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Posts Tagged ‘Ticagrelor’


UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2019

Extended DAPT with Brilinta: No Benefit for Stable CAD in T2D

Substudy in those with prior PCI might identify group where bleeding tradeoff is worthwhile

PARIS — Ticagrelor (Brilinta) as part of a dual antiplatelet therapy (DAPT) regimen didn’t improve net outcomes for stable coronary artery disease (CAD) among type 2 diabetes patients, except perhaps in the setting of percutaneous coronary intervention (PCI), the THEMIS trial showed.

Adding the potent antiplatelet agent to aspirin reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke (7.7% vs 8.5%, HR 0.90, 95% CI 0.81-0.99), reported Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) congress and online in the New England Journal of Medicine.

But it also increased

  • TIMI major bleeding (2.2% vs 1.0%, HR 2.32, 95% CI 1.82-2.94) and
  • intracranial hemorrhage (0.7% vs 0.5%, HR 1.71, 95% CI 1.18- 2.48) over aspirin alone, albeit
  • without more fatal bleeding (0.2% vs 0.1%, P=0.11).

The combined effect was neutral for the exploratory composite outcome of “irreversible harm” (death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage 10.1% vs 10.8%, HR 0.93, 95% CI 0.86-1.02).

ESC session study discussant Colin Baigent, MD, of Oxford University in England, actually calculated 12 major bleeds for every eight events prevented.

“This is a consistent story: when we add an antiplatelet agent for risk reduction, we increase the risk of bleeding,” noted Richard Kovacs, MD, of Indiana University in Indianapolis and president of the American College of Cardiology.

THEMIS is the final part of a largely-disappointing PARTHENON development program for ticagrelor, he noted. “It hasn’t changed practice. …Will the main THEMIS trial change clinical practice? In my opinion, no.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81925?xid=nl_mpt_ACC_Reporter_2019-09-01&eun=g5099207d2r

 

UPDATED on 10/4/2016

Soriot’s $3.5B Brilinta dream is dashed by yet another big trial flop for AstraZeneca

by john carroll
October 4, 2016 09:00 AM EDT
Updated: 09:33 AM

Brilinta, the drug failed to demonstrate a benefit over generic Plavix (clopidogrel) for peripheral artery disease. Back in March, the heart drug flopped in a large stroke study, unable to prove that it could beat aspirin. And Soriot can chalk up those expensive studies to proving Brilinta’s serious deficiencies.

“We don’t believe the goal of $3.5 billion is attainable. I think it would be unrealistic to believe that,” Ludovic Helfgott, head of AstraZeneca’s Brilinta business, told Reuters.

Brilinta brought in a total of $619 million last year after disappointing analysts repeatedly with lower-than-expected quarterly revenue.

Heart studies aren’t cheap. AstraZeneca recruited 13,500 patients for the EUCLID study, and it had enrolled close to that number for the earlier SOCRATES trial.

SOURCE

http://endpts.com/soriots-3-5b-brilinta-dream-is-dashed-by-yet-another-big-trial-flop-for-astrazeneca/?utm_medium=email&utm_campaign=75%20Dinner%20with%20Brent&utm_content=75%20Dinner%20with%20Brent+CID_8008d3b4f16d90576238cceef624d211&utm_source=ENDPOINTS%20emails&utm_term=Soriots%2035B%20Brilinta%20dream%20is%20dashed%20by%20yet%20another%20big%20trial%20flop%20for%20AstraZeneca

UPDATED on 9/4/2014

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction

Gilles Montalescot, M.D., Ph.D., Arnoud W. van ‘t Hof, M.D., Ph.D., Frédéric Lapostolle, M.D., Ph.D., Johanne Silvain, M.D., Ph.D., Jens Flensted Lassen, M.D., Ph.D., Leonardo Bolognese, M.D., Warren J. Cantor, M.D., Ángel Cequier, M.D., Ph.D., Mohamed Chettibi, M.D., Ph.D., Shaun G. Goodman, M.D., Christopher J. Hammett, M.B., Ch.B., M.D., Kurt Huber, M.D., Magnus Janzon, M.D., Ph.D., Béla Merkely, M.D., Ph.D., Robert F. Storey, M.D., D.M., Uwe Zeymer, M.D., Olivier Stibbe, M.D., Patrick Ecollan, M.D., Wim M.J.M. Heutz, M.D., Eva Swahn, M.D., Ph.D., Jean-Philippe Collet, M.D., Ph.D., Frank F. Willems, M.D., Ph.D., Caroline Baradat, M.Sc., Muriel Licour, M.Sc., Anne Tsatsaris, M.D., Eric Vicaut, M.D., Ph.D., and Christian W. Hamm, M.D., Ph.D. for the ATLANTIC Investigators

September 1, 2014DOI: 10.1056/NEJMoa1407024

BACKGROUND

The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.

