The Evolution of Flow Chemistry: An Opinion on Factors Driving Innovation.

This article seeks to provide an overview of the environmental factors within the pharmaceutical industry that have contributed to the emergence of flow chemistry over the past two decades. It highlights some of the challenges facing the industry and describes how they are being overcome by the exponential trajectory of scientific progress in the area. We identify current trends and offer a speculative glimpse into the future of drug development and manufacturing with some examples of progress being made at CARBOGEN AMCIS.

[The Old-Age Heart]. / Das Herz im Alter.

The Old-Age Heart Abstract. Knowledge of cardiovascular changes in old age and their therapeutic options is important. Old age can lead to hypertrophy of the left ventricle, diastolic dysfunction, heart valve changes and pulmonary hypertension. Patients often develop arterial hypertension. Valvular changes are common in people over 100 years of age (aortic stenosis and mitral insufficiency). The risk of coronary heart disease is 35 % for men and 24 % for women. In old age, sinus node dysfunction and atrial fibrillation are common. 25 % of all strokes are cardiac embolisms in atrial fibrillation. Cardiac interventions in the elderly are increasingly frequent and include coronary catheter revascularization or valve interventions (percutaneous aortic valve replacement or MitraClip). Optimal therapy in old age includes not only cardiovascular interventions also include drugs and a lifestyle modification and mainly serves to improve the quality of life.

Procedural Results and Clinical Outcomes of Transcatheter Aortic Valve Implantation in Switzerland: An Observational Cohort Study of Sapien 3 Versus Sapien XT Transcatheter Heart Valves.

BACKGROUND: New generation transcatheter heart valves (THV) may improve clinical outcomes of transcatheter aortic valve implantation. METHODS AND RESULTS: In a nationwide, prospective, multicenter cohort study (Swiss Transcatheter Aortic Valve Implantation Registry, NCT01368250), outcomes of consecutive transfemoral transcatheter aortic valve implantation patients treated with the Sapien 3 THV (S3) versus the Sapien XT THV (XT) were investigated. An overall of 153 consecutive S3 patients were compared with 445 consecutive XT patients. Postprocedural mean transprosthetic gradient (6.5±3.0 versus 7.8±6.3 mm Hg, P=0.17) did not differ between S3 and XT patients, respectively. The rate of more than mild paravalvular regurgitation (1.3% versus 5.3%, P=0.04) and of vascular (5.3% versus 16.9%, P<0.01) complications were significantly lower in S3 patients. A higher rate of new permanent pacemaker implantations was observed in patients receiving the S3 valve (17.0% versus 11.0%, P=0.01). There were no significant differences for disabling stroke (S3 1.3% versus XT 3.1%, P=0.29) and all-cause mortality (S3 3.3% versus XT 4.5%, P=0.27). CONCLUSIONS: The use of the new generation S3 balloon-expandable THV reduced the risk of more than mild paravalvular regurgitation and vascular complications but was associated with an increased permanent pacemaker rate compared with the XT. Transcatheter aortic valve implantation using the newest generation balloon-expandable THV is associated with a low risk of stroke and favorable clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01368250.

Short-term clinical outcomes among patients undergoing transcatheter aortic valve implantation in Switzerland: the Swiss TAVI registry.

AIMS: To evaluate short-term clinical outcomes following transcatheter aortic valve implantation (TAVI) using CE-mark approved devices in Switzerland. METHODS AND RESULTS: The Swiss TAVI registry is a national, prospective, multicentre, monitored cohort study evaluating clinical outcomes in consecutive patients undergoing TAVI at cardiovascular centres in Switzerland. From February 2011 to March 2013, a total of 697 patients underwent TAVI for native aortic valve stenosis (98.1%), degenerative aortic bioprosthesis (1.6%) or severe aortic regurgitation (0.3%). Patients were elderly (82.4±6 years), 52% were females, and the majority highly symptomatic (73.1% NYHA III/IV). Patients with severe aortic stenosis (mean gradient 44.8±17 mmHg, aortic valve area 0.7±0.3 cm²) were either deemed inoperable or at high risk for conventional surgery (STS 8.2%±7). The transfemoral access was the most frequently used (79.1%), followed by transapical (18.1%), direct aortic (1.7%) and subclavian access (1.1%). At 30 days, rates of all-cause mortality, cerebrovascular events and myocardial infarction were 4.8%, 3.3% and 0.4%, respectively. The most frequently observed adverse events were access-related complications (11.8%), permanent pacemaker implantation (20.5%) and bleeding complications (16.6%). The Swiss TAVI registry is registered at ClinicalTrials.gov (NCT01368250). CONCLUSIONS: The Swiss TAVI registry is a national cohort study evaluating consecutive TAVI procedures in Switzerland. This first outcome report provides favourable short-term clinical outcomes in unselected TAVI patients.

