Daily Exercise May Halve Risk for Heart Failure

Daily exercise may significantly reduce the risk of heart failure, according to new research.

Heart failure, a common, disabling condition in older adults, was nearly half as likely in those who got an hour of moderate exercise or a half hour of vigorous exercise every day, researchers in Sweden found.

"The study shows that high levels of physical activity are associated with considerably lower risk of heart failure," said study researcher Dr. Kasper Andersen, a physician at Uppsala University.

It's important to note that Andersen's study found a link, not a proven cause-and-effect relationship, between activity and lower heart failure risk. Even so, he said, the association makes sense. Physical activity is known to lower the risk of developing high blood pressure, for instance, which is a risk factor for heart failure.

Exercise also lowers the odds of developing obesity and diabetes, which boost the risk of heart failure, he said. Even after adjusting for those risk factors in the study, he said, physical activity still lowered the risk of heart failure.

For the study, the researchers evaluated nearly 40,000 adults of all ages who supplied information on a regular basis to a national Swedish database beginning in 1997. None had heart failure when they began the study.

Andersen's team evaluated their total and leisure time activity and then looked at how it related to their risk of getting heart failure later.

By 2010, about 4 percent had been hospitalized for heart failure -- the heart's inability to pump enough blood and oxygen to the body's other organs.

Nearly 6 million Americans have congestive heart failure, according to the Centers for Disease Control and Prevention. As many as half of those people die within five years of their diagnosis.

In the study, published Sept. 2 in the journal Circulation: Heart Failure, the group with the highest activity levels -- more than one hour of moderate or half an hour of vigorous activity daily -- had a 46 percent lower risk of developing heart failure.

The study findings reinforce recommendations to get at least 150 minutes of moderate intensity exercise a week, Andersen said. Higher-level activity can produce additional benefit, he said.

The study data didn't include what type of exercise was done. However, Andersen recommends exercise aimed at cardiovascular conditioning, such as jogging or walking. However, any type of activity is better than nothing, he said.

The study also didn't address whether starting to exercise at midlife is too late to obtain benefits. However, Andersen said, "I think there is good evidence [from other research] that no matter at what age you start to exercise, it has positive effects on your health."

While many studies have looked at the link between exercise and heart disease risk, few have looked at the specific link between exercise and the risk of developing heart failure, said Dr. Gregg Fonarow, professor of cardiology at the University of California, David Geffen School of Medicine.

Fonarow, who wasn't involved in the study, agreed with Andersen that exercise has many favorable effects -- on blood pressure, blood cholesterol and heart muscle health, for instance.

"Exercise lowers the risk of heart attack, which in turn can lower the risk of subsequent heart failure," said Fonarow, a spokesman for the American Heart Association. "There may be other favorable effects of exercise that directly impact the risk of heart failure."

Some other studies have shown that even after heart failure is diagnosed, patients can benefit from exercise, Fonarow said. "Exercise and cardiac rehabilitation programs are recommended in national guidelines for the treatment of heart failure," he added.

The bottom line? "If preventing heart attacks, strokes, diabetes and premature cardiovascular death were not enough," said Fonarow, "this study provides an additional rationale for all adults to engage in regular physical activity."

More information

To learn more about exercising with a heart condition, visit National Jewish Health.

Posted: September 2014

10 Tips to Prevent Heart Disease And Stroke

1. Take responsibility for your health.

Cardiovascular disease is the major cause of death in America, accounting for 34 percent of deaths, many suddenly and almost all of them premature. This is down from 40 percent just four decades ago, mainly due to treatment of common risk factors. If you have diabetes, your risk increases dramatically. The best prevention against heart disease and stroke is to understand the risks and treatment options. The greatest risk is ignorance or misinformation. The first step is to take responsibility for your health.

2. Know your risks.

The most influential risk factor for cardiovascular disease is age – the older you are, the greater your risk. The second is your genetic make-up. Although everyone is excited by the scientific progress in genomics research, conclusive gene tests are still in their infancy. But, as I tell our medical students, “A good family history is a poor man’s gene test.” We have long known that if your parents, grandparents, or other relatives were afflicted with or died of heart disease, diabetes or stroke, your risk is much greater.

