2004

One of my vivid childhood memories is of an NBC TV show in the early 1960s—That Was the Week That Was (known popularly as TW3) with “special correspondent” David Frost, broadcast live from New York City late Tuesday nights. This show was derived from an earlier, edgier BBC version (that David Frost had also hosted) and was the Ur-ancestor of a number of subsequent humor shows (such as Saturday Night Live, which debuted more than a decade later, in 1975). Aside from the fact that TW3 was one of the few TV shows that my parents would let me watch during the week, this was also one of the first times that I realized how important it was to get a different, more complete perspective on current events. There was so much more to the news than the relatively sanitized vanilla-Wonder®-Bread version presented by the news media in 1964. Yes, it could be hysterically funny, but—more seriously—it also fostered independent thinking on my part and taught me, at an early age, to avoid blind acceptance of things that “everybody knows.”

As we look back at 2004 and at some of the major advances in cardiovascular medicine that took place, I think we need to individually ask ourselves the hard question, “What have I really learned this year?” I present to you some of what I regard as the high points of new knowledge for myself in 2004.

Defibrillators and Resynchronization Therapy: SCD-HeFT and COMPANION

The Sudden Cardiac Death Heart Failure Trial (SCD-HeFT)¹ was a placebo-controlled trial in which 2,521 patients were randomized to treatment with either amiodarone or a shock-only implantable cardioverter-defibrillator (ICD). Patients had ischemic or nonischemic NYHA class II/III heart failure symptoms and an ejection fraction (EF) £35%. The object was to determine whether one of these treatments would reduce all-cause mortality; the median follow-up was 45.5 months. The 5-year event rate was 36.1% in the placebo group, 34% in the amiodarone group (P = NS), and 29% in the ICD group (P = 0.007).

Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)² was a study comparing optimal pharmacologic therapy (OPT) to OPT plus cardiac resynchronization therapy (CRT), and to OPT plus CRT and a defibrillator (CRT-D). The study comprised 1,520 patients with NYHA class III/IV congestive heart failure (CHF) symptoms, a QRS ≥120 ms, and an EF ≤35%. The primary endpoint (the composite incidence of all-cause mortality and all-cause hospitalization) at 12 months was 68% in the OPT alone group, 56% in the CRT group, and 56% in the CRT-D group. All-cause mortality was 19% in the OPT alone group, 15% in the CRT group, and 12% in the CRT-D group.

Comment: SCD-HeFT and COMPANION have demonstrated that electrically directed therapy (with defibrillators and resynchronization) conveys substantial benefit in reducing mortality and improving cardiac function in appropriately selected patients.

Cholesterol and Statins: PROVE IT/TIMI-22, A to Z, and REVERSAL

The lipid portion of PROVE IT/TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22)³ was a study of 4,162 patients, recently hospitalized for acute coronary syndrome (ACS), who were randomized to 40 mg/day of pravastatin or 80 mg/day of atorvastatin. The study was originally designed to test for equivalence of the 2 treatment regimens. However, at a mean follow-up of 24 months, the primary event rate (all-cause mortality, myocardial infarction [MI], unstable angina requiring hospitalization, revascularization, or stroke) was 26.3% in the pravastatin group and 22.4% in the atorvastatin group (P = 0.005).³ Patients in whom statin therapy was associated with C-reactive protein levels of less than 2 mg/L had better clinical outcomes regardless of the LDL cholesterol level achieved with therapy.⁴

The Z phase of the A to Z trial (Aggrastat to Zocor)⁵ was designed to compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. The study involved 4,497 ACS patients who were randomized to a 1-month, 40-mg/day regimen of simvastatin followed by 80 mg/day thereafter versus a 4-month course of placebo followed by 20 mg/day of simvastatin thereafter. The primary endpoint (a composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke) occurred in 14.4% of the early/intensive simvastatin group and in 16.7% of the early placebo/lower dose simvastatin group. No difference in the primary endpoint was noted during the first 4 months of treatment.

