Vasopressin Antagonist in Acute Heart Failure - Mixed Results | EVEREST trial (ACC.07)

American College of Cardiology's 56th annual scientific session (ACC.07) Update | March 26, 2007:

Vasopressin V2 receptor antagonist tolvaptan¹ is again showing mixed results with efficacy limited only to short-term benefits in fluid overload status. Previously, tolvaptan was found to be effective in patients with euvolemic or hypervolemic hyponatremia in increasing serum sodium concentrations at day 4 and day 30; with recurrence of hyponatremia was noted in a week after discontinuation of tolvaptan on day 30.² Now, EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Trial) outcome presented at ACC.07 ³ suggested tolvaptan moderate efficacy only in short-term cure of acute decompensated hear failure (ADHF) without difference in all-cause mortality or the composite of CV death or heart failure hospitalization compared with placebo at long-term follow-up; suggesting that early, in-hospital therapy with tolvaptan is beneficial but longer therapy may be unnecessary. Explaining study results, Dr Marvin A Konstam said, tolvaptan can "facilitate fluid management" and alleviate symptoms in this population " with a well-defined and acceptable long-term safety profile." ⁴ This might because of drug action in decreased body weight, reduction in edema, and subsequent improvement in patient assessed dyspnea. The results of the present study are similar to those observed in the ACTIV in CHF trial⁵, which also showed improvements in acute heart failure symptoms but no difference in clinical endpoints with chronic therapy.

Reference:
1. Tolvaptan (OPC-41061) - In process of New Drug Application | Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) is developing tolvaptan for the treatment of congestive heart failure, hyponatremia and polycystic kidney disease.
2. Previous article on SBAmin.com | N Engl J Med 2006;355:2099-2112 | ClinicalTrials.gov numbers, NCT00072683 [SALT-1] and NCT00201994 [SALT-2]
3. ACC.07 EVEREST trial link
4. EVEREST: "Modest" Gains, No Apparent Harm From Vasopressin Antagonist in Acute Heart Failure | Heartwire (WebMD) article
5. ACTIV in CHF | ACC.07 link
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Ranolazine (Ranexa) has no role in Acute Coronary Syndrome (ACS) cases

Hello All!
I am lagging behind updating this blog with several important clinical trial updates¹ recently presented at American College of Cardiology's 56th annual scientific session (ACC.07) and Innovation in Intervention: i2 Summit 2007 (see reference for official outline links)
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ACC.07 update (March 27, 2007): Ranolazine (Ranexa) has no role in Acute Coronary Syndrome (ACS) cases | MERLIN TIMI-36 results
Ranolazine (Ranexa)² is a new class of anti-anginal drug, approved by FDA³ in January 2006 for the treatment of chronic angina patients who have failed to other forms of angina treatments (long-acting nitrates, calcium channel blockers and beta blockers). This indication was based on initial clinical trials, namely ERICA⁴ (Efficacy of Ranolazine in Chronic Angina) and CARISA⁴ (Combination Assessment of Ranolazine In Stable Angina) involving more than 1300 patients. Studies found prolong QT interval as a adverse reaction which might lead to proarrythmic effects and hence, drug is restricted for use in chronic angina patients as a second-line option.

The new trial named, MERLIN TIMI-36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes)⁴ was started in May 2006 which was a multi-national, double-blind, randomized, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of Ranexa during acute and long-term treatment in approximately 6,500 patients with non-ST elevation ACS treated with standard therapy. The primary efficacy endpoint in MERLIN TIMI-36 is time to first occurrence of any element of the composite of cardiovascular death, myocardial infarction or recurrent ischemia in patients with non-ST elevation ACS receiving standard therapy. The study was also evaluating the safety of long-term treatment with Ranexa compared to placebo.⁵ Results of MERLIN TIMI-36 were presented at ACC.07 which showed no role of Ranolazine in management of patient with ACS and also it has not disease-modifying effects in stable angina patients. However, trial showed no adverse effects of drug in terms of arrhythmia and increase mortality because of its prolong QT interval side-effect and suggested that it might have antiarrhytmic effects.