3. Don’t smoke or expose yourself to second-hand smoke.

The evidence is overwhelming that cigarette smoking and second-hand exposure to smoke increases the risks of heart disease, lung disease, peripheral vascular disease and stroke.

4. Maintain a healthy blood pressure.

High blood pressure, called hypertension, is known as “the silent killer” as it goes without symptoms in most individuals. High blood pressure causes wear and tear of the delicate inner lining of your blood vessels. The higher your blood pressure (BP) the greater your risk. The risk begins to increase from a pressure of 115/70 mmHg and doubles for each 10 mmHg increase in systolic (the larger number) and 5 mmHg increase in the diastolic (the smaller number). Heredity and increasing age raise the risks. Measuring blood pressures at home reflects more accurately your risk than having the blood pressure taken at a physician’s office. It is worth the investment to get a cuffmeter.

It is best not to rely only on the readings at your doctor’s office as some individuals suffer from “white coat” hypertension – their BP is up only when they are at the doctor’s office. Others have “masked” hypertension – higher when not in the doctor’s office. Prognosis is best related to home BP. But for home blood pressurereadings, you should not use finger or wrist units – only regular upper arm units.

5. Monitor your cholesterol (blood lipids).

Abnormal or high blood lipids (fats) are a major contributor to cardiovascular disease. Your blood lipids include the LDL (bad cholesterol; remember as “Lousy cholesterol”), HDL (good cholesterol; remember as “Healthy cholesterol”) and triglycerides. The lower your LDL and the higher your HDL, the better your prognosis. The amount of cholesterol in your blood is determined mainly by three factors: the amount produced by the liver (this is largely genetic), the amount absorbed from the intestinal tract (some from what you eat, but a lot more from cholesterol produced by the liver and excreted into the digestive tract) and, finally, age – your cholesterol increases with age. If you are at risk, medication is almost always necessary to lower the LDL or to raise your HDL. The ideal ratio of total cholesterol divided by HDL cholesterol is 3.0. If higher, you might need diet as therapy. The problem with diet is that, in general, it can only decrease total blood cholesterol by about 10 percent. If you have a strong family history or elevated Lp(a) (a rare abnormal cholesterol that increases the risk), drug therapy is usually needed.

6. Limit your calories.

Fad diets do not work. If any of them did, we all would be on THAT one, wouldn’t we? The obesity rate in Americans is alarming, contributing to a near epidemic of diabetes, which is a cardiovascular disease. If you have diabetes, your risk is the same as someone who already had a heart attack. Obesity is caused by consuming more calories than your body burns. Abdominal obesity is the major risk. Portion sizes and the amount of sugars in the American diet have dramatically increased over the past few decades. At the same time, the daily amount of exercise has been decreasing. It is good advice to “drink slim” (water, tea, coffee). Use portion control before you start eating and push away from the table before you are “full.”

7. Make exercise a daily habit.

The lack of exercise is contributing to the obesity epidemic in Americans. Studies indicate that walking two miles a day is optimal for overall health, and those two miles of walking do not have to be done all at once. Exercise does more than burn calories; it also activates genes that are beneficial to health in other ways. Plus, exercise is one of the best treatments for depression and anxiety. However, exercise alone cannot control or reduce your weight – you must also modify your diet.

8. Pick your pills wisely.

There is a great interest in alternative medicine and understandably so, because patients want to be empowered to take responsibility for their own health. However, many take alternative medicines because of the way they are marketed. The mere fact that a substance is “natural” does not prove its health benefit. After all, nobody in their right mind would take arsenic simply because it is “natural.” It is important to know that research data are often lacking for alternative medications, supplements and vitamins, none of which are regulated by the U.S. Food and Drug Administration (FDA).