The Reversal of Atherosclerosis with Aggressive Lipid Lowering study (REVERSAL)⁶ was designed to compare the effect of moderate lipid-lowering therapy (40 mg of pravastatin daily) with intensive lipid-lowering therapy (80 mg of atorvastatin daily) on the rate of coronary disease progression (evaluated by intravascular ultrasonography) in 502 patients with angiographically documented coronary artery disease. Intravascular ultrasonography was performed at baseline and at 18 months; disease progression was measured with volumetric analysis of reconstructed images. Intensive lipid-lowering therapy was shown to significantly reduce both atherosclerotic progression and adverse clinical outcomes.⁶ These benefits were associated with significantly greater concomitant reductions in C-reactive protein and atherogenic lipoproteins.⁷

Comment: PROVE IT/TIMI 22, A to Z, and REVERSAL have shown that lower LDL cholesterol is better. Moreover, they suggest that exactly how you lower it may make a difference. Other mechanisms (especially inflammation, as manifested by C-reactive protein) may play an important role in the profound therapeutic effect of statins.

Hydralazine and Isosorbide Dinitrate in African-Americans: A-HeFT

The African-American Heart Failure Trial (A-HeFT)⁸ randomized 1,050 African-American patients with advanced heart failure, already on standard medical therapy, to either placebo or a fixed-dose combination of isosorbide dinitrate and hydralazine (BiDil®, NitroMed, Inc.; Lexington, Mass). The dosage was started at 1 tablet (37.5 mg hydralazine, 20 mg isosorbide dinitrate) 3 times a day, increasing to 2 tablets 3 times a day. Patients were studied for up to 18 months; the primary endpoint was a composite score consisting of weighted values for all-cause mortality, 1st hospitalization for heart failure, and quality of life (QOL) scores. The trial was stopped early by the Data Safety Monitoring Board because of a clear mortality benefit in the active therapy group (6.2%) versus the placebo group (10.2%; P = 0.02). There was also a significant reduction in the rate of 1st hospitalization for heart failure (16.4% vs 22.4%, respectively) and a significant improvement in QOL (P = 0.02). From a mechanistic standpoint, the emerging feeling is that these benefits may be due to a nitric oxide-enhancing effect, rather than the traditional hemodynamic/vasodilator view.

Comment: A-HeFT has shown that there are opportunities for therapeutic benefit in selected CHF patients who are already on effective neurohormonally-directed therapy. The mechanism of benefit of the nitrate-hydralazine combination may be mediated by enhancing nitric oxide. Whether these benefits can be generalized to non-black patients remains to be proved.

Carotid Stenting with Distal Protection: SAPPHIRE

SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy)⁹ was designed to compare carotid stenting (with the use of a distal emboli-protection device) to surgical carotid endarterectomy. These methods were carried out in 334 patients with high-risk features who had either symptomatic (≥50%) or asymptomatic (≥80%) carotid-artery stenosis. The primary endpoint was the 1-year composite incidence of adverse clinical events, including death, stroke, or MI within 30 days, or death or ipsilateral stroke from 31 days to 1 year. The intent was to test for noninferiority of carotid stenting in this setting. The incidence of the primary endpoint was 12.2% in the carotid stent group and 20.1% in the surgical endarterectomy group (P = 0.004 for noninferiority; P = 0.053 for superiority). At 1 year, the incidence of repeat revascularization was 0.6% in the stent group and 4.3% in the endarterectomy group (P = 0.04).

Comment: SAPPHIRE showed that carotid stenting with distal protection, in appropriately selected patients, is at least as good as surgical endarterectomy. Carotid stenting is here to stay.

Endocannabanoid Receptor Antagonism for Weight Loss, Smoking Cessation, and Metabolic Syndrome: RIO-Lipids, RIO-Europe, RIO-North America, and STRATUS-US

RIO-Lipids (Rimonabant in Obesity)¹⁰ was a placebo-controlled trial of rimonabant (5 mg or 20 mg) versus placebo in 1,036 overweight or obese patients who were treated for 1 year. In the 20-mg group, 44% lost more than 10% of their body weight, compared with 16.3% in the 5-mg group and 10.3% in the placebo group. The 20-mg group also had a dramatic reduction in the number of patients with metabolic syndrome.

