The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes
2006; Lippincott Williams & Wilkins; Volume: 114; Issue: 25 Linguagem: Inglês
10.1161/circulationaha.106.655761
ISSN1524-4539
AutoresVictor J. Dzau, Elliott M. Antman, Henry R. Black, David L. Hayes, JoAnn E. Manson, Jorge Plutzky, Jeffrey J. Popma, William Stevenson,
Tópico(s)Healthcare cost, quality, practices
ResumoHomeCirculationVol. 114, No. 25The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBThe Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient OutcomesPart II: Clinical Trial Evidence (Acute Coronary Syndromes Through Renal Disease) and Future Directions Victor J. Dzau, Elliott M. Antman, Henry R. Black, David L. Hayes, JoAnn E. Manson, Jorge Plutzky, Jeffrey J. Popma and William Stevenson Victor J. DzauVictor J. Dzau From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). , Elliott M. AntmanElliott M. Antman From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). , Henry R. BlackHenry R. Black From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). , David L. HayesDavid L. Hayes From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). , JoAnn E. MansonJoAnn E. Manson From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). , Jorge PlutzkyJorge Plutzky From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). , Jeffrey J. PopmaJeffrey J. Popma From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). and William StevensonWilliam Stevenson From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women's Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Originally published19 Dec 2006https://doi.org/10.1161/CIRCULATIONAHA.106.655761Circulation. 2006;114:2871–2891This is the second part of a 2-part article that presents a critical and comprehensive update of the current evidence for a cardiovascular disease (CVD) continuum based on the results of pathophysiological studies and the outcome of a broad range of clinical trials that have been performed in the past 15 years. In part I, we reviewed the current understanding of CVD pathophysiology and discussed data from clinical trials on subjects ranging from risk factors for disease through stable coronary artery disease (CAD). The present article continues the review of clinical trials, beginning with acute coronary syndromes (ACS) and continuing through extension of the concept of the CVD continuum to include stroke and renal disease. The article concludes with a discussion of areas in which future research might further clarify our understanding of the CVD continuum.Acute Coronary SyndromesACS represent a spectrum of events ranging from unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI) to ST-segment elevation myocardial infarction (STEMI). ACS events are frequently the consequence of thrombotic occlusion of a coronary artery. Intervention at this point in the CVD continuum clearly interrupts disease progression by preventing cardiac muscle death, decreasing the risk of a recurrent ischemic event, slowing progression to heart failure, and reducing mortality. Patients presenting with an ACS must receive prompt treatment to prevent ischemic complications; optimal management includes anti-ischemic therapy (eg, supplemental oxygen, nitroglycerin, and β-blocker), antiplatelet agents (eg, aspirin, clopidogrel, or platelet glycoprotein [GP] IIb/IIIa inhibitor), antithrombotic therapy (unfractionated heparin, low-molecular-weight heparin [LMWH]), and the use of invasive reperfusion procedures (ie, percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]). For STEMI patients, optimal therapy also includes fibrinolytic agents to restore blood flow in the occluded coronary artery.Treatment of UA/NSTEMIUA and NSTEMI are considered closely related conditions and may be indistinguishable in their early stages in terms of clinical presentation. UA and NSTEMI encompass a wide range of risk, but NSTEMI is more severe and is considered to have occurred if biochemical biomarkers of myocardial injury have been released.1Pharmacological TherapyNumerous clinical trials involving a variety of agents provide data on the beneficial role of medical therapy in patients with UA/NSTEMI.2–33 These trials are summarized in Table I of the online data supplement.Aspirin is routinely initiated in ACS patients and continued in the long term to reduce the risk of future events. The addition of clopidogrel to aspirin therapy appears to confer further benefit. Treatment of UA/NSTEMI patients for 3 to 12 months with clopidogrel (plus aspirin) significantly reduced the risk of combined cardiovascular death, nonfatal myocardial infarction (MI), and stroke compared with placebo.6 However, the risk of bleeding was increased with clopidogrel, especially in patients undergoing CABG surgery within 5 days of discontinuing clopidogrel therapy.The role of platelet GP IIb/IIIa receptor inhibitors in ACS patients who did not have persistent ST-segment elevation and who were not scheduled for immediate revascularization was examined in a meta-analysis of 6 randomized trials.34 Compared with placebo or control, GP IIb/IIIa inhibitors were associated with a significant 16% relative risk (RR) reduction in death or nonfatal MI at 5 days (95% CI 7% to 23%; P=0.0003) and a 9% RR reduction at 30 days (95% CI 2% to 15%; P=0.015).34 However, the treatment effect in the average patient is modest.1,35 Much stronger evidence exists for the benefit of using GP IIb/IIIa inhibitors