Rivaroxaban

In the recent issue of NEJM results of two studies involving Rivaroxaban have been published. One was an open-label, randomized study that compared oral Rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous Enoxaparin followed by a vitamin K antagonist (either Warfarin or Acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. 

 The second parallel study was a double blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism.

The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.

The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin–vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001).

The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001).

 Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).

The authors have concluded that Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.

http://www.nejm.org/doi/full/10.1056/NEJMoa1007903

Anzemet (dolasetron mesylate)

The U.S. Food and Drug Administration (FDA) has informed that the injection form of Anzemet (dolasetron mesylate) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy (CINV) in pediatric and adult patients.

New data demonstrate that Anzemet injection can increase the risk of developing an abnormal heart rhythm (torsade de pointes), which in some cases can be fatal. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. Anzemet causes a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram (ECG).

Anzemet injection may still be used for the prevention and treatment of postoperative nausea and vomiting (PONV) because the lower doses used for PONV are less likely to affect the electrical activity of the heart and result in abnormal heart rhythms. 

Anzemet tablets may still be used to prevent CINV because the risk of developing an abnormal heart rhythm with the oral form of this drug is less than that seen with the injection form.

However, a stronger warning about this potential risk is being added to the Warnings and Precautions sections of the Anzemet tablet label. Anzemet tablets may also still be used for prevention of PONV. 

Nausea and vomiting are common side effects of chemotherapy and general anesthesia used in surgery. Additional highlights:

• Torsade de pointes, an abnormal heart rhythm, has been reported in some patients receiving Anzemet injection.
• Anzemet should not be used in patients with congenital long-QT syndrome.
• Hypokalemia and hypomagnesemia should be corrected before administering Anzemet. These electrolytes should be monitored after administration as clinically indicated.
• Use electrocardiogram (ECG) monitoring in patients with congestive heart failure, patients with bradycardia, patients with underlying heart disease, the elderly and in patients who are renally impaired who are taking Anzemet.
• No dose adjustment is necessary for renal-impaired patients, hepatic-impaired patients, or the elderly.
• Anzemet also causes dose-dependent PR and QRS prolongation. Drugs known to prolong the PR interval (such as verapamil) or QRS interval (such as flecainide or quinidine) should be avoided in patients taking Anzemet.

http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm

Avastin (bevacizumab): Process for Removal of Breast Cancer Indication Begun

FDA recommended removing the breast cancer indication for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use.

The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.

FDA has made this recommendation after reviewing the results of four clinical studies of Avastin in women with breast cancer and by determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients.

 None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

FDA recommends that the Oncologists currently treating patients with Avastin for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

Patients currently receiving Avastin for breast cancer should speak with their oncologists about whether to continue their treatment or explore other treatment options. 

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm237172.htm

Long-term effect of aspirin on colorectal cancer incidence and mortality

In the November issue of Lancet, a study assessing the effect of aspirin (low doses i.e. 75-300 mg daily) on the incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour was published.

Four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) were followed and the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data was established.

Results

In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60—0·96, p=0·02; mortality HR 0·65, 0·48—0·88, p=0·005), but not rectal cancer (0·90, 0·63—1·30, p=0·58; 0·80, 0·50—1·28, p=0·35).

 Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28—0·74, p=0·001; 0·34, 0·18—0·66, p=0·001), but not the distal colon (1·10, 0·73—1·64, p=0·66; 1·21, 0·66—2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01).

 However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20—0·63; 0·24, 0·11—0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36—0·92, p=0·02; 0·47, 0·26—0·87, p=0·01).

There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61—2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75—300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70—6·05, p=0·15).

The authors concluded that Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.

http://www.lancet.com/journals/lancet/article/PIIS0140-6736(10)61543-7/abstract 

Tessalon (benzonatate): Drug Safety Communication - Potential for Accidental Ingestion by Children

The U.S. Food and Drug Administration (FDA) has issued a warning to the public that accidental ingestion of benzonatate (Tessalon)  by children under the age of 10 years can result in death from overdose.

Benzonatate is a prescription drug approved for relief of cough in patients over 10 years of age. The safety and effectiveness of benzonatate in children under 10 years of age have not been established. Benzonatate is sold under the brand-name Tessalon and is also sold in generic preparations. 

