Double Combination Therapy Research Articles

Patient Characteristics and Treatment Patterns with Macitentan in Pulmonary Arterial Hypertension: Insights from the OPUS Registry

Purpose To describe the real-world use and safety profile of macitentan in patients with pulmonary arterial hypertension (PAH) enrolled in the OPsumit® USers registry (OPUS; NCT02126943). Methods OPUS is an ongoing long-term, prospective, multicenter, observational drug registry of patients newly treated with macitentan in the USA. Patient characteristics, treatment patterns, safety of macitentan and survival were analyzed for PAH patients. Results As of April 2018, OPUS included 1455 PAH patients with follow-up data. At enrollment, median (range) age was 62 (13-92) years and 75.2% were female. The median (Q1, Q3) time from PAH diagnosis was 6.2 (1.5, 37.0) months. WHO functional class (FC) was assessed in 1062 patients, 39.3% were in FC I/II and 60.7% in FC III/IV; median (Q1, Q3) 6-minute walk distance, assessed in 620 patients, was 305 (206, 383) meters. Use of macitentan in double or triple combination therapy regimens is shown in the Table. Median (Q1, Q3) exposure to macitentan was 11.6 (3.9, 22.2) months and macitentan was discontinued by 28.7% of patients, with adverse events (AEs) as the most common reason. At least 1 AE was experienced by 1076 (74.0%) patients; the most common were dyspnea (18.2%), headache (9.5%) and peripheral edema (8.8%). In total, 485 (33.3%) patients experienced ≥1 hospitalization. The Kaplan-Meier survival estimates (95% CI) were 91% (90, 93) at 12 months and 84% (82, 87) at 24 months. Conclusion OPUS represents the largest cohort of patients newly treated with macitentan, providing insight into macitentan use in the real-world. These analyses show that macitentan is most commonly initiated as monotherapy or in combination with a phosphodiesterase type 5 inhibitor in PAH. The safety profile of macitentan in OPUS is consistent with that observed in clinical trials.

Risk stratification and medical therapy of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) remains a severe clinical condition despite the availability over the past 15 years of multiple drugs interfering with the endothelin, nitric oxide and prostacyclin pathways. The recent progress observed in medical therapy of PAH is not, therefore, related to the discovery of new pathways, but to the development of new strategies for combination therapy and on escalation of treatments based on systematic assessment of clinical response. The current treatment strategy is based on the severity of the newly diagnosed PAH patient as assessed by a multiparametric risk stratification approach. Clinical, exercise, right ventricular function and haemodynamic parameters are combined to define a low-, intermediate- or high-risk status according to the expected 1-year mortality. The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy. Further treatment escalation is required in case low-risk status is not achieved in planned follow-up assessments. Lung transplantation may be required in most advanced cases on maximal medical therapy.

MACITENTAN IN PORTOPULMONARY HYPERTENSION: REAL-WORLD EVIDENCE FROM THE OPSUMIT USERS REGISTRY

MACITENTAN IN PORTOPULMONARY HYPERTENSION: REAL-WORLD EVIDENCE FROM THE OPSUMIT USERS REGISTRY

Long-term survival in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Insights from a referral center in Portugal

ObjectivesThis study aims to assess the long-term survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients followed in a Portuguese pulmonary hypertension (PH) referral center. MethodsWe studied PAH and CTEPH patients diagnosed between January 2005 and December 2016. Cumulative survival was estimated using the Kaplan-Meier method. Survival trends were compared over two periods (2005-2010 vs. 2011-2016). ResultsOf the 142 studied PH patients (age 54±18 years; 31% male), 47 had CTEPH and 95 had group 1 PH. Most patients with CTEPH and idiopathic/heritable PAH (I/HPAH) were in NYHA III-IV at diagnosis (64% and 57%, respectively). At the time of death, 31% of patients with connective tissue disease (CTD)-associated PAH (CTD-PAH) and all I/HPAH patients were on double or triple combination therapy. No patient underwent lung transplantation. Pulmonary endarterectomy or angioplasty were performed in 36% of CTEPH patients. Age at diagnosis tended to increase over time in CTD-PAH (53±15 vs. 63±15 years; p=0.13) and I/HPAH (39±15 vs. 51±19 years; p=0.10). The five-year survival estimates for I/HPAH, CTD-PAH and CTEPH patients were 80%, 52%, and 81%, respectively. Over time, CTD-PAH and CTEPH showed better five-year survival (33 vs. 67% and 77 vs. 84%), but I/HPAH did not (84 vs. 75%). ConclusionsOur data indicate a trend toward improved survival over time of CTD-PAH and CTEPH patients treated at a Portuguese referral PH center. Earlier diagnosis, increasing use of parenteral prostanoids, and surgical treatment may further improve PH prognosis.