Effect of Ranolazine in preventing recurrent angia is supported by all major clinical trials. It is a unique agent that, unlike other classes of anti-anginal therapy, does not significantly reduce heart rate or blood pressure. As MERLIN study has shown better safety profile of Ranolazine, it is likely that Ranolazine will gain one more indication as a first-line therapy in stable angina patients in coming years.⁶ Precise mechanism of action of Ranolazine is unclear but it is believed to be a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion.⁷

Reference:
1. ACC.07 | i2 Summit 2007 : Official Text and Multimedia Resources | MERLIN TIMI-36 outline
2. Ranolazine (Ranexa)^® prescribing information from CV Therapeutics
3. FDA approval of Ranolazine: January 31, 2006
4. Clinical trial summary from ACC: CARISA | ERICA | MERLIN TIMI-36 (May require ACC account access)
5. CV Therapeutics article, dated 9 July 2006 - medicalnewstoday.com
6. MERLIN: No Role for Ranolazine in ACS but First-Line Indication in Stable Angina Now Likely - Heartwire (WebMD) news
7. Hale SL, Kloner RA | Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit | J Cardiovasc Pharmacol Ther. 2006 Dec;11(4):249-55 | PMID: 17220471
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Patch: Pfizer stopped phase 3 trial of potential HDL raising drug

This is a patch to an update posted earlier 03 Dec 2006.

Today NEJM has published (available free at this time) early release articles¹ to coincide with presentations at a meeting of the American College of Cardiology². These articles elaborate possible mechanisms of adverse effects of CETP inhibitor torceptrapib (Pfizer Inc.) because of which Pfizer has terminated phase III clinical trials³ of promising HDL lowering agent drug.

Reference:
1. Articles available free for the time being at NEJM homepage. These articles will be in print format in March 29 and April 19, 2007 issue of NEJM.
2. American College of Cardiology 56th annual scientific session in New Orleans & 2nd Annual Innovation in Intervention | ACC.07 and i2 Summit 2007
3. Terminated clinical trials: Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) (ClinicalTrails.gov search: Torcetrapib/Atorvastatin) | Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial (NCT00134173)
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Original post - 03 Dec 2006:

On December 2, 2006, FDA was notified that Pfizer will suspend a large, Phase 3 trial evaluating the investigational cardiovascular therapy torceptrapib/atorvastatin (T/A) due to an increased rate of mortality (death) in patients receiving the combination compared to those receiving atorvastatin alone...excerpt from FDA News

Torceptrapib was a potent inhibitor of cholesteryl ester transfer protein (CETP). Read Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol NEJM 350:1505-1515 (2004)
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Creatine for Parkinson's Disease - Phase III trial

The National Institute of Neurological Disorders and Stroke (NINDS), NIH institute yesterday¹ launched double-blind, placebo-controlled, phase III study to learn if the nutritional supplement creatine can slow the progression of Parkinson's disease (PD). Currently there is no treatment that has been shown to slow the progression of PD. It is one of the largest PD clinical trials to date, enrolling 1720 people with early-stage PD at 51 medical centers in the United States and Canada. Till date, creatine is not an approved therapeutic agent for PD or any other condition. Earlier studies² suggest its ability to improve exercise performance possibly by improving mitochondrial function and potential neuroprotection by antioxidant property. Creatine - a widely used dietary supplement has been investigated as a possible therapeutic approach for the treatment of muscular, neurological, neuromuscular diseases and neuroprotective effects.³ Participation in this study lasts a minimum of 5 years and includes at least 9 follow-up clinic visits and at least 3 telephone calls.

Reference:
1. NET-PD LS-1 Creatine in Parkinson’s Disease | NCT00449865
2. PubMed search using keywords: creatine parkinson
3. Creatine and treatment of muscular diseases | Wikipedia.org

Estriol pills for Multiple Sclerosis

UCLA researchers have begun phase II/III multi-center clinical trial¹ of Estriol treatment for Relapsing Remitting Multiple Sclerosis (RRMS). Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy as described in earlier clinical studies. This proposal will establish whether oral treatment with estriol, the major estrogen of pregnancy, induces a decrease in relapses in relapsing remitting multiple sclerosis (RRMS) subjects when used in combination with injectable Copaxone (glatiramer acetate)². Previously, in a pilot study, it has been demonstrated that treatment of RRMS subjects with oral estriol for six months resulted in a significant reduction (approximately 80%) in gadolinium enhancing lesions on serial brain MRIs³ and caused a favorable shift in immune responses⁴. Current study is an add-on study aiming to extend these previous findings by treating longer and focusing on clinical outcomes. The combination of Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a double blind trial. The duration of treatment will be two years and the primary outcome measure will be relapse rate. Treatment with estriol is believed to be a neuroprotective against new MS attacks as well as to reduce severity of inflammatory reaction seen with MS. Trial is expected to be completed by July 2011 and team expect to come up with promising results which would be helpful to cut down existing expensive MS treatment with cheaper hormone pills. Recently University of Calgary team shown protective effect of hormone prolactin in preventing demyelinating episodes in animal studies.