Benzonatate may be attractive to children because of the drug's appearance (it is a round-shaped liquid-filled gelatin capsule).

Overdose with benzonatate in children less than 2 years of age has been reported following accidental ingestion of as few as 1 or 2 capsules. Individuals who experience overdose of benzonatate may exhibit restlessness, tremors, convulsions, coma, and cardiac arrest. Signs and symptoms of overdose can occur rapidly after ingestion (within 15-20 minutes). Deaths in children have been reported within hours of the accidental ingestion.  

The FDA has issued guidelines for the healthcare professionals and patients.

http://www.fda.gov/Drugs/DrugSafety/ucm236651.htm

Contrave, a novel combination of naltrexone and bupropion for obesity

Highlights of the document of 7th December, 2010 summarizing the data in support of the approval of Contrave, a novel combination product for the treatment of obesity composed of bupropion and naltrexone developed by Orexigen, Inc. of La Jolla, California.

Proposed Indication: The treatment of obesity and weight management, including weight loss and maintenance of weight loss, used in conjunction with lifestyle modification. Recommended for patients with an initial body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more risk factors (e.g. diabetes, dyslipidemia, or hypertension).

Proposed Dosing: The recommended daily dose of Contrave is two 8 mg naltrexone/90 mg bupropion (8/90) tablets taken twice daily for a total daily dose of 32 mg naltrexone/360 mg bupropion (32/360). Upon initiation, Contrave dosing should be escalated starting with one tablet taken daily for the first week, followed by the addition of another tablet each day during each subsequent week, until the total daily maintenance dose of two tablets twice a day (32/360)is reached at the start of Week 4.

Contrave, a novel combination product for the treatment of obesity, is composed of bupropion (a relatively weak inhibitor of the neuronal uptake of norepinephrine [NE] and dopamine [DA]) combined with naltrexone (a mu-opioid receptor antagonist).

Bupropion has been shown to stimulate hypothalamic proopiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α- MSH) which, in turn, binds to melanocortin 4 (MC4) receptors. The binding of α-MSH to MC4 receptors initiates a cascade of actions that results in weight loss via reduced energy intake and increased energy expenditure. When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid

receptor that mediates a negative feedback loop on POMC neurons leading to a decrease in

the release of α-MSH. Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying effects on energy balance. As a result, co-administration of bupropion and naltrexone produces a substantially greater effect on the POMC firing rate than either compound administered

alone, suggesting that the drugs act synergistically.

Adverse events: The observed Contrave safety and tolerability profile was generally comparable to the well-established safety profiles associated with naltrexone and bupropion, each with more

than 20 years of post-marketing experience and approximately 1 million and more than 50 million unique exposures, respectively.  With the exception of nausea and vomiting, the NB combination of naltrexone and bupropion did not appear to be associated with increased adverse events (AEs) relative to the individual components. The adverse events were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM235672.pdf

Somatropin-containing medicines

On 10^th December 2010, The European Medicines Agency announced  that it is starting a review of the safety of somatropin-containing medicines authorised centrally or by national procedures in the European Union. The review will look into all available data on somatropin to reassess the benefit-risk balance of these medicines.

This review is being initiated further to information received from the French medicines agency on a long-term epidemiological study in patients treated during childhood with somatropin-containing medicines. The study results suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics). The study looked at patients treated during childhood for growth hormone deficiency or short stature of unknown cause. Based on this observational study alone, the risk cannot be associated with certainty to the growth hormone treatment. The results need to be confirmed and complemented with further analyses. The French safety study, “Santé Adulte GH Enfant” (SAGhE), had been initiated in October 2007 and aims at improving the knowledge on recombinant growth hormone and evaluating the health of young adults who have been treated during childhood with recombinant growth hormone. Using the national compulsory France-Hypophyse register, investigators of the SAGhE study identified more than 10,000 young adults who started a recombinant growth hormone treatment between 1985 and 1996. The available analysis covers approximately 7,000 of these patients.