Impact of body mass index on the one-year clinical outcome of patients undergoing multivessel revascularization with sirolimus-eluting stents (from the Arterial Revascularization Therapies Study Part II).

The differential safety and efficacy profiles of sirolimus-eluting stents when implanted in patients with multivessel coronary artery disease who have increased body mass indexes (BMIs) compared with those with normal BMIs are largely unknown. This study evaluated the impact of BMI on 1-year outcomes in patients with multivessel coronary artery disease treated with sirolimus-eluting stents as part of the Arterial Revascularization Therapies Study Part II (ARTS II). From February to November 2003, 607 patients were included at 45 centers; 176 patients had normal BMIs (<25 kg/m(2)), 289 were overweight (> or =25 and < or =30 kg/m(2)), and 142 were obese (>30 kg/m(2)). At 30 days, the cumulative incidence of the primary combined end point of death, myocardial infarction, cerebrovascular accident, and repeat revascularization (major adverse cardiac and cerebrovascular events) was 3.4% in the group with normal BMIs, 3.1% in overweight patients, and 2.8% in obese patients (p = 0.76). At 1 year, the cumulative incidence of major adverse cardiac and cerebrovascular events was 10.8%, 11.8%, and 7.0% in the normal BMI, overweight, and obese groups, respectively (p = 0.31). In conclusion, BMI had no impact on 1-year clinical outcomes in patients with multivessel coronary artery disease treated with sirolimus-eluting stents in ARTS II.

Distal embolic protection during percutaneous coronary intervention in patients with acute coronary syndromes: the RUBY study.

OBJECTIVE: To assess the safety and feasibility of the GuardWire system as an embolic protection device during percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS). BACKGROUND: Distal embolization occurs in approximately 15% of patients after primary angioplasty and is associated with reduced myocardial reperfusion, more extensive myocardial damage and a poor prognosis. Distal embolic protection could reduce the rate of embolic complications and improve outcome. METHODS: 329 patients (mean age 60+/-12 years) were included: 278 (84.5%) with ST-elevation myocardial infarction (STEMI), 50 (15.2%) with unstable angina/non-STEMI and 1 (0.3%) with post-infarction angina. Primary endpoint was the incidence of major adverse cardiac events (MACE) at 30 days. Secondary endpoints were the magnitude of ST-segment resolution at 90 and 180 min post-procedure, myocardial blush grade, and angiographically visible distal emboli. RESULTS: The GuardWire system was successfully positioned in 99% of patients. Complete ST-elevation resolution (>70%) was observed in 28.5% immediately post-procedure, and in 35.4% and 41.6% at 90 and 180 min post-procedure. TIMI-3 flow grade was achieved by 89.8% of patients after intervention and mean corrected TIMI frame count was 20.2+/-13.2. Grade-3 myocardial blush was seen in 47.7% of patients and distal emboli were angiographically visible in 7.4%. Incidence of MACE at 30 days was 3.3% (death 1.2%; Q-wave MI 0.3%; non-Q-wave MI 0.3%; coronary artery bypass graft 0.6%; repeat PCI 0.9%). CONCLUSION: The GuardWire system was successfully positioned in nearly all patients without complications. The use of this embolic protection device in ACS patients undergoing PCI was associated with low rates of distal embolization and 30-day MACE.

Comparison of costs and safety of a suture-mediated closure device with conventional manual compression after coronary artery interventions.

The aim of this study was to assess costs and safety of immediate femoral sheath removal and closure with a suture-mediated closure device (Perclose, Menlo Park, CA) in patients undergoing elective (PCI). A total of 193 patients was prospectively randomized to immediate arterial sheath removal and access site closure with a suture-mediated closure device (SMC; n = 96) or sheath removal 4 hr after PCI followed by manual compression (MC; n = 97). In the SMC group, patients were ambulated 4 hr after elective PCI if hemostasis was achieved. In the MC group, patients were ambulated the day after the procedure. In addition to safety, total direct costs including physician and nursing time, infrastructure, and the device were assessed in both groups. Total direct costs were significantly (all P < 0.001) lower in the SMC group. Successful hemostasis without major complication was achieved in all patients. The time to achieve hemostasis was significantly shorter in the SMC group (7.1 +/- 3.4 vs. 22.9 +/- 14.0 min; P < 0.01) and 85% of SMC patients were ambulated on the day of intervention. Suture-mediated closure allows a reduction in hospitalization time, leading to significant cost savings due to decreased personnel and infrastructural demands. In addition, the use of SMC is safe and convenient to the patients.

High density-lipoprotein subfractions of patients using cardio-selective beta-blockers.

