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Stop Stenting; Start Reversing Atherosclerosis

Published:November 08, 2020DOI:https://doi.org/10.1016/j.amjmed.2020.10.009

      Rationale

      Progress in translating clinical care of patients is slow, sometimes requiring decades for new discoveries to alter the standard of care of the patient. The reasons for this delay are multiple: resistance of physicians to change, delay in changes to guidelines, guideline disagreements between professional societies, and the limited time that practicing physicians have to update their knowledge base. This delay not only can cost billions of dollars, but the patient with a progressive disease may also be harmed. An example of this conundrum is the patient presenting with stable angina.
      Cardiovascular disease (CVD) is the number one cause of death in the United States, a death rate that exceeds all cancers combined. These patients may present with stable angina, putting them at high risk for a future cardiovascular event. The goal of management for patients with stable angina is 2-fold: 1) to improve mortality and 2) to achieve resolution or reasonable control of symptoms such that functional status is optimized. The treatment modalities for this condition can be divided into 2 approaches (Figure). The first is an invasive approach requiring coronary angiography that often leads to percutaneous coronary intervention (PCI; ie, stenting) or coronary artery bypass grafting. The second approach is aggressive medical therapy with the intent of stabilizing and, at least, partially reversing the atherosclerotic plaque. The first approach is expensive and may require hospitalization. The second approach is much less costly, particularly if both generic statins and ezetimibe are prescribed. The question to be asked is the following: “Which approach results in better patient-centered outcomes?”
      Figure
      FigureStepwise procedure to provide a new patient presenting with angina with a rational choice of antianginal therapy. For individuals in which the diagnosis of angina is equivocal, a coronary artery calcium score may be helpful in diagnosing atherosclerosis.

      Clinical Trial Data

      There has recently been a series of large, multicenter studies all reaching the same conclusion: In patients with stable angina, long-term treatment with intensive medical therapy results in the same cardiovascular endpoints as does PCI. In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, 2287 patients with severe coronary artery disease (CAD) and stable angina were randomly assigned to either PCI plus intensive medical therapy or intensive medical therapy alone.
      • Boden WE
      • O'Rourke RA
      • Teo KT
      • et al.
      Optimal medical therapy with or without PCI for stable coronary disease.
      Stenting in a coronary artery did not reduce the risk of death, myocardial infarction, or other major cardiovascular events compared with medical therapy, nor were there significant differences in the change in anginal symptoms between groups. In a unique double-blind, randomized, placebo-controlled clinical trial (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina [ORBITA]), 230 patients with ischemic symptoms were randomized to either PCI or medical therapy.
      • Al-Lamee R
      • Thompson D
      • Dehbi H-M
      • et al.
      Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial.
      The primary endpoint was exercise tolerance at the end of 6 weeks. The authors concluded that stenting did not increase exercise tolerance more than the medically treated patients on placebo. In 2020, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial was published, a randomized controlled trial comparing PCI and medical therapy for 5179 patients with stable CAD and moderate or severe ischemia. This study demonstrated no significant difference in ischemic cardiovascular events or mortality between treatment groups over a median of 3.2 years.
      • Maron DJ
      • Hochman JS
      • Reynolds HR
      • et al.
      Initial invasive or conservative strategy for stable coronary disease.
      In an accompanying editorial, the authors state: “Patients with stable ischemic heart disease who fit the profile of those in ISCHEMIA and do not have unacceptable levels of angina can be treated with an initial conservative strategy.”
      • Antman EM
      • Braunwald E
      Managing stable ischemic heart disease.
      Although there was a statistically significant improvement in lifestyle measures favoring an invasive strategy, the actual clinical differences were minimal.
      • Spertus JA
      • Jones PG
      • Maron DJ
      • et al.
      Health-status outcomes with invasive or conservative care in coronary disease.