Somatropin is a human growth hormone, manufactured using recombinant DNA technology. It promotes growth during childhood and adolescence, and also affects the way the body handles proteins, fat and carbohydrates.

Somatropin is used to treat a number of conditions associated with a lack of growth hormone and short stature. This includes children who fail to grow due to a lack of growth hormone, Turner syndrome or chronic renal insufficiency.

There are three centrally authorised somatropin medicines in the EU: NutropinAq, Omnitrope and Valtropin. Several other somatropin medicines have been authorised through national procedures throughout the EU.

The Agency will provide further information on this review after the CHMP plenary meeting of 13-16 December 2010. In the meantime, the Agency is reminding prescribers to strictly follow the indications and the approved doses.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/12/news_detail_001160.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1

Withdrawal of Thelin (sitaxentan) due to cases of unpredictable serious liver injury

Pfizer has informed The European Medicines Agency about its voluntary decision to withdraw Thelin from the market worldwide because of the new information on two cases of fatal liver injury. Pfizer has also decided to discontinue all ongoing clinical trials.

Thelin, which contains the active substance sitaxentan, has been authorised in the European Union (EU) since 2006 for the treatment of pulmonary arterial hypertension.

Thelin has been known to be associated with liver toxicity and since its initial marketing authorisation has been contra-indicated in patients with mild to severe hepatic impairment (Child-Pugh Class A-C) and elevated aminotransferases prior to initiation of treatment.

At this stage, patients taking Thelin or participating in Thelin studies are advised not to stop treatment and to consult their treating physician to review their treatment at their next scheduled appointment.

The Agency’s scientific Committee for Medicinal Products for Human Use (CHMP) will look at this issue during their plenary meeting on 13–16 December 2010 and will provide detailed advice for patients and prescribers.

What is Thelin?

Thelin is used to treat adults (aged 18 years or over) with pulmonary arterial hypertension (PAH) to improve exercise capacity (the ability to carry out physical activity). PAH is abnormally high blood pressure in the arteries of the lungs. Thelin is used in patients with class III disease. The ‘class’ reflects the seriousness of the disease: ‘class III’ involves marked limitation of physical activity. Thelin has been shown to be effective in PAH with no identified cause and PAH caused by connective tissue disease.

As the number of patients with pulmonary arterial hypertension is low, the disease is considered ‘rare’, and Thelin was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 21 October 2004.

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/12/WC500099707.pdf

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000679/human_med_001091.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125

Management of Stevens Johnsons Syndrome and Toxic Epidermal Necrolysis

Diagnosis

TEN  and SJS are characterized by:

·       Typically, the disease process begins with influenza-like symptoms which are a part of a 1- to 14-day prodrome during which fever, sore throat; chills, headache, and malaise may be present.

·       Mucocutaneous lesions develop abruptly. The rash can begin as macules that develop into papules, vesicles, bullae, or confluent erythema. Characteristic skin lesions are flat, irregular, atypical target lesions or diffuse purpuric macules that frequently have necrotic centers (particularly in TEN) and tend to coalesce over the course of time.

·       In TEN, loss of epidermis is often sheet-like with a frequently positive Nikolsky sign (in which there is lateral displacement of the necrotic epidermis in response to slight pressure). As a result of cell death in the basal layer and stratum spinosum, the epidermis detaches from the dermis, giving rise to flaccid blisters. Although minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, gastrointestinal, and lower respiratory tract mucous membranes may develop in the course of the illness. Gastrointestinal and respiratory involvement may progress to necrosis.

·       Ocular involvement is seen in many patients with typical manifestations.

The physician is responsible for the early recognition of the reaction and the withdrawal of all potentially responsible drugs, especially those introduced within 1 month from the reaction.

Even if SJS or TEN is primarily diagnosed clinically, the diagnosis should be confirmed through histopathology. Histopathology classically shows widespread keratinocyte apoptosis and full-thickness epidermal necrosis and detachment, whereas the underlying dermis is not greatly altered and the epidermidis is infiltrated by activated lymphocytes, mainly CD8 cells, and macrophage.

