Long term follow-up of the tacrolimus in combination, tacrolimus alone compared (TICTAC) trial.

BACKGROUND: Tacrolimus (TAC) monotherapy has been compared to TAC and mycophenolate mofetil (MMF) in the randomized Tacrolimus in Combination, Tacrolimus Alone Compared (TICTAC) trial. Long term results are now reported. METHODS: Demographics are presented with descriptive statistics. Time to event was determined with Kaplan-Meier plots and Mantel-Cox Logrank statistics used to compare groups. RESULTS: One hundred and forty-seven (98 %) of the initial 150 TICTAC trial patients had long-term follow-up data available. The median follow-up was 13.4 years (interquartile range 7.2-15.1 years). Post-transplant survival at 5, 10 and 15 years in the TAC monotherapy group was 84.5 %, 66.9 %, and 52.7 %, and 94.4 %, 78.2 % and 56.1 % for patients randomized to TAC / MMF (p = 0.19 logrank). The freedom from cardiac allograft vasculopathy (≥grade 1) was 100 %, 87.5 %, 69.3 % and 46.5 % at 1, 5, 10 and 15 years in the monotherapy group and 100 %, 76.9 %, 68.1 % and 54.4 % in the TAC/MMF group respectively (p = 0.96 logrank). Crossover of treatment assignment did not alter these findings. The freedom from dialysis or renal replacement was 92.8 %, 84.2 % and 68.4 % for TAC monotherapy patients versus 100 %, 93.4 % and 82.3 % for TAC/MMF patients at 5, 10 and 15-years post-transplant (p = 0.15 logrank). CONCLUSIONS: Patients randomized to TAC/ MMF with 8-week steroid weaning had comparable outcomes to those with similar steroid regimen but discontinuation of MMF at 2 week post-transplant. The best outcomes were noted for patients initiated on TAC/ MMF including those where MMF was discontinued for intolerance. Both strategies are reasonable alternatives for patients post heart transplant. CONDENSED ABSTRACT: Tacrolimus monotherapy was compared to TAC and mycophenolate mofetil without long term steroids in the randomized Tacrolimus in Combination, Tacrolimus Alone Compared (TICTAC) trial. Post-transplant survival at 5, 10 and 15 years in the TAC monotherapy group was 84.5%, 66.9 %, and 52.7 %, and 94.4 %, 78.2 % and 56.1 % for patients randomized to TAC / MMF (p = 0.19 logrank). Cardiac allograft vasculopathy and kidney failure were similar between groups. Immunosuppression should be individualized to avoid over treating some patients while undertreating others.

Recurrent Silicone Embolism Syndrome requiring VA ECMO.

The illegal use of liquid silicone in injectable procedures has been on the rise for the last few years. While originally thought to be an inert material, today, silicone is associated with several inflammatory complications-including Silicone Embolism Syndrome (SES). SES is the most dreaded complication of unlicensed liquid silicone injections. It is characterized by pneumonitis, diffuse alveolar and silicone pulmonary emboli leading to acute respiratory distress syndrome and cardiopulmonary failure. We present a case of a patient who was diagnosed with SES after she received unlicensed liquid silicone injections for gluteal augmentation. Her disease necessitated treatment with veno-arterial extracorporeal membrane oxygenation. Her neurological status remained poor. Our patient was also treated for SES status-post illicit silicone injections several years prior to the current episode. To our knowledge, this is the only reported instance of the same patient experiencing SES status-post illicit silicone injections on two separate occasions. Our patient's case suggests that robust education is needed for patients and the general public regarding the dangers of illicit body modifications. Given the widespread availability of counterfeit "medical grade" silicone, it is likely that the number of SES cases will continue to increase. Physicians must to be able to recognize the symptoms of SES, and not discount the possibility that patients will continue to receive illicit injections-even if they experienced devastating consequences the first time.

Differences in Short-Term Outcomes and Hospital-Based Resource Utilization Between Septal Reduction Strategies for Hypertrophic Obstructive Cardiomyopathy.