RIO-EUROPE¹¹ involved 1,507 overweight or obese subjects, randomized to placebo, or to 5 or 20 mg of rimonabant. Significantly greater weight loss was noted in the 20-mg rimonabant group at 2 years. In that group, 39% lost more than 10% of their body weight, compared with 15.3% of those in the 5-mg group and 12.4% of those in the placebo group. In addition, rimonabant therapy was associated with salutary effects on lipid and glycemic profiles.

RIO-North America¹² was a randomized, double-blind placebo-controlled trial in which 3,040 overweight patients were randomized to placebo or to 5 or 20 mg of rimonabant. This study continued for 2 years; patients in the rimonabant arms were re-randomized at 1 year either to continue therapy or to switch to placebo. The primary endpoints of the study were the change in weight at 1 year, and the ability to maintain the changes in weight from year 1 to year 2. At the end of year 1, the 20-mg group had experienced significantly greater reductions in weight than had the placebo group, as well as more favorable effects on triglycerides, HDL cholesterol, and insulin sensitivity. At 2 years, only those patients who continued taking rimonabant were able to maintain their weight loss. Of note, at 2 years, the changes noted in lipids and insulin sensitivity in the 20-mg group were about twice that expected from a comparable degree of weight loss without the medication.

STRATUS-US (Studies with Rimonabant in Tobacco Use–United States)¹³ was a placebo-controlled study of rimonabant in 787 smokers who had failed to quit on an average of 4 previous occasions. After 10 weeks of treatment, the 20-mg rimonabant group was about twice as likely to have quit as the placebo group. Moreover, the 20-mg group lost about ½ lb, while the placebo group gained almost 2½ lbs.

Comment: From the results of RIO-Lipids, RIO-Europe, RIO-North America, and STRATUS-US, it appears that rimonabant is an effective agent for weight loss and smoking cessation, although therapy must be maintained for continued benefit. The new therapeutic target of endocannabanoid receptors holds substantial promise for the future.

Clopidogrel versus Abciximab in PCI: ISAR-REACT and ISAR-SWEET

The ISAR-REACT study (Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment)¹⁴ was a randomized, double-blind, placebo-controlled study evaluating the efficacy of the glycoprotein (GP) IIb/IIIa inhibitor abciximab in low-risk patients pretreated with a 600-mg dose of clopidogrel, who were undergoing elective percutaneous coronary intervention. Of the 2,159 patients enrolled, 1,079 received abciximab and 1,080 received placebo. All patients were scheduled to undergo elective percutaneous coronary intervention (PCI) of native coronary vessels and had been pretreated (≥2 h before the procedure) with 600 mg of clopidogrel. Patients who were excluded were those undergoing primary PCI, those who had experienced an MI within 14 days, and those with ongoing unstable angina, a target lesion in a venous bypass graft, chronic total occlusion, angiographically visible thrombus, a left ventricular EF less than 30%, evidence of hemodynamic instability, or insulin-dependent diabetes mellitus. The primary composite endpoint of death, myocardial infarction, and urgent target-vessel revascularization within 30 days after randomization was not different in the group receiving the GP IIb/IIIa inhibitor in addition to clopidogrel versus the group receiving clopidogrel alone (4% in both groups; P = NS).

Similarly, the ISAR-SWEET study (Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics)¹⁵ sought to determine whether abciximab provided incremental clinical benefit over a high loading dose of clopidogrel in 701 low-risk diabetic patients undergoing elective PCI. All patients received a 600-mg loading dose of clopidogrel at least 2 hours before the procedure and were subsequent-ly randomized to abciximab (0.25 mg/kg bolus plus 0.125 μg/kg per min infusion for 12 h) or placebo. Patients receiving abciximab were given a 70-U/kg unfractionated heparin (UFH) bolus, whereas patients in the placebo group received a 140-U/kg bolus, with no monitoring of activated clotting time (ACT) in either group. At 1 year, the incidence of death or MI was 8.3% in the abciximab group and 8.6% in the placebo group (P = NS).

Comment: ISAR-REACT and ISAR-SWEET have shown that alternative antiplatelet strategies (aggressively loaded clopidogrel) may be just as effective as GP IIb/IIIa antagonists in low-risk patients (even low-risk diabetic patients) undergoing PCI. Not everyone undergoing PCI needs a GP IIb/IIIa antagonist.