METHODS

We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours’ duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days.

RESULTS

The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used.

CONCLUSIONS

Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1407024?query=TOC

 

 

UPDATED on 2/7/2014

PLATO Controversy Hits the Wall Street Journal

February 05, 2014

NEW YORK, NY – The controversy surrounding the PLATOtrial of ticagrelor (Brilinta, AstraZeneca) continues unabated, according to a story published in the Wall Street Journal. Specifically, a sealed complaint filed in US district court in the District of Columbia by a researcher contends that the cardiovascular events in the study “may have been manipulated” [1].

Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who has long been a thorn in the side of AstraZeneca and the PLATO investigators, filed the complaint under the False Claims Act, reports theWall Street Journal. The Journal notes that the US attorney’s office in Washington, DC, has contacted Serebruany and is currently investigating the clinical trial.As reported by heartwirein October 2013, the US Department of Justice issued a civil investigative demand from its civil division “seeking documents and information regarding PLATO.” AstraZeneca is complying with the request.

First reported by heart wirein 2009 , the PLATO trial was a positive study involving more 18 000 patients from 43 countries. PLATO investigators, led by Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), showed that treating acute coronary syndrome patients with ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with patients taking clopidogrel. Results were presented at the European Society of Cardiology 2009 Congress and reported in the New England Journal of Medicine.

PLATO has been dogged by questions, including prior to approval. In the sealed complaint, Serebruany takes issue with a number of things, many of which have been reported previously. He alleges that the

  • number of clinical events among those taking clopidogrel was high compared with other studies, pointing out that the rate of all-cause death was 5.9% among clopidogrel-treated patients—nearly twice as high as earlier studies. In addition,
  • the sealed complaint documents the geographic discrepancies in the trial, noting there was a trend toward worse outcomes with ticagrelor at North American sites.The complaint also alleges that
  • an initial count of clinical events suggested the two drugs were equivalent, but adjudication by the Duke Clinical Research Institute attributed another 45 MIs to the clopidogrel group, which tipped the results in favor of ticagrelor. Other questions raised about the study include
  • site monitoring and timing of clinical events. Serebruany also alleges that
  • the trial may have unintentionally been unblinded because of the shape of clopidogrel’s “split capsules,” which would have enabled doctors and nurses to know which drug patients received.

AstraZeneca rebutted these issues, telling the Journal that it is cooperating with the government. It said it is confident in the integrity of the trial and noted the overall study showed the superiority of ticagrelor over clopidogrel. There is no evidence the trial was unblinded and researchers used the same standards when qualifying all clinical events, including MIs, they noted. In addition, the company said it is not possible to compare event rates with clopidogrel in PLATO with other studies because the patient populations differ.

The Journal reports that Serebruany became embroiled in the controversy when asked by the FDA‘s Dr Thomas Marciniak to advise the agency about the PLATO data in 2010. Marciniak, who led the FDA’s review of PLATO, called AstraZeneca’s submission on serious adverse events the “worst submission” he ever encountered. According to the submission, he noted, 12 patients reported their own deaths by telephone. Before approving ticagrelor, the FDA requested an additional analysis of PLATO, and it was eventually approved in the US in July 2011. Ticagrelor was approved in Europe in December 2010 and is authorized for use in more than 100 countries.

The Journal called Serebruany an expert in the antiplatelet field but said he is a “controversial figure,” partly because of his financial ties to industry and repeated criticisms of new drug approvals. Through HeartDrug Research, Serebruany has worked on prasugrel (Effient, Lily/Daiichi-Sankyo), a competing antiplatelet agent, but has also done work for AstraZeneca.

REFERENCE

Burton TM. Doctor challenges testing of AstraZeneca’s Brilinta. Wall Street Journal, February 2, 2014. Available here.

SOURCE

http://www.medscape.com/viewarticle/820236?nlid=47583_1984&src=wnl_edit_medn_card&uac=93761AJ&spon=2

UPDATED 3/28/2013

How AstraZeneca Will Use A Diagnostic To Market Its Blood Thinner

by Matthew Harper, Forbes Staff on 3/21/2013

Earlier today I wrote about how AstraZeneca is telling investors that its blood-thinner Brilinta, used to prevent second heart attacks, could be a multi-billion dollar drug, at least twice as big as Wall Street analysts expect. So far the drug has been a disappointment.