The differential diagnosis of SJS or TEN includes a variety of skin reactions such as erythema multiforme (EM) major and atypical EM major, acute generalized erythematous pustulosis, intermediate burns, generalized fixed bullous drug eruption, staphylococcal scalded skin syndrome, edematous erythroderma, bullous pemphigoid, paraneoplastic pemphigus, exfoliative dermatitis, and acute graft-versus-host disease.

Erythema multiforme (EM) presents as initial target-like lesions characterized by an erythematous raised and palpable rim surrounding a gray center, whereas lesions of the SJS/TEN group are flat. In addition to these clinical and etiologic differences, EM and SJS/TEN can be distinguished histologically.

Treatment

No treatment modality has been established as standard for patients with SJS/TEN. Obviously, withdrawal of the suspected offending agent is critically important.
Immunoglobulin: A therapy with intravenous immunoglobulin (IVIG) was adopted on the basis of the identification of the mechanism of keratinocytes apoptosis in SJS/TEN. Nevertheless, at present, there is no strong evidence supporting IVIG administration in these patients.
Corticosteroids: The use of corticosteroids is controversial. A retrospective comparative study reported that combination therapy with corticosteroid and IVIG shows a tendency to reduce the mortality rate in comparison with the administration of corticosteroids alone.
Further studies are needed to determine the true efficacy of other agents such as tumor necrosis factor-α inhibitors, cyclosporine, cyclophosphamide, plasmapheresis and thalidomide.
Treatment, therefore, is primarily supportive and symptomatic and is similar to the therapy for burn patients.
Optimal treatment of SJS/TEN involves a multidisciplinary approach.

·       Fluid replacement must be initiated using macromolecules or saline solutions. Early and continuous enteral nutrition reduces the risk of stress ulcer and enterogenic infection. Total parenteral nutrition should be started in patients with hemodynamic instability or who are unable to take food.

·       Control of infection is crucial in the management of these patients because the high mortality is mostly attributed to bacterial sepsis; however, antibiotic use is generally reserved for the presence of documented infections or signs of sepsis.

·        Given that the majority of patients have ocular involvement, an ophthalmologist often is needed to assess and minimize the risk of infection ocular damage with treatments including topical lubricants-antibiotics and steroid drops.

·       Also, treatment of multiorgan damage, and prevention of further systemic complications. Special attention to airway and hemodynamic stability and pain control.

http://journals.lww.com/drug-monitoring/Fulltext/2010/12000/Stevens_Johnson_Syndrome_and_Toxic_Epidermal.1.aspx?WT.mc_id=EMxj15x20101206xL3 

European Commission Approves Brilique™ (Ticagrelor Tablets)

AstraZeneca announced on 6^th December 2010 that the European Commission has granted marketing authorisation to BRILIQUE™ (ticagrelor tablets) for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (ACS). This decision follows the positive opinion from the Committee for Medicinal Products for Human Use on 23rd September and is applicable to the 27 Member States and the 3 European Economic Area countries of the European Union.(1)

BRILIQUE (Ticagrelor) is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines (CPTPs). Ticagrelor is the first reversibly-binding oral ADP receptor antagonist.

BRILIQUE, a prescription oral antiplatelet treatment, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (unstable angina, NSTEMI, or STEMI), including patients managed medically and those who are managed with percutaneous coronary intervention (PCI) or Coronary Artery Bypass Grafting (CABG).

The majority of launches will occur in the second half of the year due to pricing and reimbursement negotiations.

The marketing authorisation for BRILIQUE is based on a review of the ticagrelor clinical programme, including results from PLATO (A Study of PLATelet Inhibition and Patient Outcomes), which established the superiority of ticagrelor over clopidogrel, and showed that treating 54 ACS patients with ticagrelor instead of clopidogrel for one year prevented one atherothrombotic event and treating 91 patients prevented one cardiovascular death, with no increase in overall major/fatal bleeding over the course of one year of treatment (11.6% for BRILIQUE vs. 11.2% for clopidogrel, p=0.43).