Treatment of hypertension with beta-adrenergic blockers (BB) slightly increases plasma triglycerides and decreases high density lipoprotein (HDL) cholesterol levels. However, only little is known about BB-related lipid changes in patients with coronary artery disease (CAD), who usually a priori have decreased HDL cholesterol levels; and even less data exist on HDL subfraction cholesterol in these patients. We therefore quantified levels of lipids, lipoprotein lipids including HDL2 and HDL3 cholesterol, and apolipoproteins in 107 consecutive men undergoing elective coronary angiography. Of the 107 patients, 84 had angiographically established coronary atherosclerosis (>or=1 lesion with >or=50% narrowing, CAD+), and 23 had no major lesion (CAD-); 67 were taking ss1-selective BB (metoprolol or atenolol) for treatment of angina and/or hypertension and 40 were not. Patients using BB had significantly higher cholesterol levels than patients not using BB (5.99 +/- 0.93 vs. 5.63 +/- 1.07 mmol/l, mean +/- SD, p = 0.029). Their HDL cholesterol and HDL2 cholesterol levels were significantly lower (1.19 +/- 0.27 vs. 1.28 +/- 0.33 mmol/l, p = 0.048, and 0.22 +/- 0.12 vs. 0.27 +/- 0.18 mmol/l, p = 0.038, respectively). Accordingly, the total cholesterol/HDL cholesterol ratio was significantly higher in patients taking BB than in those not taking BB (5.23 +/- 1.27 vs. 4.68 +/- 1.63, p = 0.010). Considering CAD+ and CAD- patients separately, there was a trend towards lower HDL cholesterol and its subfractions with significantly lower HDL2 cholesterol in patients with BB in the CAD- group, suggesting a stronger dyslipidemic effect of BB in these patients with a priori normal or near normal baseline lipid levels.

Percutaneous transluminal therapeutic ultrasound for high-risk thrombus-containing lesions in native coronary arteries.

We assessed the short-term outcome of percutaneous coronary ultrasound thrombolysis (CUT) for high-risk thrombus-containing lesions in native coronaries in the setting of acute coronary syndromes (ACS). Data were prospectively collected in a multicenter (n = 32) registry of consecutive ACS patients. The study population (n = 126) had mostly (84%) totally occluded vessels. The mean age of clot was 5.7 +/- 9.5 days (range, 0-60 days). CUT (41 kHz, 18 W) led to device success in 112 (89%) patients, with a residual stenosis of 69% +/- 20%. Adjunct PTCA or stenting was used in 97% of the patients. Procedural success was achieved in 124 (98%) patients, with a final residual stenosis of 6% +/- 10%. There were no major adverse clinical events during hospitalization. Ultrasound thrombolysis is a feasible procedure that offers a safe and probably effective adjuvant device solution for the treatment of high-risk, thrombus-containing lesions in the native coronary arteries.

Clinical and quantitative angiographic outcomes following elective implantation of the self-expanding Wallstent for longer coronary artery lesions--final results of the Wellstent native study.

BACKGROUND: Implantation of short balloon-expandable stents provides superior clinical and angiographic outcome compared with balloon angioplasty in selected patients. The purpose of the Wellstent study was to evaluate the safety and efficacy of the self-expanding Wallstent combined with aspirin and ticlopidine in patients with stable or unstable angina related to a native coronary lesion up to 45 mm in length. METHODS: 105 patients (111 lesions) with stable (57%) or unstable (43%) angina were included in this prospective multicentre evaluation. Angiography before and after Wallstent implantation and at 6-month follow-up was analysed at the core lab using the CAAS 2 system. The primary end-point was incidence of major adverse cardiac events (MACE) at 30 days. Secondary end-points were angiographic outcome at 6 months and MACE at 6 months and 1 year. RESULTS: Acute procedural success (successful stent implantation with residual stenosis <20%) was achieved in 99%. Mean reference diameter was 3.18 +/- 0.66 mm, minimal luminal diameter was 1.00 +/- 0.50 mm pre- and 2.84 +/- 0.47 mm poststent (diameter stenosis 16 +/- 6%). The mean hospital stay was 2.2 days. At 30 days, 95% of patients were free of MACE. At 6 month and 1 year clinical follow-up, 75% and 71% of patients, respectively, remained free of MACE, the majority of which (19 of 30) were re-interventions at re-angiography. In 90% of eligible patients, MLD at follow-up was 1.65 +/- 0.75 mm (late loss 1.20 +/- 0.66 mm, loss index 0.66), diameter stenosis 42 +/- 15%, with a restenosis rate of 32%. Longer stents were associated with greater luminal loss (P = 0.001) and less-favourable clinical outcome. CONCLUSIONS: Wallstent implantation, combined with aspirin and ticlopidine, achieved excellent acute and 30 day clinical results in a heterogenous high-risk patient group. Clinical outcome at 6 months and 1 year remained good, and most adverse events were re-PTCA during follow-up angiography. The loss index of 0.66 and restenosis rate of 32%, related in part to the use of longer stents, emphasizes the continuing need for effective anti-proliferative therapy.