Abstract 4704: Triple combination of IMO-2125, epacadostat and anti-PD-1 antibody demonstrates maximal antitumor efficacy and eradicates large established tumors in preclinical models

Abstract Immune checkpoint blockade has revolutionized cancer therapy; however, the majority of patients fails to demonstrate a durable response. This suboptimal outcome is due to multiple mechanisms that range from low immunogenicity to inadequate generation or activation of tumor-specific T cells. Combination therapies targeting multiple checkpoints are likely to overcome the inadequate antitumor immune responses by a single agent. Intratumoral injection of IMO-2125, a TLR 9 agonist, activates dendritic cells to present tumor specific antigens and enhances T-lymphocyte infiltration within injected tumors. These activities lead to the priming and trafficking of tumor-specific cytotoxic T-cells against metastatic tumors. Intratumoral IMO-2125 is a personalized cancer therapy that enhances antitumor activity by synergizing with checkpoint blockade to elicit a productive immune response in cancer patients. In the present study, we evaluated a combination immunotherapy regimen that involves an immune activator, IMO-2125, and checkpoint inhibitors targeting two negative immune regulators, IDO-1 and PD-1, to eliminate large tumors in syngeneic tumor models. BALB/c mice were implanted with CT26.CL25 tumors in the right and left flanks. Treatment was initiated on Day 10 after tumor implantation when tumors were fully established (311 ± 89 mm3). IMO-2125 (2.5 mg/kg) was intratumorally (i.t) injected in the right flank tumor 2x/week for 2 weeks. Epacadostat (EPA, Incyte IDO-1 inhibitor, 100 mg/kg) was administered by intragastric administration 5x/week for 2 weeks. Anti-PD-1 mAb (clone RMP1-14, 10 mg/kg) was administered by intraperitoneal injection 3x/week for 2 weeks. Treatment with IMO-2125 i.t alone resulted in 73% and 59% growth reductions in the treated tumors and untreated distant tumors, respectively. EPA and anti-PD-1 monotherapy or the double combination therapy did not demonstrate significant antitumor activity. The addition of IMO-2125 to either EPA or anti-PD-1 led to 84% and 81% tumor reductions in the i.t. treated tumors, and 71% and 69% reductions in the untreated distant tumors, respectively. Triple combination therapy with IMO-2125, EPA and anti-PD-1 exhibited maximal antitumor activity, with 98% and 88% tumor growth reductions in the treated and distant tumors, respectively. All treatments were well tolerated. Similar antitumor activities were also observed in a murine peritoneal model with NSCLC 3LL-C75. Combination of IMO-2125 with checkpoint inhibitors targeting IDO-1 and PD-1 induces maximal antitumor efficacy and eradicates large established tumors in preclinical models. A Phase 2 clinical trial of IMO-2125 in combination with ipilimumab in patients with metastatic melanoma is ongoing (NCT02644967) and a Phase 3 multi-center, global trial in the same population is initiating enrollment. Citation Format: Evren Kocabas Argon, Fugang Zhu, Sudhir Agrawal, Jonathan Yingling, Daqing Wang. Triple combination of IMO-2125, epacadostat and anti-PD-1 antibody demonstrates maximal antitumor efficacy and eradicates large established tumors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4704.