In the PLATO trial (2) the ticagrelor and clopidogrel groups did not differ significantly with regard to the rates of major bleeding as defined in the trial (11.6% and 11.2%, respectively; P = 0.43). There was also no significant difference in the rates of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) criteria (7.9% with ticagrelor and 7.7% with clopidogrel, P = 0.57) or fatal or life-threatening bleeding (5.8% in both groups, P = 0.70). The absence of a significant difference in major bleeding according to the trial definition was consistent among all subgroups, without significant heterogeneity, except with regard to the body-mass index (P = 0.05 for interaction). The two treatment groups did not differ significantly in the rates of CABG-related major bleeding or bleeding requiring transfusion of red cells. How-ever, in the ticagrelor group, there was a higher rate of non–CABG-related major bleeding according

to the study criteria (4.5% vs. 3.8%, P = 0.03) and the TIMI criteria (2.8% vs. 2.2%, P = 0.03). With ticagrelor as compared with clopidogrel, there were more episodes of intracranial bleeding (26 [0.3%] vs. 14 [0.2%], P = 0.06), including fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%], P = 0.02). However, there were fewer episodes of other types of fatal bleeding in the ticagrelor group (9 [0.1%], vs. 21 [0.3%] in the clopidogrel group; P = 0.03). Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8% of patients vs. 7.8%)

Other uncommonly reported side effects include headache, dizziness, abdominal pain, diarrhea, rash, itching, and upset stomach.

(1) http://www.astrazeneca.com/Media/Press-releases/Article/European-Commission-Approves-Brilique

(2) http://www.nejm.org/doi/pdf/10.1056/NEJMoa0904327

DEFINE ( Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial

The results of the DEFINE ( Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial were presented at the recent AHA meet. It was a double-blind randomized trial in which patients received either 100 mg of anacetrapib or matching placebo daily. Anacetrapib is an orally active, potent, selective CETP inhibitor that has had an acceptable side-effect profile in initial studies involving healthy volunteers and patients with hyperlipidemia.

The primary efficacy end points were the percentage change from baseline in LDL cholesterol after 24 weeks of treatment and the safety and side-effect assessments (i.e., assessment of adverse events; laboratory testing related to safety, including measurement of electrolyte and aldosterone levels; and assessment of vital signs, including blood-pressure measurement, electrocardiography, and physical examination) throughout the 76-week treatment period. Secondary efficacy end points included the change in LDL cholesterol from baseline to week 76 and the levels of HDL cholesterol, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I after 24 and 76 weeks of treatment.

By 24 weeks, LDL cholesterol levels had decreased from 81 mg per deciliter to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a change from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group — a 39.8% reduction with anacetrapib beyond that seen with placebo (P<0.001).

HDL cholesterol levels had increased from 41 mg per deciliter to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with a change from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group — a 138.1% increase with anacetrapib beyond that seen with placebo (P<0.001).

In the anacetrapib group, apolipoprotein B levels decreased by 21.0% and apolipoprotein A-I levels increased by 44.7% beyond the changes seen in the placebo group (P<0.001).

 Treatment with anacetrapib was associated with a 31.7% reduction in non-HDL cholesterol, a 36.4% reduction in lipoprotein(a) levels, and a 6.8% reduction in triglyceride levels, beyond the changes seen in the placebo group. All the changes in lipid levels were sustained throughout the 76-week treatment period. There were no significant differences in C-reactive protein levels between the two treatment groups.

Adverse events: There were no appreciable differences between the anacetrapib group and the placebo group in the percentage of patients with adverse events that were thought to be related to the study drug or that led to its discontinuation. There were also no significant differences between the two groups in the mean change in systolic or diastolic blood pressure or in the percentage of patients with a reported increase in blood pressure.

There were no cases of rhabdomyolysis in either study group and no significant differences in the percentages of patients with myalgias or other muscle symptoms or with elevations in creatine kinase.

In the current study, anacetrapib treatment did not alter blood pressure, electrolyte levels, or serum aldosterone levels, and the distribution of cardiovascular events between the two treatment groups provided a 94% predictive probability (confidence) that treatment with anacetrapib is not associated with the rate of adverse cardiovascular effects reported with torcetrapib. These findings have opened the door to retesting the hypothesis that inhibition of CETP is cardioprotective.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1009744

CTT meta-analysis: Safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy.