BACKGROUND: Given clinical equipoise in a subset of obstructive hypertrophic cardiomyopathy (OHCM) patients who are candidates for both alcohol septal ablation (ASA) or septal myectomy (SM), other considerations such as cost, readmissions, and hospital length of stay (LOS) may be important to optimize healthcare resource utilization and inform shared decision making. METHODS: In this retrospective observational analysis of the United States Nationwide Readmissions Database years 2012-2014, we identified adults who underwent isolated septal reduction (SR) for OHCM. We studied the differences in short-term outcomes (inpatient mortality and 90-day readmission rate) and in-hospital resource utilization (LOS and costs) between the SR strategies. RESULTS: Of the 2250 patients in this study, ASA was performed in 1113 (49.5%) and SM in 1137 (50.5%). Inpatient mortality occurred in 21 patients (0.9%), with similar rates between strategies (10 SM patients [0.9%] vs 11 ASA patients [1.0%]; P=.30). Of the 2229 patients who survived to discharge, 298 (13.4%) were readmitted 386 times within 90 days with a similar readmission rate between SM (14.9%) and ASA (11.8%; P=.16). During the index admission, average LOS and cost were significantly lower for ASA (3.9 days, United States [US] $20,322) compared with SM (7.6 days, US $39,470; P<.001). Average LOS and cost during 90-day readmissions were similar between ASA and SM. Combining index admissions and readmissions, patients undergoing ASA had significantly lower LOS and hospitalization costs. CONCLUSIONS: In this non-randomized observational study of OHCM patients undergoing isolated septal reduction, ASA was associated with similar short-term outcomes, including mortality, but substantially lower hospitalization costs and LOS compared with SM.

Drug Therapy of Dyslipidemia in the Elderly.

Abnormal lipoprotein metabolism is an important and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD), which has been shown in numerous studies to lead to adverse cardiovascular outcomes. As cardiovascular disease (CVD) remains the major cause of morbidity and mortality globally, management of dyslipidemia is a key component of primary and secondary risk-reduction strategies. Because ASCVD risk increases with age, as the population ages, many more people-particularly the elderly-will meet guideline criteria for drug treatment. Statins (HMG-CoA reductase inhibitors) have an unequivocal benefit in reducing ASCVD risk across age groups for secondary prevention. However, the benefit of these drugs for primary prevention in those > 75 years of age remains controversial. We strongly believe that statins should be offered for primary prevention to all older individuals after a shared decision-making process that takes polypharmacy, frailty, and potential adverse effects into consideration. When considering statin therapy in the very old, competing risks of death, and therefore the likelihood that patients will live long enough to benefit from drug therapy, should inform this process. Combination therapies with ezetimibe or proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors should be considered to facilitate the use of tolerable doses of statins. Future investigations of dyslipidemia therapies must appropriately include this at-risk population to identify optimal drugs and drug combinations that have a high benefit:risk ratio for the prevention of ASCVD in the elderly.

Benefit-risk review of different drug classes used in chronic heart failure.

INTRODUCTION: Heart failure (HF) is an important public health problem with an increasing prevalence across the globe. The mortality rates from this complex clinical problem have stabilized in the recent years with the use of pharmacotherapeutics which demonstrated survival benefits in patients with HF with reduced ejection fraction (HFrEF). AREAS COVERED: We reviewed the seven classes of medications which constitute the guideline-directed medical therapy (GDMT) in chronic HF patients. We discussed clinical trials which support or contradict their use, potential adverse events, and available real-world data on utilization and safety. EXPERT OPINION: Loop diuretics form a major component of baseline therapy in HF patients to maintain euvolemia. As diastolic HF is more volume sensitive then systolic HF, diuretic use should be judiciously monitored to prevent states of volume depletion and associated complications. Neurohormonal modulation with pharmacotherapies are efficacious in reducing morbidity and mortality in the chronic HFrEF population. However, registry data showed that treatment intolerance and adverse events result in lower prescription rates of GDMT. Sacubitril/valsartan represents a major therapeutic advance in the treatment of HFrEF patients and can be safely used in addition to other GDMTs. Therapies to improve outcomes in diastolic HF  patients are needed.

Investigational drugs for the treatment of acute myocardial infarction: focus on antiplatelet and anticoagulant agents.

BACKGROUND: Advances in our understanding of the complex pathophysiologic mechanisms responsible for high-risk atherosclerotic plaque rupture resulting in acute myocardial infarction (AMI) have led to the development of numerous antiplatelet and anticoagulant agents for treatment of AMI. AREAS COVERED: We review various antithrombotic drugs which were recently investigated for the treatment of AMI. A MEDLINE search for relevant articles on newer antiplatelet agents and anticoagulants drugs for the treatment of AMI was performed, and important original investigations were reviewed. We also briefly discuss agents that completed evaluation and were recently recommended by expert guidelines. EXPERT OPINION: The antiplatelet agents cangrelor and vorapaxar and the anticoagulant rivaroxaban, have shown promise for the reduction of ischemic events when administered during, and in the acute phase following AMI. However, these agents have not been compared with more potent P2Y12 inhibitors, prasugrel, and ticagrelor. Finding an optimum combination of these agents to achieve an appropriate risk (bleeding) - benefit (reduction in ischemic events) balance is challenging. Further evaluation of agents that show promise is important for enhancing our armamentarium of pharmacologic agents for the successful treatment of AMI.