PCV2 - Characterizing Patients Treated With Macitentan For Pulmonary Arterial Hypertension (PAH) In The U.S. Opsumit Users Registry (OPUS)

Health plans look beyond randomized controlled trials (RCTs) in making formulary decisions. There are three approved endothelin receptor antagonists, but no head-to-head trials. Real world evidence (RWE) informs the application of RCT results to healthcare decision making by assessing care and patient outcomes in routine clinical practice. RWE is derived from registries, medical records, pragmatic trials, and claims databases. OPUS registry (NCT02126943) is a US-based, multi-center, longitudinal, observational drug registry of newly treated macitentan patients. The objective of this analysis is to describe clinical characteristics, co-morbidities, and treatment of PAH patients with macitentan. Patients newly treated with macitentan (initiated < 30 days prior to enrollment visit) were included in the registry, regardless of prior or concomitant PAH therapy. Planned observation period was at least one year. Data collected at enrollment or follow-up included: demographics, clinical characteristics, outcomes, adverse events, macitentan treatment and registry discontinuation. As of June 2017, 1136 patients with PAH had follow-up data--74.2% females and 25.8% males. Of this cohort, 44.5% of patients were > 65 years of age; 57.9% patients had idiopathic PAH, and 24.9%, PAH associated with connective tissue disease. Common baseline comorbidities included: hypertension (52.6%), edema (24.5%), signs of right heart failure (15.8%), and diabetes mellitus (22.5%). Median exposure to macitentan was 9.6 months. Macitentan was initiated as monotherapy in 41.7%, and double or triple combination therapy in 58.2% of patients. Most common adverse events were dyspnea (18.0%) and peripheral edema (8.9%). 12.4% of patients experienced ≥1 PAH-related hospitalization. OPUS reports macitentan use and safety in real world clinical settings. Reported comorbidities are consistent with other large registries and claims analyses. Macitentan is initiated most commonly as double or triple combination therapy. PAH related hospitalizations were lower than previously reported in both claims analysis and registries.

A COMPARATIVE EVALUATION OF THE EFFICACY OF TRIPLE DRUG THERAPY WITH DUAL DRUG THERAPY IN COPD PATIENTS

Objective: The present study was conducted with the objective of analyzing the efficacy of triple-drug combination therapy (formoterol, ciclesonide, tiotropium) by comparing it with double drug combination therapy (formoterol, budesonide).Methods: A prospective observational study was conducted. Sixty patients were enrolled, and divided into two groups of thirty each; one group was treated with the double-drug and the other with a triple drug combination. FEV1 and FVC pre-and post-treatment in either group were assessed spirometrically. Score ranges of 0-10, 11-20 and 21-30 were allotted to mild, moderate and severe categories and results were analyzed statistically.Results: Of the 60 patients recruited, 61-70 y olds constituted the majority (35%) of the population. Males (63.3%) were more in number compared to females (36.6%). Twenty-three of thirty-eight men smoked (60.5%); there were no female smokers. Common symptoms included cough (93.3%), dyspnoea (85%), fever (45%) and haemoptysis (15%). Hypertension accounted for 70% of patient comorbidities, followed by diabetes (60%) and cardiovascular diseases (40%). Three months after treatment with triple therapy, a significant increase in the differences of means of both FEV1 (14.27) and FVC (14.90) values was observed. Further analysis based on score ranges demonstrated that triple therapy administration markedly reduced the number of patients suffering from severe COPD.Conclusion: Our comparative analysis indicated that triple therapy was more effective in improving lung function, enhancing patients’ quality of life (evidenced from score ranges) thereby reducing mortality. While much is known about the greater effectiveness of triple over dual therapy, researchers to formulate the most effective triple therapy are in progress.

Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines.

The use of heat shock protein 90 inhibitors like 17-allylamino-17-demethoxy-geldanamycin (17-AAG) has been recently introduced as an attractive anticancer therapy. It has been shown that 17-AAG may potentiate the inhibitory effects of some classical anticolorectal cancer (CRC) agents. In this study, two panels of colorectal carcinoma cell lines were used to evaluate the effects of 17-AAG in combination with capecitabine and oxaliplatin as double and triple combination therapies on the proliferation of CRC cell lines. HT-29 and all HCT-116 cell lines were seeded in culture media in the presence of different doses of the mentioned drugs in single, double, and triple combinations. Water-soluble tetrazolium-1 (WST-1) assay was used to investigate cell proliferation 24 h after treatments. Then, dose-response curves were plotted using WST-1outputs, and IC50 values were determined. For double and triple combinations respectively 0.5 × IC50 and 0.25 × IC50 were used. Data was analyzed with the software CompuSyn. Drug interactions were analyzed using Chou-Talalay method to calculate the combination index (CI).The data revealed that 17-AAG shows a potent synergistic interaction (CI < 1) with oxaliplatin and capecitabine in double combinations (0.5 × IC50) in both cell lines. In the case of triple combinations, the findings showed an antagonistic interaction (CI > 1) in HT-29 and a synergistic effect (CI < 1) in HCT-116 (0.25 × IC50) cell lines. It was concluded that double combinations of 17-AAG with oxaliplatin or capecitabine might be effective against HCT-116 and HT-29 cell lines. However, in triple combinations, positive results were seen only against HCT-116. Further investigation is suggested to confirm the effectiveness of these combinations in clinical trials.