In the  Cholesterol Treatment Trialists  Collaboration (CTT) meta-analysis all those trials were eligible for inclusion if: the main effect of the intervention was to lower LDL cholesterol; no other differences in risk factor modification were intended; and at least 1000 participants were to be recruited with at least 2 years' scheduled treatment duration. Five trials comparing more intensive with less intensive LDL-C lowering were taken and 21 trials were of comparison of statin therapy with control.

Overall, among the 39 612 participants in five trials, the weighted mean baseline LDL cholesterol concentration was estimated to be 2·53 mmol/L, the weighted mean difference at one year was 0·51 mmol/L, and the weighted median follow-up duration among survivors was 5·1 years (2·1 years for patients with acute coronary syndrome and 5·8 years for those with stable disease).

First major vascular events were recorded in the five trials of more versus less intensive statin therapy in 3837 (4·5% per annum) of 19 829 participants allocated more intensive versus 4416 (5·3% per annum) of 19 783 allocated less intensive therapy, corresponding to a highly significant further proportional risk reduction of 15% (95% CI 11—18; p<0·0001) associated with the mean 0·51 mmol/L further LDL cholesterol reduction.

In the updated meta-analysis of 21 trials of statin versus control, 7136 (2·8% per annum) of 64 744 participants allocated statin therapy had first major vascular events versus 8934 (3·6% per annum) of 64 782 allocated control, corresponding to a highly significant 22% (95% CI 19—24; p<0·0001) risk reduction with a 1·07 mmol/L LDL cholesterol reduction. Overall, the weighted average reduction in major vascular events was 21% (95% CI 19—23; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol.

Taking all 26 trials together, the risk reduction was 22% (95% CI 20—24; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol at 1 year, with a significant 12% reduction during the first year after randomisation (p<0·0001) and highly significant reductions of about a quarter during each subsequent year (all p<0·0001).

In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11—18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7—19; p<0·0001), in coronary revascularisation of 19% (95% CI 15—24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5—26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control.

Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87—0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74—0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81—0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84—1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81—1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92—1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96—1·04; p=0·9), even at low LDL cholesterol concentrations.

Overall, there was a 22% proportional reduction in the risk of major vascular events for each 1 mmol/L reduction in LDL cholesterol, which implies that, at least within the range of LDL cholesterol studied to date, a 2 mmol/L reduction would reduce the risk by about 40% (since the combination of risk ratios of 0·78×0·78 yields a risk ratio of about 0·6), and a 3 mmol/L reduction could reduce the risk by about 50%.

In the combined meta-analysis coronary mortality was reduced by about a fifth per 1·0 mmol/L LDL cholesterol reduction, but the reduction in cardiac deaths that were not attributed to coronary disease was only about half as large.

There was no evidence in the analyses of an increase in incidence of cancer.The lowering of LDL cholesterol with statin therapy was associated with a non-significant excess (257 vs 220; p=0·2 of incidence of haemorrhagic strokes

These findings suggest that the primary goal for patients at high risk of occlusive vascular events should be to achieve the largest LDL cholesterol reduction possible without materially increasing myopathy risk.

Current therapeutic guidelines tend to emphasise the need to reach a particular LDL cholesterol target—for example, US National Cholesterol Education Program guidelines suggest that the objective in high-risk patients should generally be to reduce LDL cholesterol to below 100 mg/dL (2·6 mmol/L) or, optionally, for very high risk patients, to below 70 mg/dL (1·8 mmol/L).

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61350-5/fulltext#

SEARCH trial

The results of SEARCH trial have been published in the November issue of Lancet.(1) It was a double blind randomized trial involving 12 064 men and women aged 18—80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not.

The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. 

Aim was to establish reliably the balance of efficacy and safety of more intensive LDL-cholesterol-lowering therapy by comparing long-term treatment with 80 mg versus 20 mg simvastatin daily in a large population of patients at high risk of cardiovascular events.

Mean follow-up duration was 6·7 (SD 1·5) person-years: 40 129 person-years in those allocated 80 mg and 40 158 person-years in those allocated 20 mg simvastatin daily.