Do we ever prescribe alternative medicines? On occasion we do! The major risk with many alternative medications is that the patient thinks they are doing something to improve health, when in fact they are not. Although some vitamins have been shown to possibly help some conditions, to date none have been shown to decrease the risk of cardiovascular disease. There are some rare exceptions, such as fish oils and niacin(vitamin B). It is also important to note that high doses of some vitamins may interfere or counteract the beneficial effects of some prescription drugs.

9. Reduce stress.

Stress contributes to cardiovascular disease and, if severe, can cause a heart attack or sudden death. There are plenty of options that help reduce stress, such as regular exercise, adequate sleep, striving for a good marriage, laughing, volunteering or attending religious services. Watching TV generally does not relieve, but can aggravate stress. Also, try to avoid situations and people who make you anxious or angry.

10. Stay informed: Science changes constantly.

The only constant is change. This is especially true in medicine as new techniques and new insights develop constantly. Do not believe every piece of “scientific information” you find in the media or advertisements. An overwhelming number of research studies that make it into scientific publications are poorly designed or yield data that are not representative, e.g., due to a lack of a sufficient number of participants. Keep in mind that many studies are financed or sponsored by individuals or companies with a vested interest in gaining favorable results. The situation can be especially confusing when scientific studies yield different or even contradicting results, and this happens quite often.

Source: heart.arizona.edu.com

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes - Study PLATO

In patients who have acute coronary syndromes with or without ST-segment elevation, current clinical practice guidelines1-4 recommend dual antiplatelet treatment with aspirin and clopidogrel. The efficacy of clopidogrel is hampered by the slow and variable transformation of the prodrug to the active metabolite, modest and variable platelet inhibition,5,6 an increased risk of bleeding,7,8and an increased risk of stent thrombosis and myocardial infarction in patients with a poor response.9 As compared with clopidogrel, prasugrel, another thienopyridine prodrug, has a more consistent and pronounced inhibitory effect on platelets,5,6 resulting in a lower risk of myocardial infarction and stent thrombosis, but is associated with a higher risk of major bleeding in patients with an acute coronary syndrome who are undergoing percutaneous coronary intervention (PCI).10

Ticagrelor, a reversible and direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12, provides faster, greater, and more consistent P2Y12 inhibition than clopidogrel.11,12 In a dose-guiding trial, there was no significant difference in the rate of bleeding with the use of ticagrelor at a dose of 90 mg or 180 mg twice daily and the rate with the use of clopidogrel at a dose of 75 mg daily. However, dose-related episodes of dyspnea and ventricular pauses on Holter monitoring, which occurred more frequently with ticagrelor, led to the selection of the dose of 90 mg twice daily for further studies.13 We conducted the Study of Platelet Inhibition and Patient Outcomes (PLATO) to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients presenting with an acute coronary syndrome.

METHODS

Study Design

PLATO was a multicenter, randomized, double-blind trial. The details of the design have been published previously.14 The executive and operations committee, consisting of both academic members and representatives of the sponsor, AstraZeneca, designed and oversaw the conduct of the trial. An independent data and safety monitoring board monitored the trial and had access to the unblinded data. The sponsor coordinated the data management. Statistical analysis was performed by Worldwide Clinical Trials, a contract research organization, in collaboration with investigators at the academic centers and the sponsor, all of whom had full access to the final study data. The manuscript was drafted by the chairs of the executive and operations committee, who were academic authors and who vouch for the accuracy and completeness of the reported data. The study design was approved by the appropriate national and institutional regulatory authorities and ethics committees, and all participants provided written informed consent.

Study Patients

Patients were eligible for enrollment if they were hospitalized for an acute coronary syndrome, with or without ST-segment elevation, with an onset of symptoms during the previous 24 hours. For patients who had an acute coronary syndrome without ST-segment elevation, at least two of the following three criteria had to be met: ST-segment changes on electrocardiography, indicating ischemia; a positive test of a biomarker, indicating myocardial necrosis; or one of several risk factors (age ≥60 years; previous myocardial infarction or coronary-artery bypass grafting [CABG]; coronary artery disease with stenosis of ≥50% in at least two vessels; previous ischemic stroke, transient ischemic attack, carotid stenosis of at least 50%, or cerebral revascularization; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of <60 ml per minute per 1.73 m2 of body-surface area). For patients who had an acute coronary syndrome with ST-segment elevation, the following two inclusion criteria had to be met: persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left bundle-branch block, and the intention to perform primary PCI. Major exclusion criteria were any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours before randomization, a need for oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.