Comparative assessment of the pattern of anti-hypertensive drugs prescribed in medicine and cardiology outpatient department

Background: Hypertension or high blood pressure is one of the strongest modifiable risk factors for cardiovascular and renal diseases and is a condition that afflicts almost 1 billion people worldwide. The objective of the present study was to compare the prescribing pattern of antihypertensive drugs in patient attending medicine and cardiology OPD. Methods: It was an observational, cross sectional study conducted in the department of pharmacology in collaboration with the medicine and the cardiology department. Results: The present study which was conducted for a period of 6 months in the medicine and cardiology OPD showed unequal distribution of the patients in the medicine and cardiology OPD, with 223 patients attended medicine OPD while 434 patients attended cardiology OPD. Amongst the patients attending medicine OPD, majority of the patients (61.88%) were stage I hypertensive (>140/90 mmHg) according to JNC VII classification whereas majority (69.38%) of those attending cardiology OPD were stage II hypertensive (>160/100). Calcium channel blockers (CCB) were the most commonly prescribed drug in medicine OPD followed by angiotensin converting enzyme inhibitors (ACE I) whereas beta blockers (BB) were most commonly prescribed in cardiology OPD followed by ACE I. Conclusions: The study concludes that there is a wide variation in the prescription of the anti-hypertensive drugs among medicine and cardiology OPD. CCBs were most commonly used in medicine OPD whereas beta blockers were preferred in cardiology OPD. Monotherapy was preferred in medicine OPD, whereas combination therapy was preferred by cardiologist. Double and triple drug combination therapies were used more in comparison to monotherapy.

Abstract 4548: Simultaneous hyperthermic-chemotherapy for glioblastoma using a single anti-cancer compound with intrinsic magnetism

Abstract Background: Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor in humans. In spite of advances in treatment strategies, survival rate of GBM remains poor. We have recently reported a novel anti-cancer compound with intrinsic magnetism(EI236). In addition to its anti-cancer effect, EI236 generates a large amount of heat upon an alternating magnetic field (AMF) application because of its magnetism, i.e., hyperthermic effect. In this study, we have examined the effect of EI236 on human GBM in vitroand vivo. Materials and Methods: Human GBM cell lines, U251MG, YKG-1, and U87, were used in this study. Cell proliferation was assessed by methyl thiazolyl tetrazorium (MTT) assays in the presence of EI236, in comparison to temozolomide (TMZ) and calmustine (BCNU), i.e. the clinical standard drugs for GBM. Apoptosis was analyzed by fluorescence activated cells sorting. In addition, we have examined whether EI236 inhibited the tumor growth with/without AMF application in animal models. Tumors were induced by implantation of U251MG cells into the hip of female Balb-c mice. Seven days after the implantation of GBM cells, EI236, BCNU or normal saline (control) was injected respectively into the tumors and mice were exposed to an AMF application(330.8A, 280kHz) for 30 minutes. Therefore, we calculated the tumor volume and the regression rate of tumors twice a week. Result: EI236 inhibited the proliferation of all cell lines and increased apoptosis in a dose dependent manner. Moreover, we found that EI236 had much greater anti-cancer effect than the clinical standard drugs. Mice bearing GBM cancer cells in their hip were then subjected to a double combination therapy, consisting of local injection of EI236 and hyperthermic treatment by AMF application. Tumor sizes in both drug stimulation groups were reduced, especially that in EI236 with AMF application group was highly reduced, while that in control group was increased. Conclusion: EI236 has greater anti-cancer effect than TMZ and BCNU, i.e. the clinical standard drugs. Besides this strong anti-cancer effect, EI236 has hyperthermic effect upon an AMF application because of heat generation. Accordingly, EI236 may enable us to develop novel strategies in GBM treatment, i.e. hyperthermic-chemotherapy with a single-drug compound. Note: This abstract was not presented at the meeting. Citation Format: Makoto Ohtake, Masanari Umemura, Itaru Sato, Kayoko Oda, Akane Nagasako, Ayako Makino, Haruki Aoyama, Mayumi Katsumata, Haruki Eguchi, Nobutaka Kawahara, Yoshihiro Ishikawa. Simultaneous hyperthermic-chemotherapy for glioblastoma using a single anti-cancer compound with intrinsic magnetism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4548. doi:10.1158/1538-7445.AM2015-4548

Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: real-world insights.

Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option.This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting.Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3-4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003).The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting.

Double or triple antithrombotic combination therapy in patients who need anticoagulation and antiplatelet therapy in parallel.

The optimal strategy to balance bleeding and ischaemic events in patients with atrial fibrillation, requiring antiplatelet therapy on top of anticoagulation, is subject to debate, since specifically designed and powered randomized trials are not available yet. The review aims to highlight the current developments in the light of the 2014 joint consensus document of the European Society of Cardiology (ESC) Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS) and of the 2014 ESC myocardial revascularization guidelines, both published recently.

Triple immunosuppressive therapy in steroid-resistant nephrotic syndrome children with tacrolimus resistance or tacrolimus sensitivity but frequently relapsing.

The treatment strategy for steroid-resistant nephrotic syndrome remains uncertain at present, especially in those with calcineurin inhibitor resistance or intolerance. To date, few studies have been published using multiple combination therapy of immunosuppressive reagents for children with calcineurin inhibitor-resistant or -intolerant nephrotic syndrome. Eighteen consecutive children with steroid- and tacrolimus (TAC)-resistant (n = 10) or TAC-sensitive but frequent relapsing nephrotic syndrome (n = 8) were randomly recruited in the present study. All of them received further triple-combination therapy by cyclophosphamide (CTX, n = 6), mycophenolate mofetil (MMF, n = 5) or leflunomide (LEF, n = 7). Their clinical data were collected and efficacy of triple-combination therapy was evaluated. Compared with previous double-combination therapy of prednisone (Pre) and TAC, the short-term remission rate in all 18 patients was significantly improved after the triple-combination therapy, while the frequent relapse rate in the following 12 months was also significantly decreased. Among three different subgroups with CTX, MMF or LEF therapy, no significant difference was found in short-term remission rate and the relapse rate within 1 year follow up by Kaplan-Meier plot. Triple-combination therapy with Pre + TAC + CTX/MMF/LEF is effective for short-term response and 1 year remission, without significant additional side-effects seen in children with steroid-resistant and tacrolimus-resistant or tacrolimus-sensitive but frequently relapsing nephrotic syndrome. Further study for evaluating long-term efficacy and safety of triple-combination therapy with Pre + TAC + CTX/MMF/LEF would be necessary for these patients.

A Galleria mellonella infection model reveals double and triple antibiotic combination therapies with enhanced efficacy versus a multidrug-resistant strain of Pseudomonas aeruginosa

The aim of this study was to compare the inhibitory effect of antibiotic combinations in vitro with efficacy in Galleria mellonella larvae in vivo to identify efficacious combinations that target Pseudomonas aeruginosa. P. aeruginosa NCTC 13437, a multidrug-resistant strain resistant to β-lactams and aminoglycosides, was used. Susceptibility to cefotaxime, piperacillin, meropenem, amikacin, levofloxacin and colistin alone, or in dual or triple combinations, was measured in vitro via a 24 h time-kill assay. In vitro results were then compared with the efficacy of the same dual or triple antibiotic combinations versus G. mellonella larvae infected with P. aeruginosa. G. mellonella haemolymph burden of P. aeruginosa was determined over 96 h post-infection and treatment with the most potent combination therapies. Many dual and triple combinations of antibiotics displayed synergistic inhibition of multidrug-resistant P. aeruginosa in vitro. There was little correlation between combinations that were synergistic in vitro and those that showed enhanced efficacy in vivo versus infected G. mellonella larvae. The most potent dual and triple combinations in vivo were cefotaxime plus piperacillin, and meropenem plus piperacillin and amikacin, respectively. Fewer combinations were found to offer enhanced therapeutic benefit in vivo compared with in vitro. The therapeutic benefit arising from treatment with antibiotic combinations in vivo correlated with reduced larval burden of P. aeruginosa. This study has identified antibiotic combinations that merit further investigation for their clinical potential and has demonstrated the utility of using G. mellonella to screen for novel antibiotic treatments that demonstrate efficacy in vivo.

