single-dose oral administration (50 mg/kg). The ovulated oocytes were of good quality as demonstrated by successful fertilization and implantation of normal embryos. In male rats, testosterone production was substantially induced after oral administration. CONCLUSIONS: Org 43553 is the first LMW LH-R mimetic with demonstrated in vivo efficacy upon oral administration and could therefore replace subcutaneously administered hCG. The elimination half-life of Org 43553 is substantially shorter than hCG, which could potentially represent a clinical benefit in reducing the risk of ovarian hyperstimulation syndrome (OHSS).