Study Treatment

Patients were randomly assigned to receive ticagrelor or clopidogrel, administered in a double-blind, double-dummy fashion. Ticagrelor was given in a loading dose of 180 mg followed by a dose of 90 mg twice daily. Patients in the clopidogrel group who had not received an open-label loading dose and had not been taking clopidogrel for at least 5 days before randomization received a 300-mg loading dose followed by a dose of 75 mg daily. Others in the clopidogrel group continued to receive a maintenance dose of 75 mg daily. Patients undergoing PCI after randomization received, in a blind fashion, an additional dose of their study drug at the time of PCI: 300 mg of clopidogrel, at the investigator's discretion, or 90 mg of ticagrelor for patients who were undergoing PCI more than 24 hours after randomization. In patients undergoing CABG, it was recommended that the study drug be withheld — in the clopidogrel group, for 5 days, and in the ticagrelor group, for 24 to 72 hours. All patients received acetylsalicylic acid (aspirin) at a dose of 75 to 100 mg daily unless they could not tolerate the drug. For those who had not previously been receiving aspirin, 325 mg was the preferred loading dose; 325 mg was also permitted as the daily dose for 6 months after stent placement.

Outpatient visits were scheduled at 1, 3, 6, 9, and 12 months, with a safety follow-up visit 1 month after the end of treatment. The randomized treatment was scheduled to continue for 12 months, but patients left the study at their 6- or 9-month visit if the targeted number of 1780 primary end-point events had occurred by that time. Initially, patients were to be assessed by means of Holter monitoring for 7 days after randomization, until a repeat assessment at 1 month had been obtained for 2000 of the enrolled patients.

End Points

Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular causes and any death without another known cause. Myocardial infarction was defined in accordance with the universal definition proposed in 2007.14,15 Evaluation for stent thrombosis was performed according to the Academic Research Consortium criteria.16 Stroke was defined as focal loss of neurologic function caused by an ischemic or hemorrhagic event, with residual symptoms lasting at least 24 hours or leading to death.

We defined major life-threatening bleeding as fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin level of 5.0 g per deciliter or more, or the need for transfusion of at least 4 units of red cells. We defined other major bleeding as bleeding that led to clinically significant disability (e.g., intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in the hemoglobin level of at least 3.0 g per deciliter but less than 5.0 g per deciliter or requiring transfusion of 2 to 3 units of red cells. We defined minor bleeding as any bleeding requiring medical intervention but not meeting the criteria for major bleeding.

An independent central adjudication committee adjudicated all suspected primary and secondary efficacy end points as well as major and minor bleeding events.

Statistical Analysis

The primary efficacy variable was the time to the first occurrence of composite of death from vascular causes, myocardial infarction, or stroke. We estimated that 1780 such events would be required to achieve 90% power to detect a relative risk reduction of 13.5% in the rate of the primary end point in the ticagrelor group as compared with the clopidogrel group, given an event rate of 11% in the clopidogrel group at 12 months. Cox proportional-hazards models were used to analyze the data on primary and secondary end points. All patients who had been randomly assigned to a treatment group were included in the intention-to-treat analyses.

The principal secondary efficacy end point was the primary efficacy variable studied in the subgroup of patients for whom invasive management was planned at randomization. Additional secondary end points (analyzed for the entire study population) were the composite of death from any cause, myocardial infarction, or stroke; the composite of death from vascular causes, myocardial infarction, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, transient ischemic attack, or other arterial thrombotic events; myocardial infarction alone; death from cardiovascular causes alone; stroke alone; and death from any cause.

To address the issue of multiple testing, a hierarchical test sequence was planned. The secondary composite efficacy end points were tested individually, in the order in which they are listed above, until the first nonsignificant difference was found between the two treatment groups. Other treatment comparisons were examined in an exploratory manner. No multiplicity adjustment was made to the confidence intervals for the hazard ratios for the ticagrelor group as compared with the clopidogrel group.