I wrote:

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

via Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug – Forbes.

But will the Food and Drug Administration allow Astra to tell doctors that? Stratification using troponin is not in Brilinta’s FDA-approved label, and off-label promotion is illegal. But Ferguson says that communications about troponin will be allowed because all patients with high troponin are patients who would be included in the FDA-approved indication. He confirms that use of troponin testing will be part of the new marketing plan for Brilinta.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/how-astrazeneca-will-use-a-diagnostic-to-market-its-blood-thinner/

Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug

by Matthew Herper, Forbes Staff on 3/21/2013

This morning in New York, new AstraZeneca chief executive Pascal Soriot is telling investors how he is going to turn around the company that has had the absolute worst track record in research and development among any big pharmaceutical firm. The plan is fairly wide-ranging and involves a lot of the steps one might expect:

  • new layoffs (2,300 jobs);
  • a re-focusing of research and development on three areas: heart disease and diabetes; oncology; and respiratory and inflammation;
  • new R&D initiatives involving Moderna, a biotech company, and the Karolinska Instutet;
  • moving the company’s headquarters to its R&D hub in Cambridge, U.K.;
  • re-focusing on emerging markets, where AZ already gets $6 billion in sales, especially China.

But the short-term key to delivering on his promises today seems to come down to a single drug: Brilinta, the Plavix competitor thatAstraZeneca introduced in 2011 which has so far disappointed, generating  just $324 $89 million in global sales last year. This is a medicine to prevent heart attacks and strokes in patients who suffer acute coronary syndrome, the condition that occurs after a heart attack or serious heart-related chest pain. It works by preventing the formation of blood clots.

Plavix was the second biggest drug in the world, with $6 billion in annual sales, but it is now generic. The conventional wisdom is that it will be difficult to compete with cheap generics. Brilinta is actually trailing Effient, a similar medicine from Eli Lilly, in usage. Wall Street consensus currently sees Brilinta growing to become a moderate-sized drug in 2018, with $1.3 billion in annual sales. But AstraZeneca is saying that it thinks Brilinta can be a multi-billion dollar product. Astra has confirmed that this means Brilinta will have to surpass Effient. The newer drugs also cause more bleeding than Plavix.

What is the company’s argument? In his presentation today, Paul Hudson, Astra’s Executive Vice President, North America, said that the key would be focusing on one key fact: Brilinta reduced cardiovascular deaths by 21% compared to Plavix in a big clinical trial. That would mean that if everyone eligible for Brilinta got it, 100,000 lives would be saved.

But the reality is that doctors have been skeptical of that data because in the part of that trial that was run in North America, the benefit was less clear. AstraZeneca says that this may have been due to an interaction of Brilinta and aspirin and that, according to current cardiovascular guidelines, doctors should be prescribing less aspirin anyway.

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

A lot of what Astra will do in the short term on Brilinta will be blocking and tackling. It needs to pay bigger rebates to insurers to make sure that patients can get cheap access to the drug. (This is how discounts happen in the American insurance system: the patient pays a co-payment and the insurer pays full price for the drug, but then the drug maker gives the insurer money back to make the end cost cheaper.) It will also be doing a lot of medical marketing, involving its internal experts or paid, external doctors, to get the word out about the benefits of Brilinta.

Brilinta has other advantages (it stops acting quickly) and disadvantages (it must be given twice a day). But the other big question for expanding results is whether large clinical trials that are now ongoing will show that it works in a broader array of heart patients. Astra is starting a big trial to show Brilinta prevents strokes. These trials are risky and expensive, but there will be a big payoff if they work.

Astra has some other commercial levers to point to. It’s diabetes pill Onglyza, which is sold with Bristol-Myers Squibb, will have results in a big study of its efficacy in preventing heart disease before a similar study of Merck’s top-selling Januvia, which started first. Soriot has smart ideas about which drugs to advance into later testing. But Brilinta is going to be the biggest single indicator of whether Soriot’s new strategies are paying off.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/can-pascal-soriot-turn-around-astrazeneca-it-may-come-down-to-one-drug/

BRILINTA is an antiplatelet medication

Taking BRILINTA is a first step in the treatment your physician has chosen for you. At BRILINTA.com, you will find helpful information and useful learning tools to help you complete your course of BRILINTA therapy. Make sure you and your loved ones read through all of the sections.

What is BRILINTA?