Courtesy: EurekAlert! 22-Mar-2007

Reference:
1. A Combination Trial of Copaxone Plus Estriol in RRMS (Estriol in MS) | NCT00451204
2. Copaxone prescribing information | PDF
3. Annals of Neurology, 2002; 52:421-428
4. Journal of Immunology, 2003; 171:6267-6274

Eculizumab (Soliris) for paroxysmal nocturnal hemoglobinuria (PNH)

FDA recently (March 19) approved Eculizumab - a humanized monoclonal antibody with long-acting C5 terminal complement inhibitor property. It is a new class in immunotherapy selectively blocking terminal complement activation - one of the main component of innate immune system. Patients with PNH are hypersensitive to complement mediated intravascular hemolysis as their RBCs lacks complement-regulating surface proteins, i.e. decay-accelerating factor (DAF) or CD55, homologous restriction factor (HRF) or C8 binding protein, and membrane inhibitor of reactive lysis (MIRL) or CD59. However, Soliris helps only in preventing complement mediated hemolysis and decreasing need for excess blood transfusions but it does not alter the course of PNH as well as potential risks of thrombosis and aplastic anemia associated with PNH. A boxed warning showing risk for serious meningococcal infection and need for meningococcal vaccination is affixed following results of clinical trials.

Reference:
1. FDA Okays Eculizumab (Soliris) for Paroxysmal Nocturnal Hemoglobinuria - MedPage Today
2. Hilmen P et al. | Effect of Eculizumab on Hemolysis and Transfusion Requirements in Patients with Paroxysmal Nocturnal Hemoglobinuria | N Engl J Med 2004;350:552-559
3. eMedicine.com article on PNH
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Don't kiss, focus on chest

I mean title for cardiopulmonary resuscitation (CPR) ! 

Chest compressions alone are more life saving than combined chest compressions with mouth-to-mouth rescue breathing in adults having cardiac arrest - based on results from a large scale study in Japan involving 4000 cases of cardiac arrest outside hospital in presence of bystanders. This is because patients in whom heart has just stopped working can have adequate oxygen saturation in flowing blood to support brain and other vital organs functions until heart recovers and restart pumping oxygenated blood. Hence, rather spending time on rescue breathing from those precious early life-saving minutes, it is prudent to deliver continuous effective chest compressions in anticipation of restarting heart pump and preventing ischemic brain damage.

However, this conclusion was based from a single study data involving patients having failing heart and it is important to note that rescue breathing can be a vital task when it comes to respiratory component in cardiac arrest. i.e. narcotic and drug over-dosage, drowning and others. There have been no change in CPR guidelines so far from American Red Cross and American Heart Association (AHA).

Reference:
1. 'Kiss of life' increases risk after heart attack - NewScientist News 16 March 2007
2. American Red Cross - Video showing current CPR technique
3. Cooper et al. | Cardiopulmonary Resuscitation: History, Current Practice, and Future Direction | Circulation 2006;114:2839-2849
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FDA MedWatch: Erythropoiesis Stimulating Agents & Interferon Gamma 1-b

Erythropoiesis Stimulating Agents
FDA MedWatch has issued black box warning for use of Erythropoiesis Stimulating Agents (ESAs) namely, darbepoetin (Aranesp) and epoetin alfa (Epogen and Procrit)

Studies showed aggressive use of ESAs to correct hemoglobin 12 g/dl or more is associated with increase risk of thrombotic events and stimulate progression of some cancers. (DAHANCA 10, CREATE, CHOIR and other studies)

in raising hemoglobin to 12 g/dl or higher in cancer patients which is associated with higher chance of serious and life-threatening side effects or death. Revision took place after results of four clinical trials evaluating an unapproved dosing regimen, a patient population for which ESAs are not approved, or a new unapproved ESA. Patients treated with Aranesp had a higher death rate and no reduction in the need for transfusions compared to those treated with placebo. The findings in the Aranesp study may apply to other ESAs. Additionally, the findings show that treating anemic cancer patients not currently on chemotherapy with an ESA may offer no benefit and may cause serious harm.

Current recommendation for all indicated patients are:

• To start the lowest possible dose of ESAs.
• Checking hemoglobin twice a week for two to six weeks after any dosage change to ensure that hemoglobin has stabilized in response to the dose change.
• Withhold the dose of the ESAs if the hemoglobin increase reaches 12 g/dL or more or rises by 1g/dL in any two-week period.