The consistency of treatment effects over time was assessed by determining the relative risk ratios for the periods from randomization to 30 days and from 31 to 360 days. Another predefined objective was to compare the two treatment groups with respect to the occurrence of stent thrombosis. The primary safety end point was the first occurrence of any major bleeding event. Additional safety end points included minor bleeding, dyspnea, bradyarrhythmia, any other clinical adverse event, and results of laboratory safety tests. The consistency of effects on efficacy and safety end points was explored in 25 prespecified subgroups and 8 post hoc subgroups, without adjustment for multiple comparisons.

RESULTS

Study Patients and Study Drugs

We recruited 18,624 patients from 862 centers in 43 countries from October 2006 through July 2008. The follow-up period ended in February 2009, when information on vital status was available for all patients except five. The two treatment groups were well balanced with regard to all baseline characteristics (Table 1TABLE 1Baseline Characteristics of the Patients, According to Treatment Group.) and nonstudy medications and procedures (Table 2TABLE 2Randomized Treatment, Other Treatments, and Procedures, According to Treatment Group.). Both groups started the study drug at a median of 11.3 hours (interquartile range, 4.8 to 19.8) after the start of chest pain. In the clopidogrel group, taking into account both open-label and randomized treatment, 79.1% of patients received at least 300 mg, and 19.6% at least 600 mg, of clopidogrel between the time of the index event and up to 24 hours after randomization. Premature discontinuation of the study drug was slightly more common in the ticagrelor group than in the clopidogrel group (in 23.4% of patients vs. 21.5%). The overall rate of adherence to the study drug, as assessed by the site investigators, was 82.8%, and the median duration of exposure to the study drug was 277 days (interquartile range, 179 to 365).

Efficacy

The primary end point occurred significantly less often in the ticagrelor group than in the clopidogrel group (in 9.8% of patients vs. 11.7% at 12 months; hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001) (Table 3TABLE 3Major Efficacy End Points at 12 Months. and Figure 1FIGURE 1Cumulative Kaplan–Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point.). The difference in treatment effect was apparent within the first 30 days of therapy and persisted throughout the study period. As shown in Table 3 (and Figure 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org), the hierarchical testing of secondary end points showed significant reductions in the ticagrelor group, as compared with the clopidogrel group, with respect to the rates of the composite end point of death from any cause, myocardial infarction, or stroke (10.2% vs. 12.3%, P<0.001); the composite end point of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, recurrent ischemia, transient ischemic attack, or other arterial thrombotic events (14.6% vs. 16.7%, P<0.001); myocardial infarction alone (5.8% vs. 6.9%, P=0.005); and death due to vascular causes (4.0% vs. 5.1%, P=0.001). This pattern was also reflected in a reduction in the rate of death from any cause with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). The rate of stroke did not differ significantly between the two treatment groups, although there were more hemorrhagic strokes with ticagrelor than with clopidogrel (23 [0.2%] vs. 13 [0.1%], nominal P=0.10). Concerning our first secondary objective of ascertaining the effect in patients for whom invasive treatment was planned, the rate of the primary end point was also lower with ticagrelor (8.9%, vs. 10.6% with clopidogrel; P=0.003). Among patients who received a stent during the study, the rate of definite stent thrombosis was lower in the ticagrelor group than in the clopidogrel group (1.3% vs. 1.9%, P=0.009).

The results regarding the primary end point did not show significant heterogeneity in analyses of the 33 subgroups, with three exceptions (Figure 2 in the Supplementary Appendix). The benefit of ticagrelor appeared to be attenuated in patients weighing less than the median weight for their sex (P=0.04 for the interaction), those not taking lipid-lowering drugs at randomization (P=0.04 for the interaction), and those enrolled in North America (P=0.045 for the interaction).