Prognosis of Pulmonary Arterial Hypertension

The study of rare diseases is limited by just that, their infrequency. Pulmonary arterial hypertension (PAH), for example, has a prevalence of 15 cases per million.1 Although there has been an explosion in knowledge of and therapies for this life-threatening disease over the past decade, most of our insight is based on small studies. The first therapy that was approved by the Food and Drug Administration in 1995, intravenous epoprostenol, was based on the results of an 81-patient trial.2 The most recently approved therapy, inhaled treprostinil, in 2009, was based on the results of a 235-patient trial.3 Similarly, our understanding of the natural history of this disease is based on small observational series. Articles see pp 156 and 164 To further our comprehension of rare diseases, we often turn to “registries,” constructed as multicenter cohorts of patients who have the disease with longitudinal follow-up. Despite the inherent limitations of their observational and uncontrolled nature, which also represent strengths, these cohorts are useful to describe and compare patient characteristics, practice patterns, and outcomes. Observations from such registries can generate hypotheses that subsequently form the basis of further studies. Lastly, such cohorts facilitate the study of the prognostic profile of the disease via the derivation and validation of clinical prediction tools. In this issue of Circulation , data from the 2 of the most important present-day registries in PAH give us the opportunity to better understand the prognosis of PAH, its determinants, and outcomes in the current treatment era. Humbert and colleagues4 share data from the French National Registry, in which 354 consecutive idiopathic, heritable, and anorexigen-associated patients with PAH were enrolled from October 2002 to October 2003. They report 1-, 2-, and 3-year survival rates of 82.9%, 67.1%, and 58.2%, respectively. Sadly, despite the many advances in …

BLOOD PRESSURE CONTROL OF FIXED DOSE, PERINDOPRIL/AMLODIPINE COMBINATION TREATMENT IN HYPERTENSIVE PATIENTS UNCONTROLLED ON MONOTHERAPY OR ON TWO DRUG COMBINATION THERAPY: PP.5.167

Objective: The objective of this study is to assess the antihypertensive efficacy and tolerability of a FDC of an angiotensin converting enzyme inhibitor (perindopril), and a calcium channel blocker (amlodipine). Methods: Physicians recruited 855 patients uncontrolled (SBP>140 and / or DBP>90 mmHg) on monotherapy, or on a double combination. Patients were switched to 1 FDC tablet a day of Perindopril 4mg+Amlodipine 5 mg, along with concomitant non-antihypertensive medications for 60 days. The primary outcomes were blood pressure control (SBP<140 and DBP<90 in non diabetic, and <130 and <80 mmHg in diabetic patients) on an intention to treat basis. Results: In the 855 patients recruited, 688 (80.5%) had their BP controlled at day 60. Among the 654 patients uncontrolled on monotherapy, the mean BP declined from 165.4 ± 15.4 / 100.0 ± 8.8 mm Hg to 132.5 ± 9.5 / 82.7 ± 6.0 mm Hg (p < 0.001) at 60 days and BP control was achieved in 82.1% (537) of this population. The subpopulation of patients inadequately managed on double combination (201 patients) have their BP reduced from 167.0 ± 16.5 / 99.2 ± 7.8 mm Hg to 135.3 ± 11.4 / 83.0 ± 5.5 mm Hg, to achieve a BP control rate of 75.6% (152). Antihypertensive efficacy was observed across patient subgroups regardless of the previous antihypertensive treatment, as shown in the table. The number (%) of patients discontinuing treatment, was, due to cough, 3 (0.4%); pedal edema, 2 (0.2%); lack of efficacy, 2 (0.2%); and lost to follow up, 37 (4.3%). Conclusions: The findings from this observational study confirm that the FDC of Perindopril/Amlodipine given as a single daily dose is an effective and well tolerated treatment for patients uncontrolled on monotherapy or inadequately managed on double combination therapy.

New Strategies and Drugs in the Treatment of Hypertension: Monotherapy or Combination?