[FDA Source]

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Interferon Gamma 1-b
FDA has not approved Interferon Gamma 1-b (Actimmune) for the treatment of idiopathic pulmonary fibrosis (IPF) based on early termination of the INSPIRE clinical study of Actimmune for IPF because of an interim analysis showed that patients with IPF who received Actimmune did not benefit compare to placebo.

[FDA source]

Oral Amphotericin B - Bypassing Renal toxicity

Researchers at the University of British Columbia (Canada) discovered new drug delivery system for Amphotericin B (AmB), bypassing notable renal toxicity associated with currently available intravenous AmB formulation. Newer oral preparation containing lipid-based AmB targets specifically fungal cells while inhibiting drug's interaction with kidney cells - thereby avoiding lethal toxicity and increasing efficacy. This can be a boon for thousands of patients suffering from dreaded fungal infections associated with HIV/AIDS and other immuno compromised diseases by providing more effective, less toxic and cheaper alternative to intravenous AmB. A clinical study of the drug delivery system, involving 50-100 patients, is planned for later this year. Study led by Wasan KM will be presented today at a meeting sponsored by the American Association of Pharmaceutical Scientists in Washington, D.C. Findings will be published in July 2007 in Drug Development and Industrial Pharmacy.

Use of Liposomal AmB (AmBisome®) is associated with raised serum creatinine level in 18% to 40%; hematuria in 14% of cases and acute renal failure and/or toxic renal nephropathy in 2% to 10% of cases. However, incidence of decreased renal function and infusion-related events are lower than rates observed with conventional amphotericin B deoxycholate (Amphocin®, Fungizone®).²

Reference:
1. EurekAlert! 5-March-2007
2. Drug information by Merck Inc. - Liposomal AmB
3. AmBisome monograph
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Clinical Practice Alert: For Entecavir and Vancomycin use

Clinical Practice Alert:

1. Entecavir (Baraclude ^TM) in patients suffering from both - Chronic Hepatitis B and HIV infection:
Hopkins researchers proved deleterious effect of Entecavir in patients suffering from HBV / HIV co-infection using both laboratory and clinical tests. Entecavir - A selective HBV polymerase inhibitor is indicated for chronic active HBV and being widely used since arrival in March 2005. As there have been cases showing decrease viral load of HIV with use of entecavir in such co-infected patients, current practice widely favors use of entecavir in treating HBV in HIV/HBV patients not simultaneously receiving highly active antiretroviral therapy (HAART) in anticipation of decreasing HIV load. However, Hopkins study cautions clinicians not to use entecavir in HIV/HBV patients they revealed mutation in HIV (M184V type) which nurtures HIV resistance to more widely used Lamivudine (3TC) and related Nucleoside reverse transcriptase inhibitors (NRTIs) which might be needed for HIV therapy in later phase for those patients. At present, there is no box warning for use of entecavir in HIV/HBV co-infected patients. On 24-Feb-2007, FDA included entecavir in MedWatch [Excerpt: Current treatment guidelines recommend Baraclude as an option for treatment of HBV in the HIV/HBV co-infected adult patient who does not qualify for HAART. Healthcare professionals are advised that when considering therapy with Baraclude in an HIV/HBV co-infected patient not receiving HAART, the risk of developing HIV resistance cannot be excluded based on current information]
Reference:
1. EurekAlert! 28-Feb-2007
2. Conference on Retroviruses and Opportunistic Infections (CROI) 2007
3. Baraclude: official website | mechanism of action

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2. Vancomycin dependant immune thrombocytopenia:
A study from the Medical College of Wisconsin, published today in NEJM reports development of vancomycin-dependant antiplatelet antibody and subsequent thrombocytopenia with significant bleeding. Study found 29 patients developing such antibodies and 3 of which had fatal bleeding outcome. Vancomycin, commonly used for MRSA is out in clinical practice for 25 years and therefore, this new finding reflects possibility of rarest side-effect and/or other unknown etiology of such antibody development despite study documented exclusion of other causes of thrombocytopenia. Authors recommend to actively watch for decreasing platelet counts / asking hematology consultation if justified and to discontinue/substitute vancomycin for few days to expect improvement in platlet counts.
Reference:
1. Aster et al. | Vancomycin-Induced Immune Thrombocytopenia | N Engl J Med 2007;356:904-910