Bleeding

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) (Figure 2FIGURE 2Cumulative Kaplan–Meier Estimates of the Time to the First Major Bleeding End Point, According to the Study Criteria. and Table 4TABLE 4Safety of the Study Drugs.). 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) (Figure 4 in theSupplementary Appendix). The two treatment groups did not differ significantly in the rates of CABG-related major bleeding or bleeding requiring transfusion of red cells. However, 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) (Figure 3 in the Supplementary Appendix). 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) (Table 4).

Other Adverse Events

Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8% of patients vs. 7.8%) (Table 4). Few patients discontinued the study drug because of dyspnea (0.9% of patients in the ticagrelor group and 0.1% in the clopidogrel group).

Holter monitoring was performed for a median of 6 days during the first week in 2866 patients and was repeated at 30 days in 1991 patients. There was a higher incidence of ventricular pauses in the first week, but not at day 30, in the ticagrelor group than in the clopidogrel group (Table 4). Pauses were rarely associated with symptoms; the two treatment groups did not differ significantly with respect to the incidence of syncope or pacemaker implantation (Table 4).

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) (Table 2). The levels of creatinine and uric acid increased slightly more during the treatment period with ticagrelor than with clopidogrel (Table 4).

DISCUSSION

PLATO shows that treatment with ticagrelor as compared with clopidogrel in patients with acute coronary syndromes significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke. A similar benefit was seen for the individual components of death from vascular causes and myocardial infarction, but not for stroke. The beneficial effects of ticagrelor were achieved without a significant increase in the rate of major bleeding.

The benefits of ticagrelor over clopidogrel were seen in patients who had an acute coronary syndrome with or without ST-segment elevation. Previous trials have shown benefits of clopidogrel in the same clinical settings.8,17-19 The advantages were seen regardless of whether patients had received appropriate initiation of treatment with the currently recommended higher loading dose of clopidogrel and regardless of whether invasive or noninvasive management was planned.20-25 The treatment effects were the same in the short term (days 0 to 30) and in the longer term (days 31 to 360). This duration of treatment benefit has also been shown with clopidogrel.26 Thus, ticagrelor appears to expand on the previously demonstrated benefits of clopidogrel across the spectrum of acute coronary syndromes.

The incremental reduction in the risk of coronary thrombotic events (i.e., myocardial infarction and stent thrombosis) through more-intense P2Y12 inhibition with ticagrelor is consistent with similar effects of prasugrel.10 As noted above, the benefits with ticagrelor were seen regardless of whether invasive or noninvasive management was planned; this issue has not been investigated with other P2Y12 inhibitors. Treatment with ticagrelor was also associated with an absolute reduction of 1.4 percentage points and a relative reduction of 22% in the rate of death from any cause at 1 year. This survival benefit from more-intense platelet inhibition with ticagrelor is consistent with reductions in the mortality rate obtained by means of platelet inhibition with aspirin in patients who had an acute coronary syndrome27,28 and with clopidogrel in patients who had myocardial infarction with ST-segment elevation.22 In contrast, other contemporary trials involving patients with an acute coronary syndrome have not shown significant reductions in the mortality rate with the use of clopidogrel,8 prasugrel,10 or glycoprotein IIb/IIIa inhibitors.29 The improved survival rate with ticagrelor might be due to the decrease in the risk of thrombotic events without a concomitant increase in the risk of major bleeding, as seen with other antithrombotic treatments in patients with an acute coronary syndrome.30-32

Since P2Y12 inhibition with ticagrelor is reversible, the antiplatelet effect dissipates more rapidly than with the thienopyridines, which are irreversible P2Y12 inhibitors. Therefore, less procedure-related bleeding might be expected. Although the rates of major bleeding were not lower with ticagrelor than with clopidogrel, the more-intense platelet inhibition with ticagrelor was not associated with an increase in the rate of any major bleeding. In contrast to the experience with prasugrel,10 which is also a more effective platelet inhibitor than clopidogrel but is irreversible, there was no increased risk of CABG-related bleeding with ticagrelor. As with prasugrel,10 non–procedure-related bleeding (spontaneous bleeding), including gastrointestinal and intracranial bleeding, was more common with ticagrelor than with clopidogrel. Although the rare episodes of intracranial bleeding were often fatal, the rates of nonintracranial fatal bleeding, death from vascular causes, and death from any other cause were lower in the ticagrelor group than in the clopidogrel group, resulting in an overall reduction in the mortality rate with ticagrelor.