BRILINTA is a type of prescription antiplatelet medication for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart. BRILINTA is used with aspirin to stop platelets from sticking together and forming a blood clot that could block blood flow to the heart and cause another, possibly fatal, heart attack. Platelets are small cells in the blood that help with normal blood clotting.

Take BRILINTA and aspirin exactly as instructed by your doctor: BRILINTA twice a day, plus one 81-mg aspirin tablet once a day. You should not take a dose of aspirin higher than 100 mg each day because it can affect how well BRILINTA works. Tell your doctor about any medicines you are taking that contain aspirin. Do not take any new medicines that contain aspirin.

Why BRILINTA?

BRILINTA used with aspirin lowers your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal. In fact, in a large clinical study BRILINTA was even better than Plavix® (clopidogrel bisulfate) tablets at lowering your chances of having another heart attack.

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death.

Complete the
Course
 Program

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack or stroke, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. Instances of serious bleeding, such as internal bleeding, may require blood transfusions or surgery. While you take BRILINTA, you may bruise and bleed more easily and be more likely to have nosebleeds. Bleeding will also take longer than usual to stop.

Call your doctor right away if you have any signs or symptoms of bleeding while taking BRILINTA, including: severe, uncontrollable bleeding; pink, red, or brown urine; vomit that is bloody or looks like coffee grounds; red or black stool; or if you cough up blood or blood clots.

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Tell all your doctors and dentists that you are taking BRILINTA. To decrease your risk of bleeding, your doctor may instruct you to stop taking BRILINTA 5 days before you have elective surgery. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Take BRILINTA and aspirin exactly as instructed by your doctor. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Tell your doctor if you take other medicines that contain aspirin. Do not take new medicines that contain aspirin.

Do not take BRILINTA if you are bleeding now, especially from your stomach or intestine (ulcer), have a history of bleeding in the brain, or have severe liver problems.

BRILINTA can cause serious side effects, including bleeding and shortness of breath. Call your doctor if you have new or unexpected shortness of breath or any side effect that bothers you or that does not go away. Your doctor can decide what treatment is needed.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works.

Approved uses
BRILINTA is a prescription medicine for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal.

Please read Prescribing Information, including Boxed WARNINGS.

Please read Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are without prescription coverage and cannot afford your medication, AstraZeneca may be able to help. For more information, please visit www.AstraZeneca.com.

This product information is intended for US consumers only.

BRILINTA is a trademark of the AstraZeneca group of companies.

Plavix® is a registered trademark of sanofi-aventis.

©2012 AstraZeneca.706809-1789005 8/12

SOURCE:

http://www.brilinta.com/antiplatelet-prescription-medication.aspx#au

http://www1.astrazeneca-us.com/pi/brilinta.pdf

BRILINTA (ticagrelor)

Ticagrelor (trade name Brilinta in the US, Brilique and Possia in the EU) is a platelet aggregation inhibitor produced by AstraZeneca. The drug was approved for use in the European Union by the European Commission on December 3, 2010.[1][2] The drug was approved by the US Food and Drug Administrationon July 20, 2011.[3]

Indications

Ticagrelor is indicated for the prevention of thrombotic events (for example stroke or heart attack) in patients with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.[4] Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel significantly reduces the rate of death.[5]

Contraindications

Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzymeCYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.[4]

Adverse effects

The most common side effects are shortness of breath (dyspnea, 14%)[6] and various types of bleeding, such as hematomanosebleedgastrointestinalsubcutaneous or dermal bleeding. Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[4]

Physical and chemical properties

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity toadenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.[1]

Ticagrelor as a nucleoside analogue

The nucleoside adenosinefor comparison

Pharmacokinetics

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[7] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor’s plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as ‘coloured’ and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.[4]

Mechanism of action

Like the thienopyridines prasugrelclopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.[8] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).[9][10][11]

Comparison with clopidogrel

The PLATO trial, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084), higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding. Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001)[5] The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.[12] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials’ primary efficacy outcomes should not be significant[13]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[14] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.[4][15]

Interactions

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John’s wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxinciclosporin and other P-gp substrates. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.[4]

In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.[16]