Compliance: Among participants allocated 80 mg simvastatin, 5275 (90%) were compliant after 12 months, and 2555 (77%) after 84 months. Compliance in patients on 20 mg simvastatin was similar after 12 months, but had dropped to 69% by 84 months, with an increasing proportion of patients having started a non-study statin. The main reason for discontinuation of study treatment in participants was medical advice, generally because of a perceived need for more intensive cholesterol-lowering therapy. By contrast, slightly more of the patients allocated 80 mg simvastatin were likely to stop because of raised liver or muscle enzyme concentrations or to have reported muscle pain or weakness.

At 2 months, LDL cholesterol was reduced by 0·51 (SE 0·06) mmol/L more in those allocated 80 mg simvastatin (as originally anticipated), but that difference had decreased to 0·34 (0·02) mmol/L by 84 months (mainly because of increasing non-compliance with the allocated treatment), yielding a weighted average difference during the study of 0·35 (0·01) mmol/L.

Major vascular events occurred during the scheduled treatment period in 1477 (24·5%) of the 6031 participants allocated 80 mg simvastatin versus 1553 (25·7%) of the 6033 allocated 20 mg simvastatin. This non-significant reduction in risk did not increase significantly with duration of treatment (p value for trend=0·7). Among participants in the low, middle, and high thirds of baseline LDL cholesterol, allocation to 80 mg simvastatin produced further average reductions in LDL cholesterol of 0·30 (SE 0·02), 0·37 (0·02), and 0·36 (0·02) mmol/L, respectively, but no significant difference between the major vascular event reductions.

The numbers of deaths attributed to vascular causes (565 [9·4%] vs 572 [9·5%]) or non-vascular causes (399 [6·6%] vs 398 [6·6%]) did not differ significantly between the treatment groups.

Persistent increases of alanine aminotransferase to four times the upper limit of normal were rare, and no significant difference was found between the treatment groups. Myopathy was confirmed in 53 (1%) participants and two participants in 80 mg simvastatin and 20 mg simvastatin groups respectively.

In the larger and longer SEARCH trial, LDL cholesterol was reduced from an average of 2·52 mmol/L to an average of 2·17 mmol/L for about 7 years and, again, there were similar numbers of non-vascular deaths in both groups (399 [6·6%] on 80 mg simvastatin vs 398 [6·6%] on 20 mg simvastatin), as well as similar numbers with incident cancer (640 [10·6%] vs 677 [11·2%]). The higher absolute rate of non-vascular mortality in SEARCH reflects both the older age of the participants and the longer study duration.

(1)

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60310-8/fulltext

World Diabetes Day 14th November, 2010

The European Society of Cardiology marked the World Diabetes Day by emphasizing the simple steps for diabetics.

The press release highlights that the forecast of 330 million diabetes cases worldwide by 2050. This figure represents a staggering 3% of the predicted global population.

The mechanisms that link the onset of diabetes with subsequent development of CVD include above-average lipid levels, inflammation of vascular walls, high blood pressure, and an excess of ‘bad’ cholesterol produced by the liver. 

Additionally, the effects of continuing to smoke are particularly potent for diabetics, with a dramatic increase in mortality rates being an inevitable outcome.  Despite this, most diabetics can greatly alleviate the symptoms of CVD by making sensible diet and lifestyle choices.

The members said that the the impact of growing obesity levels is pushing Type 2 diabetes into an epidemic.  It is a very serious problem for healthcare providers due to the cost of treatment, but also for cardiologists who now see diabetes prevention as one of the main health challenges.

Around 60% of cardiovascular patients nowadays are pre-diabetic or diabetic, a significant increase from our experience of 20 years ago.”

Diabetics with CVD are urged to follow the ESC recommendations for patients which, quite simply, are summarised as:

• Eat a healthy diet
• Exercise more
• Stop smoking
• Limit alcohol intake

Following this common sense advice will have a very positive impact on the progression of CVD.  They stressed that the complications of CVD when added to the underlying effects of diabetes are a dangerous combination that should be avoided at all costs.  That is why it is important to manage the diet and lifestyle changes to prevent the progression of CVD.

The press release also highlighted the pioneering work done by “Chronic Disease Alliance” organization in Europe.

http://www.escardio.org/about/press/press-releases/pr-10/Pages/World-Diabetes-Day.aspx