|Home | About | Journals | Submit | Contact Us | Français|
The annual meeting of Transcatheter Cardiovascular Therapeutics, as its name implies, focused on catheter-based therapies, with a preponderance of sessions devoted to the environment of acute coronary syndromes and myocardial infarction. The meeting took place in Washington, D.C., from September 21 to 25, 2010. This article includes several pharmacological sessions offered to the more than 10,000 attendees. One study reviews chronic statin therapy, and two others address the problem of reducing platelet activation in at-risk patients.
Patients already taking statins may still need additional statin loading doses before percutaneous coronary intervention (PCI). Standard chronic dosing, said Dr. Feldman, fails to reduce levels of post-PCI troponin I or creatine kinase–myoglobin (CK-MB).
In statin-naive patients, pre-procedure high-dose statins can reduce post-PCI cardiac enzyme elevations and myocardial infarction (MI). It is unclear, however, whether chronic statin therapy offers protection from post-PCI MI in this population.
Drs. Feldman and Gordin conducted a review of the Cornell Angioplasty Registry Database encompassing 1,482 consecutive study patients with normal levels of pre-procedure enzymes. The goal was to investigate the effect of chronic statin therapy (for more than seven days) on in-hospital and long-term outcomes in patients undergoing non-emergent PCI.
Patients were divided into two groups: the first cohort included those using any dose of ongoing statin therapy before PCI; the second group did not receive statins before PCI. The mean follow-up period was 65.5 months. The mean age was 67 years among the 409 patients in both the “no-statin” group and in the 1,073 patients in the chronic statin group.
In a multivariate analysis, chronic statin use was not predictive of reduced post-PCI elevations in troponin I or CK-MB (more than three times the upper limit of normal). Odds ratios were 1.028 (0.907–1.165) and 1.032 (0.798–1.334), respectively. Long-term all-cause mortality after nearly six years of follow-up was also similar between the groups.
Dr. Feldman said, “We were surprised that patients on chronic statin therapy did not get a benefit of reduced cardiac enzyme elevations.”
These findings suggest the utility of a statin loading dose, he added, perhaps atorvastatin (Lipitor, Pfizer) 80 mg, given 12 to 18 hours before the procedure. He commented further that the MI protection from statins probably comes from anti-inflammatory effects with high doses rather than from the anti–low-density lipoprotein-cholesterol (LDL-C) effects of chronic dosing.
In patients with acute coronary syndrome (ACS), atopaxar (E5555, Eisai) works potently and quickly without causing significantly increased bleeding. A protease-activated receptor 1 (PAR-1) inhibitor, atopaxar targets thrombin-induced platelet activation, Dr. O’Donoghue said in a late-breaking clinical trial presentation.
LANCELOT–ACS (Lesson from ANtagonizing the CELlular Effect Of Thrombin–ACS) included 603 subjects with unstable angina or non-ST segment MI. Three atopaxar doses were tested: 400 mg as a loading dose plus 50, 100, or 200 mg once daily, versus placebo, for 12 weeks of active treatment with four weeks of follow-up. The primary endpoint was major bleeding, assessed at 12 weeks according to criteria in the CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events).
Bleeding rates were similar for all atopaxar doses (atopaxar combined, 3.1%; placebo, 2.2%; P = 0.81). The incidence of major bleeding, however, was higher with atopaxar than with placebo. It was highest at 3.2% with atopaxar 100 mg once daily; other rates were 0.6% with 50 mg once daily and 1.4% with 200 mg once daily. The overall major bleeding rate for atopaxar was 1.8%. No major bleeding occurred in the placebo patients.
Cautioning that LANCELOT–ACS was not powered for efficacy, Dr. O’Donoghue reported that the combined endpoint rate for cardiovascular death, MI, or stroke was 5.6% in the placebo group and 3.3% for the combined atopaxar population (P = 0.28). In addition, Holter-detected ischemia, evaluated at 48 hours following the atopaxar loading dose, occurred at rates of 28.1% in the placebo group of patients and 18.7% in the atopaxar group (P = 0.02).
Transient, dose-dependent elevated transaminases were observed with the higher atopaxar doses. Relative prolongation of the corrected QT (QTc) interval was also reported.
“Future studies will be required to fully establish safety and efficacy of atopaxar, but PAR-1 blockade appears promising,” Dr. O’Donoghue said.
Asked in a press conference about the implications of QTc prolongation, which has not been noted in trials of vorapaxar (SCH 530348, Schering/Merck), the other investigational PAR-1 inhibitor, Dr. O’Donoghue pointed out that atopaxar’s half-life of 22 to 26 hours is much shorter than that of vorapaxar (more than 150 hours).
“That’s a theoretical advantage for atopaxar with those who may need to go to the operating room or who need to come off antiplatelet therapy quickly.”
“QTc prolongation will be a concern going forward and needs further investigation,” stated Dr. Moliterno, discussant for results of the Late-Breaking Clinical Trial presentation of LANCELOT–ACS. He pointed out in an interview that neither atopaxar nor vorapaxar has demonstrated statistically significant increases in bleeding.
