Highlights in ischaemic cardiovascular disease

Doc dr Amra Džanković

Results from KYOTO HEART study

Designed to examine the effects of valsartan as an add-on to conventional therapy on morbidity and mortality in uncontolled hypertensive patients with one or more cardiovascular (CV) risk factors

Valsartan (up to 160mg/daily) add-on treatment to improve blood pressure (BP) control prevented more CV events than conventional

non-ARB treatment.

Results from The KYOTO HEART Study

There was significant (p<0.03) reductions in the incidents of angina pectoris, stroke, and new-onset diabetes. Adverse events were low in both groups.No benefit was seen in the reduction of MI incidence, in which most cardiologists are interested.ARBs are efficacious and even superior to other drug classes in stroke prevention, but their efficacy with regard to coronary events remains uncertain.

Results from the PROTECT Trial

The efficacy and safety of adenosine A1 receptor antagonist rolofylline versus placebo on symptoms in 2033 patients who were hospitalized with heart failure (HF) within 24 hours with signs of fluid overload, impaired renal function and high serum levels of B-type natriuretic peptide.

Rolofylline 30mg/day or placebo

Most subjects were reciving multiple HF medications within the 2 weeks prior to study enrollment, including ACE inhibitor or ARB (75%), beta-blocker (76%), aldosterone inhibitor (43%), and digoxin (28%).There was no significant difference in the primary endpoint, wherein 40.6% of rolofylline subjects versus 36% of placebo subjects achieved treatment successRolofylline appeared to incrase neurological complications , including seizures (11 subjects vs no subjects on placebo), stroke (16 vs 3).

The ACTIVE program

It was designed to evaluate the effect of additional blood pressure (BP) reduction with angiotensin receptor blocker (ARB) on common complications of patients with AF, including HF, stroke, and other embolic events.On top of this extensive background therapy, irbesartan provided an additional reduction in BP (6.8/4.5 mmHg).The composite endpoint of stroke, MI, and vascular death occurred with equal frequency in the irbesartan and placebo groups.Only one component of the primary endpoint, HF hospitalization, occurred less frequently in the irbesartan group.

BP lowering with multiple antyhipertensive agents may result in an even greater clinical benefit.

GRACE Registry Study

PCI had become the most common strategy of revascularization in emergent/serious cases but was associated with more frequent repeat revascularization in the 6 months after discharge.CABG was associated with good survival in lower-risk patients but resulted in more frequent incidents of acute stroke.PCI and CABG appear complementary, and both types of revascularization improve 6-months survival in comparsion with an initially conservative medical strategy

Primary PCI versus fibrinolysis in very elderly patients

Primary percutaneous intervention (PCI) was not found to provide an advantage over fibrinolytic therapy for very elderly patients with acute mycordial infarction.Althgouh TRIANA lacked the statistical power to demonstrate the superiority of PCI over fibrinolytic therapy, the observed risk reduction was consistent with the benefit that had been anticipated with primary PCI in the initial design of the study.Primary angioplasty should be considered the treatment of choice even for very old patients with STEMI. In situations in which primary PCI is not avaliable, safety findings from TRIANA indicate that fibrinolysis may be considered as an alternative, with an acceptable rate of intracerebral hemorrhage among old patients who are carefully selected for fibrinolytic therapy.

Results from the AAA study

Showed no support for the routine use of aspirin for the primary prevention of vascular events in people with asymptomatic atherosclerosis.There was no difference between treatment groups for either primary or secondary endpoints.There was an incrase in major hemorrhages that required hospitalization in the aspirin group (2% of subjects in the aspirin group vs 1.2% of subjects in the placebo group).Gastrointestinal ulcers were also more frequent in subjects who were taking aspirin.

Results from AAA Study

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CURRENT-OASIS 7

The clopidrogel optimal loading dose, randomized trial to determine optimal clopidrogel and aspirin dosing in subjects with acute coronary syndrome (ACS) within 24 hours of ischemic symptoms.The results of this trial are complex.Double-dose clopidrogel reduced the primary endpoint in the high-dose aspirin strata by 17% but was associated with more bleeding and transfusion overall.

Careful consideration will be important when intergating these results into clinical practice, wich likely will have bearing on future practice guidlines.

PLATO study

Ticagrelor is an investigational oral antiplatet agent that directly and reversibly inhibits the adenosine diphospathe receptor P2Y12.PLATO was designed to evaluate whether ticagrelor is superior to clopidrogel-currently therapy a component of standard therapy for ACS-in preventing vascular events and death in a broad population of patients.PLATO randomized 18,624 patients who were hospitalized with ACS with or without ST-segment elevation to ticagrelor (180-mg loading dose, 90 mg twice-daily thereafter)or clopidrogel (300-mg to 600-mg loading dose , 75mg thereafter) in double –blinded fashion and treated for up to 12 months.Of the three trials(CURE,TRITON TIMI 38 and PLATO), PLATO was only one to demonstrate a reduction in all-cause mortality with more potent platelet inhibition, reducing the risk of overall mortality compared with clopidrogel.