References

  1. a b “Assessment Report for Brilique”European Medicines Agency. January 2011.
  2. ^ European Public Assessment Report Possia
  3. ^ “FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes”. FDA. 20 July 2011.
  4. a b c d e f Haberfeld, H, ed. (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
  5. a b Wallentin, Lars; Becker, RC; Budaj, A; Cannon, CP; Emanuelsson, H; Held, C; Horrow, J; Husted, S et al. (August 30, 2009). “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”NEJM 361 (11): 1045–57. doi:10.1056/NEJMoa0904327PMID 19717846.
  6. ^ Brilinta: Highlights of prescribing information
  7. ^ Teng, R; Oliver, S; Hayes, MA; Butler, K (2010). “Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects”. Drug metabolism and disposition: the biological fate of chemicals 38 (9): 1514–21. doi:10.1124/dmd.110.032250PMID 20551239.
  8. ^ Birkeland, Kade; Parra, David; Rosenstein, Robert (2010). “Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor”Journal of Blood Medicine 1: 197–219.
  9. ^ H. Spreitzer (February 4, 2008). “Neue Wirkstoffe – AZD6140” (in German). Österreichische Apothekerzeitung (3/2008): 135.
  10. ^ Owen, RT, Serradell, N, Bolos, J (2007). “AZD6140”. Drugs of the Future 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
  11. ^ Tantry, Udaya S; Bliden, Kevin P (2010). “First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel”. Circulation: Cardiovascular Genetics 3: 556–566. doi:10.1161/CIRCGENETICS.110.958561.
  12. ^ Bernardo Lombo, José G Díez. Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes Core Evid. 2011; 6: 31–42. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065559/
  13. ^ Serebruany VL, Atar D. Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials—Common patterns in TRITON, RECORD, and PLATO? Thromb Haemost 2012; DOI: 10.1160/TH12-04-0251. http://www.theheart.org/article/1433145/print.do
  14. ^ Miller, R (24 February 2010). “Is there too much excitement for ticagrelor?”. TheHeart.org.
  15. ^ H. Spreitzer (17 January 2011). “Neue Wirkstoffe – Elinogrel” (in German). Österreichische Apothekerzeitung (2/2011): 10.
  16. ^ July 20, 2011 AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval Larry Husten cardiobrief.org/2011/07/20/astrazeneca-ticagrelor-brilinta-gains-fda-approval/

SOURCE:

 http://en.wikipedia.org/wiki/Ticagrelor
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Reporter and Curator: Aviva Lev-Ari, PhD, RN

WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting): Get Rid Of The Aspirin In Triple Therapy

According to current guidelines and clinical practice, PCI patients already taking an oral anticoagulant generally end up on triple therapy comprising the anticoagulant plus clopidogrel and aspirin. However, there is no supporting evidence base for this approach and the triple therapy regimen is known to increase bleeding complications. Now a new study– the first randomized trial to address this situation, according to the investigators–  may have a large impact on clinical practice by demonstrating that the omission of aspirin in this context appears to be safe and may reduce adverse events.

Results of the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting) trial were presented by Willem Dewilde at the ESC in Munich today. Investigators in the Netherlands and Belgium randomized 573 patients to triple therapy or dual therapy of an anticoagulant plus clopidogrel for at least one month after implantation of a bare-metal stent or one year after a drug-eluting stent. Two-thirds of the patients were receiving oral anticoagulation for atrial fibrillation.

The primary endpoint, the total number of bleeding events, was dramatically reduced in the dual therapy group at one year:

  • 44.9% in the triple therapy group versus 19.5% (HR 0.36, CI 0.26-0.50)

There were 3 intracranial bleeds in each group. Most of the difference in bleeding occurred in TIMI minor and minimal bleeding. The difference in TIMI major bleeding (3.3% versus 5.8%) did not achieve statistical significance.

Clinical events, the trials’s secondary endpoint, were numerically lower in the dual therapy group. The difference in mortality achieved statistical significance.

  • Mortality: 7 deaths (2.6%) in the dual therapy group versus 18 deaths (6.4%) in the triple therapy group, p=0.027
  • MI: 3.3% versus 4.7%, p=0.382
  • TVR: 7.3% versus 6.8%, p=0.876
  • Stroke: 1.1% versus 2.9%, p=0.128)
  • Stent thrombosis: 1.5% versus 3.2%, p=0.165

“The WOEST study demonstrates that omitting aspirin leads to less bleedings but does not increase the risk of stent thrombosis, stroke or myocardial infarction,” said Dewilde in an ESC press release. “Although the number of patients in the trial is limited, this is an important finding with implications for future treatment and guidelines in this group of patients known to be at high risk of bleeding and thrombotic complications.”

David Holmes said the trial addressed “an incredibly important issue” and predicted that it would “change the way we practice medicine, it will change practice right away.” Keith Fox said that the evidence base prior to WOEST was extremely limited and that the trial showed that there was no hazard in doing without aspirin. The ESC discussant, Marco Valgimigli, said the trial showed it was safe to drop aspirin and provided another demonstration that “we have hit the wall” with anticoagulation.