“In phase 2 trials, we actually measured chest tube drainage following bypass surgery and showed it to be similar between vorapaxar and placebo.”
Dr. Moliterno added, “Data and Safety Monitoring Committees have not altered protocols among any of the ongoing phase 3 vorapaxar trials (including about 20,000 patients receiving the agent). That suggests a lack of major bleeding concerns.”
Cytochrome P450 2C19*2 (CYP 2C19*2) genetic polymorphism is associated with reduced metabolism of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and a worse prognosis after percutaneous coronary intervention (PCI). Genotyping for CYP 2C19*2 status, according to new research, may influence medication selection in post-PCI patients, particularly when the choice is between doubling the clopidogrel maintenance dose or using prasugrel (Effient, Eli Lilly/Daiichi Sankyo).
Although clopidogrel resistance is reported at a wide range of rates (5%–60%), prevalence is unquestionably high (approximately 40%) among patients who go on to experience stent thrombosis after PCI procedures. There has been considerable speculation as to whether increasing the clopidogrel dose or administering the newer, more potent agent—prasugrel—helps clopidogrel-resistant patients.
PRO-GR (a Prospective, Randomized, Crossover Study of Maintenance High-Dose Clopidogrel versus PRasugrel in ClOpidoGRel-Resistant Patients with and without the CYP 2C19*2 Loss-of-Function Allele) was conducted to assess both the antiplatelet effects of prasugrel, compared with high-dose clopidogrel in post-PCI patients, and the impact of the CYP 2C19*2 loss-of-function allele on platelet reactivity. Investigators specifically included patients at high risk for ischemic events, including those who weighed less than 60 kg (132 pounds), were older than 75 years of age, or had high on-treatment platelet reactivity (HTPR), as defined by a Vasodilator-Stimulated Phosphoprotein Index of at least 50%.
Clopidogrel-naive patients and those taking clopidogrel 75 mg for less than seven days without initial loading received a 600-mg clopidogrel loading dose at the time of PCI. Patients receiving clopidogrel for less than seven days but with a 300-mg initial loading dose or those receiving clopidogrel for more than seven days did not receive any additional loading. Periprocedural glycoprotein IIb/IIIa inhibitors were allowed at the operator’s discretion.
Of a total of 210 patients evaluated for platelet reactivity, 71 were identified as having a level indicating HTPR reactivity. These patients were then randomly assigned to receive clopidogrel 150 mg daily or prasugrel 10 mg daily, with crossover at 30 days.
The primary endpoint was platelet reactivity at the end of two pre-crossover and post-crossover study periods.
According to platelet reactivity analysis (in platelet-reactivity units [PRUs]) at 30 and 60 days, patients receiving prasugrel showed significantly lower reactivity than those receiving clopidogrel (129.4 for prasugrel and 201.7 for clopidogrel; P < 0.001). HTPR rates were also significantly higher with clopidogrel (35.8%) than with prasugrel (7.5%, P < 0.001). Comparing CYP 2C19*2 allele carriers and non-carriers, the investigators found that HTPR rates were higher among carriers for both drugs.
Dr. Alexopoulos concluded, “Genotyping for the CYP 2C19*2 allele seems to be helpful for selection between clopidogrel maintenance dose doubling and prasugrel administration.”
He added, “In patients with HTPR post PCI, prasugrel is more effective compared with high-dose clopidogrel in reducing platelet reactivity.”
The effect, he said, is also more prominent in patients with at least one CYP 2C19*2 loss-of-function allele.
More than 4,000 clinicians and researchers from 66 countries attended the meeting in Glasgow, Scotland, from September 28 to October 1, 2010. Studies of comorbidities, quality of life, and treatment of depression associated with the disease are reviewed here.
For patients with Parkinson’s disease (PD), delayed gastric emptying and delayed drug influx to the intestine can result in inconsistent reactions to orally delivered medications. Also, retention of standard-care levodopa in the stomach lengthens its exposure to dopa-decarboxylase, which can make it less available for absorption in the duodenum.
New findings indicate that PD patients with pre-diagnosis gastrointestinal tract (GI) disorders that are linked to drug absorption problems appear to have higher rates of emotional, neurological, movement, and urinary disorders compared with PD patients without a pre-diagnosis of GI disorders.
“The most important clinical implication of this study is that when a physician treats a Parkinson’s disease patient with gastrointestinal disorders, that patient should be followed especially closely, since there is an increased risk of falls, urinary incontinence, ataxia, and other disorders,” Dr. Makaroff said.
From a large U.S. claims database, investigators identified 485 PD patients with and without a diagnosis of a GI disorder during a 12-month claims period. Eligibility required at least two claims associated with diagnosis of PD and a prescription of continuous levodopa or dopamine agonists (DAs) between September 1, 2005, and September 1, 2006.
The most common GI conditions included esophageal disorders, such as gastroesophageal reflux (GERD), digestive disorders, and dysphagia. Among patients with a GI disorder, 61% were adherent to levodopa alone, 13% to DA alone, and 26% to both levodopa and DA.
