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.
European Society of Cardiology: Prasugrel Can’t Top Clopidogrel in ACS
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.
Source reference:
Roe M, et al “Prasugrel versus clopidogrel for acute coronary syndromes without revascularization” N Engl J Med2012; DOI: 10.1056/NEJMoa1205512.
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
 |
|
|---|---|
| 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.
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 acid, gout, 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
- ^ 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.ED. PMID 15723979.
- ^ Straessen JA, Li Y, and Richart T (2006). “Oral Renin Inhibitors”. Lancet 368 (9545): 1449–56. doi:10.1016/S0140-6736(06)69442-7. PMID 17055947.
- ^ “First Hypertension Drug to Inhibit Kidney Enzyme Approved”. CBC. 2007-03-06. Retrieved 2007-03-14.[dead link]
- ^ Healthzone.ca: Blood-pressure drug reviewed amid dangerous side effects
- ^ “Chemistry & Biology : Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin”. ScienceDirect. Retrieved 2010-01-20.
- ^ Baldwin CM, Plosker GL.[1]. doi:10.2165/00003495-200969070-00004. Drugs 2009; 69(7):833-841.
- ^ 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.
- ^ PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs
- ^ 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.
- ^ a b Drugs.com: Tekturna
- ^ European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.
External links
- Prescribing Information for Tekturna
- aliskiren at the US National Library of Medicine Medical Subject Headings (MeSH)
- Chemical synthesis
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