Republished with permission from CardioExchange, a NEJM group publication.

http://www.forbes.com/sites/larryhusten/2012/08/28/woest-get-rid-of-the-aspirin-in-triple-therapy/

European Society of Cardiology: Prasugrel Can’t Top Clopidogrel in ACS

 By Todd Neale, Senior Staff Writer, MedPage Today

Published: August 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — For patients with unstable angina or non-ST-segment elevation myocardial infarction (non-STEMI) who do not undergo revascularization, increasing platelet inhibition may not improve outcomes, a randomized trial showed.

Added to a background of low-dose aspirin, prasugrel (Effient) did not significantly reduce the rate of MI, stroke, or cardiovascular death compared with clopidogrel (13.9% versus 16%, HR 0.91, 95% CI 0.79 to 1.05), according to Matthew Roe, MD, of Duke University in Durham, N.C.

The risk of severe bleeding was similar with both drugs, although minor and moderate bleeding were increased with prasugrel, Roe reported at the European Society of Cardiology meeting here. The findings were published simultaneously online in the New England Journal of Medicine.

“I think the outcome is a bit surprising because we think usually that more aggressive antiplatelet therapy, conceivably, in the face of an acute coronary syndrome and non-ST-elevation would lead to lesser adverse outcome from acute myocardial infarction or death,” said William Zoghbi, MD, from Methodist DeBakey Heart Center in Houston and president of the American College of Cardiology.

But he said clinicians need to respect the data “and start thinking about pathogenesis and what we’re trying to do with any of our new interventions.”

In patients with unstable angina or non-STEMI, practice guidelines call for angiography within 48 to 72 hours with provisional revascularization. Many of these patients do not ultimately undergo revascularization, placing them at greater risk compared with those who have their arteries opened with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG).

Recommended medical therapy is with clopidogrel and aspirin, which is an approach that will not change from the current findings, Zoghbi said.

The purpose of the TRILOGY ACS trial was to explore whether using a more powerful platelet inhibitor — prasugrel — would improve outcomes compared clopidogrel (Plavix) in this high-risk patient subset.

The primary analysis involved 7,243 patients younger than 75 (mean age 62) who were receiving aspirin and were randomized to prasugrel 10 mg daily (or 5 mg daily for those weighing less than 132 pounds) or to clopidogrel 75 mg daily. The researchers recommended a daily aspirin dose of 100 mg or less.

A secondary, exploratory analysis involved 2,083 patients, 75 or older, who were randomized to prasugrel 5 mg daily or to clopidogrel 75 mg daily.

The lack of efficacy seen in the primary analysis of patients younger than 75 remained when patients of all ages were combined. There were no between-group differences for any of the components of the primary endpoint.

A prespecified secondary analysis taking multiple recurrent ischemic events into consideration showed a lower risk of MI, stroke, and cardiovascular death with prasugrel in the younger patients (HR 0.85, 95% CI 0.72 to 1.00, P=0.04), a finding consistent with the main results of the TRITON-TIMI 38 trial, which involved patients treated with PCI. The apparent benefit appeared after 12 months of treatment.

“Although this observation is exploratory, it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional in studies involving patients who have had an acute coronary event,” the researchers wrote.

Rates of GUSTO severe or life threatening bleeding and TIMI major bleeding — as well as intracranial hemorrhage — were similar in the two groups in both the younger patients and in the overall study population. When minor and moderate bleeding events were added, the bleeding rate was higher with prasugrel.

There were no widespread differences between the groups in rates of nonhemorrhagic serious adverse events, but heart failure was more frequent with clopidogrel (1.8% versus 1.3%, P=0.045).

Douglas Weaver, MD, of Henry Ford Health System, said that he does not think the findings will have any impact on the use of prasugrel, which is not indicated for the patient population included in the study.

“It just doesn’t pass muster in improving value over clopidogrel,” said Weaver, a past president of the American College of Cardiology.

From a clinical perspective, he said, an important message from the study is the evidence of the safety of a reduced dose of prasugrel in the patients 75 and older, which is a consideration when prescribing prasugrel for patients undergoing PCI.

In comments following Roe’s presentation, Raffaele De Caterina, MD, PhD, of the G. d’Annunzio University in Chieti, Italy, provided context about how the findings fit in with the rest of the literature.

He compared the current results to those of a substudy of the PLATO trial, which involved ticagrelor (Brilinta).

In that trial, ticagrelor significantly reduced vascular death, MI, and stroke (HR 0.85, 95% CI 0.73 to 1.00, P=0.045) — the primary endpoint — and all-cause death (HR 0.75, 95% CI 0.61 to 0.93).