Dyspnea occurred more frequently with ticagrelor than with clopidogrel.13 Most episodes lasted less than a week. Discontinuation of the study drug because of dyspnea occurred in 0.9% of patients in the ticagrelor group. Holter monitoring detected more ventricular pauses during the first week in the ticagrelor group than in the clopidogrel group,13 but such episodes were infrequent at 30 days and were rarely associated with symptoms. There were no significant differences in the rates of clinical manifestations of bradyarrhythmia between the two treatment groups.

The superiority of ticagrelor over clopidogrel with regard to the primary end point, as well as the similarity in rates of major bleeding, was consistent in 62 of 66 subgroups; the differences were significant in the remaining 4 subgroups (P<0.05 for heterogeneity). These findings may have been due to chance, given the large number of tests performed. The difference in results between patients enrolled in North America and those enrolled elsewhere raises the questions of whether geographic differences between populations of patients or practice patterns influenced the effects of the randomized treatments, although no apparent explanations have been found.

In conclusion, in patients who had an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor, as compared with clopidogrel, significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke, without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding.

Supported by AstraZeneca.

Dr. Wallentin reports receiving consulting fees from Regado Biosciences and Athera Biotechnologies; lecture fees from Boehringer Ingelheim, AstraZeneca, and Eli Lilly, and grant support from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; Dr. Becker, consulting fees from Regado Biosciences, AstraZeneca, Eli Lilly, and Bristol-Myers Squibb and grant support from Momenta Pharmaceuticals, the Medicines Company, and Bristol-Myers Squibb; Dr. Budaj, consulting fees from Sanofi-Aventis and Eli Lilly and lecture fees from Sanofi-Aventis, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. Dr. Cannon reports having equity ownership in Automedics Medical Systems and receiving grant support from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Merck, Intekrin Therapeutics, Schering-Plough, Novartis, and Takeda. Drs. Emanuelsson and Horrow report being employees of AstraZeneca and having equity ownership in AstraZeneca; Dr. Horrow also reports receiving lecture fees from the Pharmaceutical Education and Research Institute. Dr. Husted reports receiving consulting fees from AstraZeneca, Sanofi-Aventis, and Eli Lilly and lecture fees from AstraZeneca, Sanofi-Aventis, and Bristol-Myers Squibb; Dr. Katus, consulting and lecture fees from AstraZeneca; Dr. Mahaffey, consulting fees from AstraZeneca, Bristol-Myers Squibb, Johnson and Johnson, Eli Lilly, Pfizer, and Schering-Plough, lecture fees from Bayer, Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, and Sanofi-Aventis, and grant support from AstraZeneca, Portola Pharmaceuticals, Schering-Plough, the Medicines Company, Johnson and Johnson, Eli Lilly, and Bayer; Dr. Scirica, consulting fees from AstraZeneca, Cogentus Pharmaceuticals, and Novartis, lecture fees from Eli Lilly, Daiichi Sankyo, and Sanofi-Aventis, and grant support from Astra Zeneca, Daiichi Sankyo, and Novartis. Dr. Steg reports receiving consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Endotis Pharma, GlaxoSmithKline, Medtronic, Merck Sharp and Dohme, Nycomed, Servier, the Medicines Company, Daiichi Sankyo, and Sanofi-Aventis, lecture fees from the Medicines Company, Servier, Menarini, Pierre Fabre, Boehringer Ingelheim, Bristol-Myers Squibb, Glaxo Smith Kline, Medtronic, Nycomed, and Sanofi-Aventis, and grant support from Sanofi-Aventis and having equity ownership in Aterovax. Dr. Storey reports receiving consulting fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, Teva, and Schering-Plough, lecture fees from Eli Lilly, Daiichi Sankyo, and AstraZeneca, and grant support from AstraZeneca, Eli Lilly, Daiichi Sankyo, and Schering-Plough; and Dr. Harrington, consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Portola Pharmaceuticals, Schering-Plough, and AstraZeneca, lecture fees from Schering-Plough, Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly, and grant support from Millenium Pharmaceuticals, Schering-Plough, the Medicines Company, Portola Pharmaceuticals, Astra Zeneca, and Bristol-Myers Squibb.