Low-Molecular-Weight Heparins in Invasively Managed ACS: A to Z and SYNERGY

In the A phase of the A to Z trial,¹⁶ 3,987 patients with acute coronary syndromes, who were first given aspirin and the GP IIb/IIIa antagonist tirofiban, were randomized to treatment with enoxaparin (1 mg/kg every 12 h) or weight-adjusted UFH. Subsequent care was left to the discretion of the treating physician, and catheterization was performed in approximately 60% of patients, at a mean time of 4.5 days. The study was designed to test the noninferiority of enoxaparin versus UFH. The primary composite endpoint of death, myocardial infarction, or refractory ischemia at 7 days was lower (but not significantly) in the enoxaparin-treated patients (8.4%) versus UFH (9.4%), and met the prespecified criteria for noninferiority. This trend was consistent both in patients treated conservatively and in those treated invasively.

The SYNERGY study (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors)¹⁷ enrolled 10,027 high-risk patients with non-ST-segment elevation ACS who were to receive early invasive management. Patients were randomized to treatment with enoxaparin (1 mg/kg subcutaneously every 12h) or intravenous aPTT-guided UFH. If enoxaparin-treated patients came to the catheterization laboratory within 8 hours of the last subcutaneous dose, no additional enoxaparin was used for PCI; if they came to the catheterization laboratory more than 8 hours after the last subcutaneous dose, an additional 0.3 mg/kg was given intravenously in the laboratory before PCI. The primary endpoint (the composite incidence of death or myocardial infarction within 30 days) was not significantly different between groups (14.0% with enoxaparin; 14.5% with UFH). These results met prespecified statistical criteria for noninferiority (OR, 0.96; 95% CI, 0.86–1.06). Patients on consistent therapy (those who did not change therapy at randomization) did significantly better with enoxaparin. The use of enoxaparin was not associated with higher rates of ischemic events during PCI (abrupt closure, threatened closure, unsuccessful PCI, or need for emergency coronary artery bypass grafting). There was slightly more bleeding with enoxaparin; in addition, the enoxaparin group had significantly more TIMI major bleeding (9.1%) versus UFH (7.6%; P = 0.008) and showed nonsignificant trends in GUSTO severe bleeding (2.7%) versus UFH (2.2%) and transfusions (17%) versus UFH (16%).

Comment: A to Z and SYNERGY have demonstrated that enoxaparin is an acceptable alternative to UFH in high-risk, invasively managed ACS patients, and that initial therapy with enoxaparin does not preclude an invasive management strategy.

ACE Inhibitors in Coronary Artery Disease: PEACE

The PEACE trial (Prevention of Events with Angiotensin Converting Enzyme Inhibition)¹⁸ was designed to evaluate the efficacy of the addition of angiotensin-converting-enzyme (ACE) inhibitor therapy in patients with stable coronary artery disease and normal or slightly reduced left ventricular function. A total of 8,290 patients were included in this double-blind, randomized, placebo-controlled trial that compared trandolapril (target dose, 4 mg/day) to placebo. Baseline therapy included lipid-lowering therapy in 70% and prior coronary revascularization in 72%. The primary endpoint was a composite of cardiovascular death, MI, and revascularization; after a median follow-up of 4.8 years, the incidence was 21.9% with trandolapril and 22.5% with the placebo (P = NS).

Comment: PEACE showed that the benefits of ACE inhibitors noted in HOPE (Heart Outcomes Prevention Evaluation) and EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) do not necessarily extend into a lower risk population. Not everybody with coronary artery disease needs to be on an ACE inhibitor.

Conclusion

If we are truly going to practice “evidence-based medicine” (as much as I dislike that term), we need to make sure that we actually take time to look at the evidence, critically evaluate it, and decide for ourselves what it means for individual patients. The studies listed here are, in my estimation, exactly the sort of evidence we need to consider as we continue to advance our own standards of care. Feel free to disagree with my comments—the important thing is that you have critically considered the data and have decided for yourself what they mean.

If 2004 is any indication, 2005 is going to be an exciting year. “The year that was” was pretty amazing.