as adjunctive therapy during PCI, both in patients with stable CAD, as previously discussed, and in ACS.Although many patients are treated long term with aspirin after their first hospitalization for UA, the risk of cardiac events remains high.4 Recurrent ischemic events in patients with UA appear to be due to ongoing thrombotic stimulus. A combination of aspirin to block platelet activation and moderate-intensity warfarin to suppress activation of the coagulation system, initiated within 12 to 24 hours of hospitalization for chest pain and continued for 3 months, may be superior to aspirin alone in reducing the risk of recurrent ischemic events in UA patients.4 However, clinicians are sometimes reluctant to use warfarin in this situation because of concern that patients may need to undergo CABG or a PCI procedure. The addition of intravenous unfractionated heparin to oral aspirin therapy may reduce the 3-month rates of death or MI in patients hospitalized for UA/NSTEMI, although none of the findings of the 6 trials included in a meta-analysis by Oler et al reached statistical significance.36LMWHs and unfractionated heparin have similar mechanisms of action, but LMWH has important pharmacokinetic advantages; for example, it can be administered subcutaneously rather than intravenously, has a longer half-life, and has a bioavailability approaching 100% (versus about 30%).36 A number of trials have evaluated the use of LMWH in acute and long-term treatment of UA/NSTEMI.1,17–25 Most18,22–24 but not all25 studies have suggested that short-term treatment with enoxaparin is superior to unfractionated heparin in reducing the risk of death or cardiac ischemic events in patients with UA/NSTEMI, although studies using other LMWH compounds have reported no difference in clinical outcomes and/or increased bleeding with LMWH.19,20Statin therapy also provides benefit in UA/NSTEMI patients. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study31 evaluated the effect of statin therapy initiated shortly after onset of an ACS (ie, UA/NSTEMI) on mortality and nonfatal ischemic events. Results indicated that administration of atorvastatin 80 mg/d within 24 to 96 hours of an ACS reduces the incidence of recurrent ischemic events in the first 4 months compared with placebo, primarily by lowering the risk of symptoms of UA that require hospitalization. Contrasting results were reported by the A to Z trial, which compared early intensive versus delayed simvastatin treatment in 4497 ACS patients.32 Patients were randomized to simvastatin 40 mg/d for 1 month followed by 80 mg/d or to placebo for 4 months followed by simvastatin 20 mg/d for the remainder of the 2-year study. At 4 months, there was no difference in occurrence of the primary outcome (composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke); however, from 4 months to the end of the study, simvastatin 80 mg/d significantly decreased the RR of the primary outcome by 25% (95% CI 5% to 40%; P=0.02) versus simvastatin 20 mg/d.32Findings from the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial33 also suggest that ACS patients may derive more benefit from long-term, aggressive lipid-lowering therapy than from more moderate therapy. Patients hospitalized for an ACS and treated with atorvastatin 80 mg/d were significantly less likely to experience a major coronary event in the following 2 years than those who received pravastatin 40 mg/d. These results were correlated with the on-treatment levels of low-density lipoprotein (LDL) cholesterol achieved (62 versus 95 mg/dL for atorvastatin and pravastatin, respectively), providing yet more support for the "lower is better" hypothesis. The clinical benefit of more intensive lipid-lowering therapy became evident as early as 30 days after initiation of treatment.33Coronary RevascularizationPatients with UA/NSTEMI who have recurrent symptoms or ischemia despite adequate medical therapy or who have high-risk indicators should be considered for coronary angiography.1 The decision to undertake a revascularization procedure follows from the results of angiographic evaluation. Numerous clinical trials37–62 have evaluated the use of PCI in patients with ACS and are summarized in Table II of the online data supplement. Pretreatment of UA/NSTEMI patients undergoing PCI with clopidogrel and aspirin followed by long-term (up to 12 months) clopidogrel therapy significantly reduces the risk of combined cardiovascular death, MI, or urgent target-vessel revascularization by 30% at 30 days (95% CI 3% to 50%; P=0.03) and decreases the risk of cardiovascular death or MI by 25% (95% CI 0% to 44%; P=0.047) at a mean follow-up of 8 months.55Numerous trials have shown that platelet GP IIb/IIIa inhibitors reduce the occurrence of early complications in patients with UA/NSTEMI undergoing PCI.1 For example, the C7E3 Fab Antiplatelet Therapy in Unstable Refractory angina (CAPTURE) trial51 evaluated the effect of abciximab versus placebo administered 18 to 24 hours before balloon angioplasty and for 1 hour thereafter. All patients had undergone coronary angiography before randomization. The rate of death, MI, or urgent revascularization within 30 days was significantly (P=0.012) reduced from 15.9% with placebo to 11.3% with abciximab. At 6 months, death or MI had occurred in 10.6% of the placebo group compared with 9% of the abciximab group; this difference was not significant.51 Recently announced results