No other potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMoa0904327) was published on August 30, 2009, at NEJM.org.

SOURCE INFORMATION

From the Uppsala Clinical Research Center, Uppsala, Sweden (L.W., C.H., S.J.); Duke Clinical Research Institute, Durham, NC (R.C.B., K.W.M., R.A.H.); Grochowski Hospital, Warsaw, Poland (A.B.); Thrombolysis in Myocardial Infarction Study Group, Brigham and Women's Hospital, Boston (C.P.C., B.M.S.); AstraZeneca Research and Development, Mölndal, Sweden (H.E.), and Wilmington, DE (J.H.); Århus University Hospital, Århus, Denmark (S.H.); Universitätsklinikum Heidelberg, Heidelberg, Germany (H.K.); Worldwide Clinical Trials U.K., Nottingham, United Kingdom (A.S.); INSERM Unité 698, Assistance Publique–Hôpitaux de Paris and Université Paris 7, Paris (P.G.S.); and the University of Sheffield, Sheffield, United Kingdom (R.F.S.).

Address reprint requests to Dr. Wallentin at Uppsala Clinical Research Center, University Hospital, 75185 Uppsala, Sweden, or at lars.wallentin@ucr.uu.se.

The Study of Platelet Inhibition and Patient Outcomes (PLATO) investigators are listed in the Appendix and theSupplementary Appendix, available with the full text of this article at NEJM.org.

APPENDIX

Members of select PLATO committees are as follows (with principal investigators at participating centers and members of other committees listed in the Supplementary Appendix): Executive Committee — Sweden: L. Wallentin (cochair), S. James, I. Ekman; H. Emanuelsson, A. Freij, M. Thorsen; United States: R.A. Harrington (cochair), R. Becker, C. Cannon, J. Horrow; Denmark: S. Husted; Germany: H. Katus; U.K.: A. Skene (statistician), R.F. Storey; France: P.G. Steg; Steering Committee — Italy: D. Ardissino; Australia: P. Aylward; Philippines: N. Babilonia; France: J.-P. Bassand; Poland: A. Budaj; Georgia: Z. Chapichadze; Belgium: M.J. Claeys; South Africa: P. Commerford; the Netherlands: J.H. Cornel, F. Verheugt; Slovak Republic: T. Duris; China: R. Gao; Mexico: G.C. Armando; Germany: E. Giannitsis; United States: P. Gurbel, R. Harrington, N. Kleiman, M. Sabatine, D. Weaver; Spain: M. Heras; Denmark: S. Husted; Sweden: S. James; Hungary: M. Keltai; Norway: F. Kontny; Greece: D. Kremastinos; Finland: R. Lassila;Israel: B.S. Lewis; Spain: J.L. Sendon; Hong Kong: C. Man Yu; Austria: G. Maurer; Switzerland: B. Meier; Portugal: J. Morais; Brazil: J. Nicolau; Ukraine: A. Nikolaevich Parkhomenko; Turkey: A. Oto; India: P. Pais; Argentina: E. Paolasso;Bulgaria: D. Raev; Malaysia: D.S. Robaayah Zambahari; Russia: M. Ruda; Indonesia: A. Santoso; South Korea: K.-B. Seung; Singapore: L. Soo Teik; Czech Republic: J. Spinar; Thailand: P. Sritara; United Kingdom: R. Storey; Canada: P. Théroux; Romania: M. Vintila; Taiwan: D.W. Wu; Data Monitoring Committee — United States: J.L. Anderson (chair), D. DeMets (statistician); the Netherlands: M. Simoons; United Kingdom: R. Wilcox; Belgium: F. Van de Werf.

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