He then highlighted the ESC guidelines on treating patients with acute coronary syndromes without persistent ST-segment elevation.

In those, ticagrelor is recommended for all patients at moderate-to-high risk of ischemic events, regardless of initial treatment strategy and including those pre-treated with clopidogrel, and prasugrel is recommended for those who have not taken another P2Y12 inhibitor, who have a known coronary anatomy, and who are proceeding to PCI.

“I believe such statements and recommendations of the guidelines should not be changed,” De Caterina said.

TRILOGY ACS was funded by Eli Lilly and Daiichi Sankyo.

Roe reported relationships with Daiichi Sankyo, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, Hoffmann-La Roche, and sanofi-aventis. The other authors reported numerous relationships with industry.

Primary source: New England Journal of Medicine

Prematurely halted ALTITUDE trial showed When added to monotherapy with either an ACE inhibitor or an angiotensin receptor blocker (ARB), aliskiren (Tekturna) did not improve outcomes in patients with type 2 diabetes who had high cardiovascular and renal risk

ESC: Aliskiren Onboard No Help in T2D

By Todd Neale, Senior Staff Writer, MedPage Today

Published: August 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — When added to monotherapy with either an ACE inhibitor or an angiotensin receptor blocker (ARB), aliskiren (Tekturna) did not improve outcomes in patients with type 2 diabetes who had high cardiovascular and renal risk, the prematurely halted ALTITUDE trial showed.

Through an average follow-up of 32 months, a composite of various cardiovascular and renal outcomes occurred in 17.9% of patients receiving the direct renin inhibitor and 16.8% of those receiving placebo (HR 1.08, 95% CI 0.98 to 1.20), according to Hans-Henrik Parving, MD, DMSc, of the University of Copenhagen and Aarhus University in Denmark.

As a Hot Line presentation European Society of Cardiology meeting here, Parving reported that there were no significant differences on any of the individual components of the endpoint — cardiovascular death, resuscitated sudden death, MI, stroke, unplanned hospitalization for heart failure, doubling of baseline serum creatinine, and onset of end-stage renal disease — or all-cause death.

The rate of stroke — mostly ischemic stroke — was numerically higher with aliskiren, although the result fell short of statistical significance (3.4% versus 2.8%; HR 1.25, 95% CI 0.98 to 1.60,P=0.07).

Thus, Parving said, using aliskiren with ACE inhibitors or ARBs in these high-risk patients “is not recommended and may even be harmful.”

The data monitoring committee for the ALTITUDE trial decided to stop the study early in December 2011 both for futility and for adverse events. Then, earlier this year, the FDA issued a warning about using aliskiren with ACE inhibitors or ARBs and changed the drug label to reflect a contraindication for such combinations in patients with diabetes or renal impairment.

The trial included 8,561 patients with type 2 diabetes who had a high risk of cardiovascular or renal disease who were randomized to aliskiren — at 150 mg daily for 1 month followed by 300 mg daily thereafter — or placebo in addition to monotherapy with either an ACE inhibitor or an ARB (but not both).

Adding aliskiren did not improve outcomes, and in fact, may have caused harm, Parving said, as indicated by the apparent increase in stroke risk.

He said that could be explained by the impaired autoregulation of patients with diabetes or by chance, as there are no indications of a stroke risk in other studies of the drug.

Johannes Mann, of Friedrich Alexander University in Erlangen, Germany, and McMaster University in Hamilton, Ontario, who served as the discussant following Parving’s presentation, agreed that it could be a chance finding, but said that it could also be a direct effect of aliskiren itself.

He concluded that the stroke risk was not explained, however, by dual renin system inhibition, because such a signal was not seen in the ONTARGET trial, which compared the combination of ramipril (an ACE inhibitor) and telmisartan (an ARB) with each drug as monotherapy.

As noted when the trial was halted last year, adverse events were more frequent in the aliskiren group.

The percentage of patients who had a potassium level of 5.5 to less than 6.0 mmol/L was greater with active treatment (21% versus 16%), as was the percentage of those with a potassium level of 6.0 mmol/L or greater (8.8% versus 5.6%).

Aliskiren carried higher risks of hyperkalemia (38.7% versus 28.6%), hypotension (12.1% versus 8%), diarrhea (9.6% versus 7.2%), and falls (2.8% versus 2.6%). There was one death caused by hyperkalemia.

Douglas Weaver, MD, of the Henry Ford Health System in Detroit, said that the findings were disappointing, but that they likely wouldn’t change how aliskiren is used in practice.