      Reversal of Atherosclerosis

      Partial reversal of atherosclerosis has been demonstrated unequivocally with the use of intravascular ultrasound.
      • Nicholls SJ
      • Ballantyne CM
      • Barter PJ
      • et al.
      Effect of two intensive statin regimens on conservative care in coronary disease.
      Reversal requires control of all major cardiovascular risk factors, including smoking, hypertension, diabetes, and dyslipidemia. Aggressive lowering of low-density lipoprotein (LDL) cholesterol is paramount because the lower the LDL cholesterol, the better the outcome.
      • Baigent C
      • Keech A
      • Kearney PM
      • et al.
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      Stabilization of the atherosclerotic plaque occurs within 30 days of beginning antilipidemic therapy,
      • Nakamura T
      • Obata JE
      • Kitta Y
      • et al.
      Rapid stabilization of vulnerable carotid plaque within 1 month of Pitavastatin treatment in patients with acute coronary syndrome.
      and initial plaque reversal is demonstrable within 1 or 2 years thereafter.
      • Nicholls SJ
      • Ballantyne CM
      • Barter PJ
      • et al.
      Effect of two intensive statin regimens on conservative care in coronary disease.
      The 2 critical components to reversal are removal of cholesterol from the plaque and elimination of the inflammatory cytokines that lead to plaque rupture.
      The reason that stenting does not necessarily reduce CVD events is that the obstructive plaque is often not the same plaque that ruptures to cause a myocardial infarction. Among patients who had undergone a coronary angiogram and then suffered a subsequent myocardial infarction with repeat coronary angiogram, in only 34% did the infarction occur as a result of the occlusion of the artery that previously contained the most severe stenosis.
      • Little WC
      • Constantinescu M
      • Applegate RJ
      • et al.
      Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?.
      Plaques of all sizes may rupture depending on their stability. Unstable plaques are characterized by a thin overlying cap, a large amount of cholesterol-laden macrophages in the core, and an excess of inflammatory cytokines. Once the cap ruptures, platelets adhere to the thrombotic, ejected plaque material into the artery lumen, which leads to obstruction and a myocardial infarction.

      Role of the Primary Care Physician

      Based on the recently published data from randomized clinical trials, it is critical that primary care physicians inform their patients with stable angina that alternative treatments to invasive procedures are available and not rely on the initial referral to a cardiologist. Specifically, patients should be informed that atherosclerosis is a partially reversible condition if improved lifestyle (to control risk factors) and medications are taken (to aggressively lower LDL cholesterol). Additionally, symptomatic control of ischemic symptoms may be achieved with an initial approach of aggressive medical intervention. When transcripts of 40 encounters between cardiologists and patients were analyzed, few cardiologists discussed the evidenced-based benefits of PCI for stable CAD, and some explicitly overstated the benefits.
      • Goff SL
      • Mazor KM
      • Ting HH
      • Kleppel R
      • Rothberg MB
      How cardiologists present the benefits of percutaneous coronary interventions to patients with stable angina: a qualitative analysis.
      Using a different approach of 3 focus groups of interventionalist and noninterventionalist cardiologists, the authors concluded, “Despite acknowledging that data showing that stenting offers no reduction in the risk of death or myocardial infarction in patients with stable coronary artery disease, cardiologists believed that PCI would benefit such patients.
      • Lin GA
      • Dudley RA
      • Redberg RF
      Cardiologists’ use of percutaneous coronary interventions for stable coronary artery disease.
      What should be the treatment goals if the patient chooses medical therapy? Guidelines from several national organizations recommend an LDL cholesterol below 70 mg/dL for individuals at high risk. We agree but recommend an LDL cholesterol below 50 mg/dL for reasons previously stated,
      • Schade DS
      • Eaton RP
      A simplified approach to reducing cardiovascular risk.
      including the observation that at an LDL of approximately 70 mg/dL, only 50% of high-risk patients reverse their atherosclerosis.
      • Baigent C
      • Keech A
      • Kearney PM
      • et al.
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      A level below 50 mg/dL is safe and can be achieved in almost all patients with the combination of rosuvastatin (10 mg/d), ezetimibe (10 mg/d), and a low cholesterol diet.
      • Schade DS
      • Eaton RP
      A simplified approach to reducing cardiovascular risk.

      Summary

      Based on the follow-up of 7696 patients with obstructive CAD,
      • Boden WE
      • O'Rourke RA
      • Teo KT
      • et al.
      Optimal medical therapy with or without PCI for stable coronary disease.
      • Al-Lamee R
      • Thompson D
      • Dehbi H-M
      • et al.
      Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial.
      • Maron DJ
      • Hochman JS
      • Reynolds HR
      • et al.
      Initial invasive or conservative strategy for stable coronary disease.
      sufficient, high-quality evidence has now been published to change the practice of medicine. No longer should invasive procedures be automatically recommended in patients with stable angina. It is important that the primary care physician discuss the role of medical treatment options with the patients prior to cardiology referral to provide an unbiased assessment of the risks and benefits of various therapeutic options. Patients with unstable angina at rest (ie, acute coronary syndrome) should be immediately referred to a cardiologist for treatment. The vast majority of patients with stable angina, however, will benefit from the conservative therapy of medical management. At least partial reversal of atherosclerosis with stabilization of the plaque should be the intended goal. Patient education and information is essential for a successful outcome.

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