of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial62 suggest that the direct thrombin inhibitor bivalirudin alone is as effective as either unfractionated heparin/enoxaparin plus GP IIb/IIIa inhibition or bivalirudin plus GP IIb/IIIa inhibition in terms of net clinical benefit and preventing ischemic events in UA/NSTEMI patients undergoing PCI. Furthermore, bivalirudin was associated with fewer major bleeding complications than either therapy that used GP IIb/IIIa inhibition.62Early Medical Therapy Versus Early Invasive ProceduresClinical trials have assessed the relative benefits of early conservative treatment (ie, medical management, with angiography and revascularization reserved for patients with recurrent ischemia and a strongly positive stress test) versus early invasive treatment (ie, routine use of angiography and revascularization).37,38,57,58 The Veterans Affairs Non-Q-Wave Infarction Strategy In-Hospital (VANQWISH) trial57 evaluated the effect of routine early coronary angiography or a conservative treatment strategy on death or recurrent nonfatal MI in patients who developed non–Q-wave MI after fibrinolytic therapy. Outcomes were similar with either strategy. However, subsequent findings from the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC II)58 and Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 (TACTICS–TIMI 18)37 trials are more relevant in the current clinical environment. Both of these trials made use of modern antiplatelet and antithrombotic therapies, and both demonstrated a reduced risk of the combined end point of death, MI, and rehospitalization with an early invasive strategy.Findings from the third Randomized Intervention Trial of Unstable Angina (RITA-3)38 showed that UA/NSTEMI patients treated with an invasive strategy had significantly reduced rates of refractory or severe angina at 4 months and at 1 year compared with those treated with a conservative strategy. There was no difference in the combined occurrence of death or nonfatal MI at 1 year; however, after 5 years, early interventional treatment decreased the RR of this composite outcome by 22% (95% CI 1% to 39%; P=0.044) and of all-cause mortality by 24% (95% CI 0% to 42%; P=0.054).59 Different results were reported by the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial60 in ACS patients without ST-segment elevation. The overall rates of combined death, nonfatal MI, or rehospitalization for anginal symptoms did not differ between the 2 groups. Some notable features of the ICTUS trial included the use of a loading dose of clopidogrel (in combination with aspirin) after this agent received an indication for treatment of ACS in 2002, the recommendation that atorvastatin 80 mg be started as soon as possible after randomization, and the high rate of in-hospital revascularizations (40%) in patients assigned to conservative therapy.60Antithrombotic pretreatment for 3 to 5 days before PCI had no clinical advantage compared with immediate ( 25 000 patients with STEMI examined the use of unfractionated heparin and LMWH when added to aspirin and fibrinolytic therapy.103 Intravenous unfractionated heparin during hospitalization did not prevent reinfarction or death; however, LMWH given for 4 to 8 days reduced reinfarction by ≈25% and death by ≈10% compared with placebo and reduced reinfarction by almost one half when directly compared with unfractionated heparin.103The potential benefit of combination therapy with platelet GP IIb/IIIa inhibitors and fibrinolytics has been evaluated in STEMI patients both in angiographic trials81–84 and in trials with "hard" clinical events as the primary outcome.86 Although mortality trials using a reduced dose of reteplase (GUSTO-V)86 or tenecteplase (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen [ASSENT-3])74 showed that combined use of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic enhanced coronary artery patency versus full-dose fibrinolytic therapy alone, combination therapy with these agents plus abciximab failed to show any early or late survival benefit over full-dose fibrinolytics alone or any reduction in the risk of intracranial hemorrhage.Aspirin is part of the early management of all patients with suspected STEMI and is continued chronically after STEMI. The addition of low-intensity anticoagulation therapy (warfarin, median international normalized ratio 1.8 IU) to aspirin does not provide any clinical advantage over aspirin monotherapy.88 However, moderate- to high-intensity anticoagulant treatment (median international normalized ratio >2.0 IU) as an adjunct to aspirin has demonstrated a positive effect on reocclusion rates89 and risk of recurrent cardiovascular events or death.90The efficacy and safety of the combination of aspirin plus clopidogrel in patients with STEMI was investigated in the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28 (CLARITY–TIMI 28) trial,91 in which patients received clopidogrel or placebo in addition to aspirin and a fibrinolytic agent. Treatment with clopidogrel resulted in a 36% RR reduction (95% CI 24% to 47%; P<0.001) in the primary efficacy end point—an occluded infarct-related artery, death, or recurrent MI by the time of angiography. The rates of major bleeding and intracranial hemorrhage were similar in the clopidogrel and placebo groups.91 Another trial that evaluated the combination of aspirin plus clopidogrel was the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT),92,98 