“I don’t think this is going to have a negative or a positive effect on it,” said Weaver, who is a past president of the American College of Cardiology.

ALTITUDE was sponsored by Novartis Pharma AG.

The executive committee and other investigators or their institutions received a consultancy fee. Some of the authors are employees of Novartis and therefore eligible for stock and stock options.

Primary source: European Society of Cardiology
Source reference:
Parving H-H, et al “The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)” ESC 2012; Abstract 399.

Aliskiren

From Wikipedia, the free encyclopedia
Aliskiren
Systematic (IUPAC) name
(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide
Aliskiren (INN) (trade names Tekturna, U.S.; Rasilez, U.K. and elsewhere) is the first in a class of drugs called direct renin inhibitors. Its current licensed indication is essential (primary) hypertension.

Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel.[1][2] It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of primary hypertension.[3]

In December 2011, Novartis had to halt a clinical trial of the drug after discovering increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension in patients with diabetes and renal impairment.[4]

The following recommendations are being added to the drug labels for aliskiren-containing products as of 4/20/12:

I) A new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia. II) A warning to avoid use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR] < 60 mL/min).

Mechanism of Action

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) toangiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure.

Aliskiren binds to the S3bp binding pocket of renin, essential for its activity.[5] Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.
Aliskiren is also available as combination therapy with hydrochlorothiazide.[6]

Many drugs control blood pressure by interfering with angiotensin or aldosterone. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, doctors have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so.[7][8]

Aliskiren may have renoprotective effects that are independent of its blood pressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. According to the AVOID study, researchers found that treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). Furthermore, the AVOID trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Therefore, direct renin inhibition will have a critical role in strategic renoprotective pharmacotherapy, in conjunction with dual blockade of the renin−angiotensin−aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II−receptor blockers, and aldosterone blockade.[9]

Adverse effects

  • Angioedema
  • Hyperkalemia (particularly when used with ACE inhibitors in diabetic patients)
  • Hypotension (particularly in volume-depleted patients)
  • Diarrhea and other GI symptoms
  • Headache
  • Dizziness
  • Cough
  • Rash
  • Elevated uric acidgout, and renal stones
  • Rarely: allergic swelling of the face, lips or tongue and difficulty breathing

Contraindications

  • Pregnancy: other drugs such as ACE inhibitors, also acting on the renin-angiotensin system have been associated with fetal malformations and neonatal death[10]
  • Breast feeding: during animal studies, the drug has been found present in milk.[10]

Aliskiren has not yet been evaluated in patients with significantly impaired renal function.

Drug interactions

Aliskiren is a minor substrate of CYP3A4 and, more important, P-glycoprotein:

  • Reduces furosemide blood concentration.
  • Atorvastatin may increase blood concentration, however no dose adjustment needed.
  • Possible interaction with ciclosporin (the concomitant use of ciclosporin and aliskiren is contraindicated).
  • Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-gp inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, amiodarone).
  • Doctors should stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB, and should consider alternative antihypertensive treatment as necessary.[11]

References

  1. ^ Gradman A, Schmieder R, Lins R, Nussberger J, Chiang Y, Bedigian M (2005). “Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients”. Circulation 111 (8): 1012–8. doi:10.1161/01.CIR.0000156466.02908.EDPMID 15723979.
  2. ^ Straessen JA, Li Y, and Richart T (2006). “Oral Renin Inhibitors”Lancet 368 (9545): 1449–56. doi:10.1016/S0140-6736(06)69442-7PMID 17055947.
  3. ^ “First Hypertension Drug to Inhibit Kidney Enzyme Approved”CBC. 2007-03-06. Retrieved 2007-03-14.[dead link]
  4. ^ Healthzone.ca: Blood-pressure drug reviewed amid dangerous side effects
  5. ^ “Chemistry & Biology : Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin”. ScienceDirect. Retrieved 2010-01-20.
  6. ^ Baldwin CM, Plosker GL.[1]doi:10.2165/00003495-200969070-00004. Drugs 2009; 69(7):833-841.
  7. ^ Ingelfinger JR (June 2008). “Aliskiren and dual therapy in type 2 diabetes mellitus”N. Engl. J. Med. 358 (23): 2503–5. doi:10.1056/NEJMe0803375.PMID 18525047.
  8. ^ PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs
  9. ^ Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. “Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy,” N Engl J Med 2008;358:2433-46.
  10. a b Drugs.com: Tekturna
  11. ^ European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.

External links

 http://en.wikipedia.org/wiki/Aliskiren

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