Novel Pharmacotherapy in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited disease characterized by unexplained left ventricular hypertrophy. Although it is estimated to affect 1 out of 500 people, the HCM gene carrier prevalence is much more common, probably as high as 1 in 200 people. Most affected individuals have a normal life expectancy, whereas some patients may develop sudden cardiac death or end-stage heart failure. Despite significant developments in the treatment of HCM with surgical, interventional, and device-based procedures, the main focus of current pharmacological therapy has not evolved from the basic objectives of relief of symptoms and improvement in functional capacity. To date, no medical treatment has been shown to prolong survival or reduce the risk of sudden cardiac death. In recent decades, research focus in HCM has shifted to identify the treatments which are able to alter the natural pathophysiological process of this disease. This article reviews the currently recommended and frequently used medications (beta-blockers, nondihydropyridine calcium channel blockers, and disopyramide) and emerging pharmacological treatment options in the management of HCM. The mechanism of action and latest clinical trials of the novel agents are discussed in greater detail.

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives.

With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF.

Complete versus culprit only revascularization in ST-elevation myocardial infarction-a perspective on recent trials and recommendations.

The presence of multivessel coronary artery disease (CAD) is strongly associated with higher 30-day mortality, reduced myocardial reperfusion success, reinfarction, and occurrence of major adverse cardiac events (MACE) at 1 year compared with single-vessel CAD. Despite higher morbidity and mortality in patients with ST-elevation myocardial infarction (STEMI) and coexistent multivessel CAD, major guidelines recommended against percutaneous coronary intervention (PCI) on non-culprit lesions at the time of primary PCI in patients with STEMI who are hemodynamically stable. The presence of multivessel CAD often poses a therapeutic dilemma for interventional cardiologists. A few larger scale randomized controlled trials (RCTs) and meta-analyses have been conducted. The conclusions regarding multivessel PCI generally trend towards lower risk of MACE, repeat revascularization, with similar risks of recurrent myocardial infarction (MI) and mortality. However, none of the RCTs were adequately powered for hard outcomes of death and MI.

Thrombotic microangiopathy associated with synthetic cannabinoid receptor agonists.

Marijuana is one of the most commonly used recreational drugs in the United States. As marijuana is illegal in the majority of countries, the use of readily available and unregulated synthetic cannabinoids (SCBs) has increased. Little is known about the potential adverse effects of SCBs especially in regards to their nephrotoxicity. Case reports of acute kidney injury (AKI) from acute tubular injury secondary to their use have been reported. However, the exact pathology, mechanism, and extent of renal injury remain unknown. We report the first case of biopsy proven thrombotic microangiopathy (TMA) associated with SCBs resulting in AKI. The patient suffered significant morbidity with loss of renal function eventually requiring renal replacement therapy.

Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated with eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome is a rare disorder which is known to cause acute thrombotic microangiopathy during pregnancy with poor maternal and fetal outcomes. Atypical hemolytic uremic syndrome is caused mostly by dysregulation of alternative complement pathway secondary to genetic mutations. Most of the cases reported have been in the post-partum period. We report a rare case of a patient who presents with thrombotic microangiopathy in the first trimester of her eleventh pregnancy and was successfully treated with eculizumab. CASE PRESENTATION: A 30-year-old woman presented at 10 weeks of gestation with hypertension, hemolytic anemia, thrombocytopenia, and acute kidney injury, consistent with thrombotic microangiopathy. She was managed initially with daily plasmapheresis. However, her kidney function did not recover, requiring hemodialysis. ADAMTS13 activity was later found to be within normal limit, hence diagnosis of atypical hemolytic uremic syndrome was strongly considered at that time and she was immediately treated with anti-C5 humanized monoclonal antibody (eculizumab). The patient responded well (resolution of thrombotic microangiopathy and recovery of renal function) to eculizumab, with continued remission after discharge and successfully delivered a healthy baby at term without any peripartum complications. CONCLUSION: Early recognition of atypical hemolytic uremic syndrome is often difficult as several other conditions also manifest as thrombotic microangiopathy during pregnancy, causing delay in initiating appropriate treatment. Our case suggests that treatment of atypical hemolytic uremic syndrome in early trimester of pregnancy with eculizumab results in good outcome to mother and fetus.