which used a 2×2 factorial design to assess the effects of early addition of clopidogrel or the β-blocker metoprolol (each compared with placebo) in STEMI patients also receiving aspirin therapy. In the clopidogrel arm of the study, the incidence of death, reinfarction, and stroke (primary composite end point) was significantly lower in the clopidogrel group than with placebo.92 The use of concomitant fibrinolytic therapy did not influence the risk reduction in the primary end point.Although β-blockers have long been considered an integral part of the treatment of ACS,104 only a few trials have evaluated early β-blockade in STEMI patients receiving fibrinolytic therapy. The results of the β-blocker arm of the COMMIT trial help to fill this void.105 COMMIT showed that metoprolol administered for a median of 16 days during hospitalization did not significantly reduce the risk of all-cause mortality or combined death, reinfarction, or cardiac arrest.98 There was a significant 18% RR reduction in reinfarction and a 17% reduction in ventricular fibrillation (both P=0.001), but these benefits were offset by an increase of 30% (P<0.00001) in the risk of cardiogenic shock, chiefly on the first day of hospitalization.98 This result suggests that use of β-blockers during acute MI be deferred until patients are hemodynamically stable.105PCI-Based ReperfusionThe 1990s saw the increasing use of PCI as a way of opening up thrombosed coronary arteries in STEMI patients. PCI has been used in various treatment settings, including as a primary intervention and after failed fibrinolysis. A review of 23 randomized trials comparing primary PCI with fibrinolytic therapy for the treatment of STEMI suggested that PCI was superior to fibrinolytic therapy in lowering the 4- to 6-week post-MI risk of death, nonfatal reinfarction, and disabling stroke.106 However, the most recent American College of Cardiology/American Heart Association guidelines for the management of STEMI patients104 emphasize that timely treatment after the onset of symptoms is the key determinant of short- and long-term outcomes regardless of whether reperfusion is accomplished by fibrinolysis or PCI. Accordingly, the goal is to facilitate expeditious recognition and treatment of patients with STEMI, so that initiation of fibrinolytic therapy can be achieved within 30 minutes or time to PCI (balloon inflation) can be kept under 90 minutes. For patients who have rapid ( 4500 STEMI patients that showed that the facilitated approach resulted in higher rates of mortality, nonfatal reinfarction, and urgent target-vessel revascularizations than primary PCI.109Post-MI PatientsSurvivors of an acute MI are at high risk for the development of heart failure and for recurrent MI and other CVD events. Interventions such as therapy with ACE inhibitors110–112 and cholesterol modification with statins113 decrease the risk of subsequent clinical cardiovascular events. Such evidence of target-organ protection, achieved by interruption of the underlying pathophysiology of CVD, further substantiates the existence of a CVD continuum.Neurohormonal BlockadeExtensive clinical trial evidence demonstrates that neurohormonal blockers, including β-blockers, ACE inhibitors, and angiotensin II type 1 receptor blockers (ARBs), are associated with benefit in post-MI patients.110–112,114–122 Representative clinical trials are reported in Table IV of the online data supplement. Overall, clinical trials of renin-angiotensin-aldosterone system (RAAS) inhibition with ACE inhibitors after MI have shown a 25% RR reduction (95% CI 17% to 33%; P<0.0001) in recurrent CVD events.123Randomized clinical trials conducted in the 1970s and 1980s conclusively demonstrated reductions in morbidity and mortality when β-blockers were used soon after an acute MI and continued chronically.124–126 These trials were conducted before the introduction of post-MI interventions such as fibrinolytic therapy and ACE inhibitors. The Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial114 was designed to test whether carvedilol, begun in the early post-MI period and added to standard therapy that included an ACE inhibitor, would demonstrate benefit in patients with left ventricular dysfunction, with or without clinical heart failure. CAPRICORN showed that long-term treatment with a combined α-/β-blocker, when added to ACE inhibitors and standard therapy, reduced all-cause mortality and recurrent MI.114Findings from the COoperative New Scandinavian ENalapril SUrvival Study II (CONSENSUS II)115 suggested that administration of an ACE inhibitor within 24 hours of an acute MI provided no survival benefit during the first 6 months after the MI. However, the Survival and Ventricular Enlargement (SAVE) trial116 demonstrated that in post-MI patients with asymptomatic left ventricular dysfunction, long-term treatment (mean 42 months) with an ACE inhibitor initiated within 3 to 16 days of MI significantly reduces the risk of morbidity and mortality due to major CVD events. The Studies Of Left Ventricular Dysfunction (SOLVD) prevention trial110 reported that treatment with enalapril of patients with asymptomatic left ventricular dysfunction during ≈3 years of follow-up reduced the incidence of heart failure by 37% compared with placebo (95% CI 28% to 44%; P<0.001). Moreover, a large-scale study117 demonstrated that in patients with acu
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