Over a period of two years, the incidence of depression (P = 0.0347), anxiety (P = 0.0062), psychosexual dysfunction (P = 0.0499), ataxia (P = 0.0286), pain (P =0.0003), movement disorders (P = 0.0053), urinary incontinence (P = 0.0156), and falls (P = 0.0356) were all significantly higher in the group with PD and a GI disorder.
Dr. Makaroff concluded that most patients with PD eventually develop at least one GI disorder, at a rate of 65% after 60 months of follow-up of all patients in this study. Further, the prevalence of GI disorders appears to increase as PD progresses.
Patients with Parkinson’s disease (PD) who receive paroxetine (Paxil, GlaxoSmithKline) or venlafaxine extended-release (Effexor ER, Pfizer) have achieved improvements in standard measures of depression.
“Depression is a frequent and disabling feature in Parkinson’s disease,” Dr. Richard said, adding, “but there have been few placebo-controlled clinical trials evaluating antidepressant medications in Parkinson’s disease.”
Dr. Richard and colleagues randomly assigned 115 patients with idiopathic PD and depression to receive paroxetine (n = 42), venlafaxine (n = 34), or placebo (n = 39). Most of the patients (73%) also had major depression. To be eligible for the study, patients needed a baseline score above 12 on the Hamilton Rating Scale for Depression (HAM–D).
The investigators followed the subjects for 12 weeks, allowing them six weeks to reach a stable dose and six weeks of maintenance. Withdrawals during the study were as follows:
Of the enrolled patients, 84% completed the trial. Mean daily dosing at week 12 was paroxetine 24 (±11) mg/day and venlafaxine 121 (±75) mg/day.
The actively treated subjects achieved significantly greater mean 12-week reductions in HAM–D scores for both treatment groups compared with placebo subjects, with a 6.2-point treatment effect for paroxetine (P = 0.0007) and a 4.2-point treatment effect for venlafaxine (P = 0.02). Secondary measures of depression showed similar results on the Montgomery-Asberg Depression Rating Scale, the Global Depression Index, and the Beck Depression Inventory.
Both drugs were generally well tolerated. Neither medication had an adverse effect on motor function.
Caucasian patients with Parkinson’s disease (PD) who received a rotigotine skin patch (Neupro, UCB Pharma) for up to 12 weeks achieved improvements in various activities of daily living as well as in total health-related quality of life (HRQoL). Findings were measured by the short-form Parkinson’s Disease Questionnaire (PDQ-8) in a substudy of RECOVER (Randomized Evaluation of the 24-hour-COVerage: Efficacy of Rotigotine). A non-ergoline dopamine agonist (DA), rotigotine is indicated for the treatment of PD and restless legs syndrome.
The mean change from baseline PDQ-8 score of −6.9 points achieved by these patients is within the minimal important difference (MID) that had been established in earlier research among Asian patients (a reduction of 5.8 to 7.4 points).1
In the phase 3b RECOVER trial, patients were randomly assigned, in a ratio of 2:1, to receive transdermal rotigotine or placebo. Treatment was titrated to an optimal dose over one to eight weeks, starting at 2 mg every 24 hours and increasing up to a maximum of 16 mg every 24 hours. The optimal or maximal dose was maintained for four weeks.
Permitted in stable doses 28 days before the baseline evaluation and during the study were immediate-release levodopa, anticholinergics, monoamine oxidase (MAO) B inhibitors, N-methyl d-aspartate (NMDA) receptor antagonists, entacapone (Comtan, Novartis), and other central nervous system drugs. Controlled-release levodopa and other dopamine agonists were excluded.
PDQ-8, a patient-rated scale that addresses problems of mobility, activities of daily living, emotional well-being, social support, cognition, communication, bodily discomfort, and stigma, was used to assess changes from baseline to the end of treatment. Total scores range from 0 to 100, as follows: 0 = never (no problem at all), 1 = occasionally, 2 = sometimes, 3 = often, and 4 = always.
Investigators assigned 191 patients to rotigotine and 96 to placebo. The mean change from baseline PDQ-8 total score was −6.9 in the rotigotine group, which differed significantly from −1.2 in the placebo group (P < 0.001). This improvement was consistent with that seen in the Asian study (effect size, −0.40; standardized response mean, −0.55).
Although no MID definition was performed in the current study, the fact that effect size and the standardized response mean for treated patients were similar to those in the Asian study suggests that the MID range identified by the PDQ-8 is valid also for these patients, Dr. Kulich said. He commented that actively treated patients in this study would consider their improvements in HRQoL to be important.
Commenting on the findings, Dr. Breen noted that although it is the physician or nurse who usually evaluates the efficacy of treatments in PD, the patient-centered PDQ-8 is a more accurate tool for evaluating QoL changes than the physician-or nurse-centered instruments. He also noted that even though rotigotine has been used for several years, this is the first study that asks patients how they feel as the result of its use.