Results from the Re-Ly trial

Eficacy and safety of two different doses of dabigatran(oral direct trombin inhibitor,similar to ximelagatran) with warfarin therapy in patients with ECG –documented nonvalvular AF and CHADS score more than 2

Dabigatran 150 mg twice daily was more effective than warfarin in reduction stroke orTIA,and risk of major bleeding was similar in both groups

New antiischaemic drugs and results od trials: Trimetazin

Beneficial effect of trimetazidin(Preductal) on myocardial ischemia due mainly to its action in mitochondrial bodies od cardiomyofibrillies     Dose -20 mg three times daily.Data on the effectiveness of the drug in acute myocardial heart attack is contradictory.      Contraindications : pregnancy and breast feeding. Studies didn’t prove its positive effect on overall cardiovascular morbidity and mortality

New antiischaemic drugs and results od trials: Ranolazin

Ranolazine, sold under the trade name Ranexa by Gilead Sciences (who acquired the developer, CV Therapeutics in 2009), is an antianginal medication. Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia Ranolazine is indicated for the treatment of Chronic angina. Ranolazine may be used with beta-blockers,nitrates, calcium channel blockers, anti-platelet, therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. ranolazine does not significantly alter either the heart rate or blood pressure. For this reason, it is of particular use in individuals with angina that is refractory to maximal tolerated doses of other anti-anginal medications.

New antiischaemic drugs and results od trials: Ranolazin

.It has also applied to US FDA for 2 more indication such as HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits(decrease insulin resistancy). This difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization or a reduction in arrhythmia symptoms.The revised labeling also includes new language noting that Ranexa produces small reductions in HbA1c. Though Ranexa should not be considered a treatment for diabetes, Ranexa may be a particularly useful medication for the reduction of chronic angina in this patient population, which is difficult to treat because some anti anginal medications such as beta blockers increase HbA1c.

New antiischaemic drugs and results od trials:Ivabradin(Procoralan)

the first selective and specific If inhibitor, for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. . Procoralan is the first pure heart rate-lowering agent and acts by selective inhibition of the cardiac pacemaker Procoralan's effects are selective to the sinus node and the new agent has no effect on intracardiac conduction, myocardial contractility or ventricular repolarization. Unlike beta-blockers, the most common current treatment for angina, Procoralan is free from sexual disturbances, respiratory side effects caused by constriction or spasm of the airways, bradycardia or rebound phenomena. Heart rate reduction is one of the main therapeutic goals in angina treatment

New antiischaemic drugs and results od trials:Ivabradin(Procoralan)

The recommended starting dose of Procoralan is 5 mg twice daily followed by uptritration to 7.5 mg

In this context, the morbidity/mortality trial BEAUTIFUL was created,but results in patients more than 75 bpm are not promising

Edoxaban-new generation oral anticoagulant to help prevent stroke in patients with AF

A potential new treatment for stroke prevention in patients with nonvalvular AF(CHADS score more than 2)

Optimal dose is 30 or 60 mg daily in one dose.It is direct Xa factor inhibitor

Edoxaban-new generation oral anticoagulant

Bleeding associated with edoxaban is most closely associated with minimum blood concentration level,these levels are better predictors of bleeding than total exposure or maximum concentration levels

Rosuvastatin in GISSI-HF

It showed that rosuvastatin(Crestor) was not very effective in preventing incidence of AF in patients with heart failure

There are a number of unanswered questions:

Whether statins prevent AF progression and reduce the burden of AF and

Whether prevention of AF by statins improves CV morbidity or mortality

New data from the RECORD study

No difference in the primary endpoint of CV hospitalization or CV death but did demonstrate increased rates od heart failure.The HF event rates began to diverge early and continued to diverge through the trial In this trial,contrary to Nissen meta analysis,there was not statistically significant increase in coronary outcomes or an excess of CV overall mortality in patients receiving RSG compared with those receiving conventional therapy

JUPITER SUBGROUPanalysis

Showed significant reduction in major cardiovascular events in elderly,apparently healthy individuals who were treated with rosuvastatin, compared with placebo

The benefit seen from rosuvastatin is in elderly subgroup,including a reduction in stroke,and

in special population-high risk patients with low LDL and elevated hs-CRP

A subpopulation analysis from TRITON-TIMI 38 study

Results show no association between PPI(proton pump inhibition) use and increased risk for cardiovascular events in patients who are also receiving clopidogrel or prasugrelThe current findings do not support the need to avoid concomitant use of PPIs in patients treated with thienopyridines

Results from SYNTAX

Designed to compare PCI with CABG for the treatment of de novo 3VD or-and LM diseaseSYNTAX score – a novel angiographic tool for measuring the complexity of coronary artery disease based on 9 anatomic criteriaThe rates of MACCE were not significantly different between patients with low SYNTAX scores who were treated with either PCI or CABG-intermediate SYNTAX score-increase MACCE in PCI groupHigh SYNTAX score-significantly increased MACCE in patients treated with PCI