Hypertension is one of the major risk factors associated with cardiovascular diseases. A range of blood pressure-lowering agents is available including diuretics, alpha- and beta-blockers, aldosterone antagonists, calcium-channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and direct renin inhibitors (DRI). Most patients require two or more medications to control their blood pressures within normal ranges. When high blood pressure cannot be controlled by low-dose monotherapy, physicians employ either high-dose monotherapy or combination therapy. High-dose ARB monotherapy is more effective for reducing proteinuria against low-dose ARB monotherapy or CCBs. Combination therapy is recommended for hypertension patients to facilitate prompt maintenance of blood pressure. Single-pill combination therapy simplifies treatment and optimizes long-term compliance. Thiazide diuretics such as hydrochlorothiazide (HCTZ), alone or in combination are still widely used as first-line hypertension treatment. Recent studies have shown that double (CCB+ARBs) or triple (CCB+ARBs+HCTZ) combination therapies have a greater lowering efficacy and are better tolerated. Moreover, the use of DRIs has been patented and proven effective in selected categories of hypertensive patients with or without concomitant target organ damage (TOD).

Combination Therapy for Wet Age-related Macular Degeneration

Increasing appreciation of the complexity of the wet type of age-related macular degeneration (AMD) has made combination therapy an area of current intense interest. Administered in dual or triple combinations, the current therapeutic mainstays ߝ corticosteroids, verteporfin photodynamic therapy (V-PDT) and inhibitors of vascular endothelial growth factor (VEGF) ߝ have more potential to successfully treat the various pathogenetic factors contributing to wet AMD than any single-therapy approach. The different mechanisms of action involved in combination therapy are intended to reduce inflammation, eradicate current and future choroidal neovascularisation and lessen VEGF expression. Evidence from clinical trials demonstrates visual acuity benefits, lower re-treatment rates and longer treatment-free intervals with combination therapies compared with monotherapies. This article summarises the rationale and the clinical evidence that support the use of double and triple combination therapy in wet AMD.

Combination therapy in the management of mixed dyslipidaemia

Whilst statin monotherapy is often sufficient to reach LDL-C goals, treatment may not reach all lipid goals in individuals with mixed dyslipidaemia typically associated with metabolic syndrome or type 2 diabetes. Double or triple combination therapy, which provides the opportunity to address multiple lipid abnormalities simultaneously, may be required to achieve targets in some patients. Addition of fenofibrate or niacin (nicotinic acid) to statin therapy is likely to be the first option, as recommended by national treatment guidelines; omega-3 fatty acids may also be useful. Careful monitoring is required when adding additional agents given the increased potential for drug interactions and side effects.

C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy

Purpose C225 anti-EGFR (epidermal growth factor receptor) antibody has been shown to enhance tumor response to radiation and a number of chemotherapeutic agents. Because of increased use of concurrent chemoradiotherapy in cancer treatment, it is important to determine whether C225 enhances also the antitumor efficacy of radiation when combined with chemotherapy. This study assessed the effect of C225 on tumor response when combined with docetaxel plus single or fractionated radiation. Methods and materials MDA468 human adenocarcinoma and A431 human epidermoid carcinoma cells growing as xenografts in the right hind leg of nude mice were used. Mice bearing 8-mm tumors were treated with C225 antibody at a dose of 1 mg given i.p. once, twice, or three times 3 days apart, 10 or 30 mg/kg docetaxel given i.v., and/or local tumor irradiation of 8 or 10 Gy single dose or fractionated irradiation consisting of 2 Gy daily for 5 days. When all three agents were combined, C225 was given 6 h before or 18 h after docetaxel, and radiation was given 24 h after docetaxel. The treatment end point was tumor growth delay. Results C225 enhanced the antitumor efficacy of docetaxel, local tumor irradiation, and docetaxel combined with radiation. The response of both MDA468 and A431 carcinomas was enhanced. The enhancement factors ranged from 1.19 to 8.52, the degree of the enhancement depending on experimental conditions such as administration of multiple vs. single dose C225 or single or fractionated irradiation. C225 given twice or 3 times was more effective than when administered as a single dose. The effect of C225 was more pronounced when combined with single than fractionated irradiation with or without docetaxel. The triple-agent therapy was more effective than a single agent or double combination therapies, expressed by both increased tumor growth delay and the rate of tumor cure. Conclusions Our results show that C225 anti-EGFR antibody is a potent enhancer of tumor response to docetaxel or radiation as single agents, and to docetaxel when combined with radiation. Thus, these findings provide strong preclinical evidence in support of combination of anti-EGFR blockade with chemoradiotherapy.