PCI in angina, ??stenting

​​An article just came out in the Lancet of a double-blind randomized controlled trial of percutaneous coronary intervention (PCI) in patients with stable angina (see doi.org/10.1016/S0140-6736(17)32714-9 ), the ORBITA study.

Details:

-- 200 patients 18 to 85 years old with angina or equivalent symptoms, at least one angiographically significant lesion (>70%) in a single vessel that was clinically appropriate for PCI. Exclusion criteria included angiographic stenosis >50% in a nontarget vessel, acute coronary syndrome, previous CABG, left main disease. All procedures were done between 2014-2017

-- Median age 66, 73% male, BMI 29, 18% diabetic/69% hypertensive/72% hyperlipidemic/13% smokers, 13% previous PCI, 6% previous MI, 92% LVEF normal/5% mild LVEF impairment/4% moderate impairment

-- Canadian Cardiovascular Society (CCS) class: 3% class I, 59% class 2, 39% class III. Angina duration of 9 months

-- Patients were enrolled after a six-week medical optimization phase to up-titrate guideline-derived anti-anginal medical therapy, focusing on prescribing at least 2 anti-anginal therapies per patient. The consultant cardiologist made 1 to 3 telephone calls per week to the patients, including evaluation of  home blood pressure and heart rate measurements

-- 98% of the patients were taking aspirin, 99% a 2^nd antiplatelet drug, 97% a statin, 80% ACE/ARB, 78% beta blocker, 90% calcium channel blocker, 66% long-acting nitrate, 55% nicorandil, 10% ranolazine​. Mean number of anti-anginal medications was 2.8 (had been 0.9 at the time of enrollment)

-- total cholesterol 131, LDL 69.  BP 125/70

-- All patients had catheterization, physiologic measurements, and then randomized to undergo PCI with a drug-eluting stent (mostly everolimus in 83 and zotarolimus in 52) vs a placebo/sham procedure.

-- 69% of patients had LAD lesions, 16% RCA, 15% serial lesions, fractional flow reserve of 0.69. The mean area of stenosis was 84.4%

-- post PCI, when done, show the FFR increased to 0.90 (ie, it worked physiologically)

-- After six-week follow-up, a physician blinded to treatment assignment assessed cardiopulmonary exercise testing, rest and stress cardiac regional wall motion with dobutamine stress echocardiography, and fluoroscopic imaging after intra-coronary nitrates

-- 39 of the 230 enrolled patients became angina-free by the pre-randomization time-point.

Results:

-- exercise time (primary endpoint): increased 28.4 seconds in the PCI group and 11.8 seconds the placebo group, a difference of 16.6 seconds which was judged nonsignificant, since the pre-study cutpoint of significance was a 30 second effect size

-- time to a 1 mm ST depression: 23 vs 21 seconds, nonsignificant

-- peak oxygen uptake: decreased 2 mL per minute the PCI group and increased 10.9 with sham surgery, nonsignificant

-- physical limitation, per the SAQ (Seattle Angina Questionnaire): difference of 2.4, nonsignificant

-- anginal frequency, per the SAQ: 14.0 vs 9.6, nonsignificant

-- angina stability, per the SAQ: -4.2 vs -5.1, nonsignificant

-- quality-of-life: no difference, nonsignificant

-- peak stress wall motion index score: -0.08 with PCI, 0.02 with sham surgery, p=0.0011 (statistically better with PCI)

-- Duke treadmill score: increment over pre-randomization of 1.22 vs 0.10, nonsignificant

-- changes in CCS anginal grade, comparing PCI vs placebo (all nonsignificant):

                -- no change or deterioration: 49% vs 55%

                -- 1 class improvement: 26% vs 24%

                -- 2 or more class improvement: 26% vs 21%

-- peri-procedural/other adverse events: major bleeding in 3 (2 with PCI, from erosive gastritis); 4 patients in the placebo group needed PCI for a pressure-wire related complication (passing the pressure wire through tight lesions disrupted the intima), 2 patients had major bleeding on dual antiplatelet therapy, and one patient developed ACS

Commentary:

-- PCI is in extremely common procedure done, with more than 500,000 procedures done annually worldwide for stable angina.

-- One common perception is that large atherosclerotic lesions are the major cause of cardiac mortality. Older studies have found that 78-97% of the culprit lesions (those that rupture and cause an acute coronary syndrome/MI) were less than 75% stenotic, half were <50% (eg, see Fuster V. NewEngJMed 1992; 326:242). Typically, small lesions with lipid cores >40% of their volume are most vulnerable, since these lesions typically have less developed fibrous caps, and these large lipid cores attract inflammatory cells which elaborate metalloproteinases, etc which further disrupt the fibrous caps, increasing the probability of rupture, thrombosis, and the development of clinical ACS. Angina, on the other hand, is caused by the demand/supply mismatch, where coronary vessels with >70% stenosis (the point where there is a significant post-obstruction pressure drop) leads to relative ischemia when insufficient nutrients are available for the myocardium (eg, physical or mental stress, the former measured by exercise stress testing and often but not always perceived as chest discomfort by the patient). Anginal relief is the main indication for PCI in patients with stable coronary artery disease, not longevity. For example, the COURAGE trial (see Boden WE. N Engl J Med 2007; 356: 1503), found no difference in myocardial infarction or death rates between patients with stable CAD who underwent PCI vs optimal medical therapy. This was also the case after up to 15 years of follow-up of the study (see Sedlis SP. N Engl J Med 2015; 373: 1937).

-- Other studies with surgery vs sham surgery reinforce the placebo effect of surgery: arthroscopy for degenerative joint disease of the knee found lack of efficacy of surgery. A study of renal denervation in patients with resistant hypertension found no difference in blood pressure 6 months after denervation vs sham surgery, both groups getting about a 12 mmHg lowering of their blood pressure (seeBhatt DL. N Engl J Med 2014; 370: 1393).  so, pretty strong placebo effect from surgery

-- PCI is also relatively safe, but there still is a complication rate of 4.5%: 0.65% death rate, 0.56% heart failure , 0.2% needed dialysis, 0.2% stroke, 2-6% vascular complications (from the 2010-11 CathPCI Registry). And there are the severe post-stent complications of stent thrombosis

-- This study was impressive in that patients had ischemic symptoms after optimal anti-anginal therapy, they had severe coronary artery stenosis at 85%, they had significant hemodynamic compromise with an FFR of 0.69 and dramatic opening of the artery after stenting. Yet no clinical benefit from dilating the artery

-- there are some concerns about the generalizability of this study: this study excluded patients with multi-vessel severe stenosis, since patients here were limited to single vessel severe disease. Also this study only had a six-week endpoint, so cannot assess longer-term endpoints like mortality benefit, myocardial infarction prevention, or even long-term anginal control (though the benefits after successfully opening the coronary artery typically are more evident early after the procedure)

-- It really would been useful to have a 3^rd group in this study, one just with optimized medical therapy and no procedure, to assess the increment of the surgical placebo effect​

So, to me, since there seems to be adequate documentation from several studies that stenting for stable anginal symptoms does not extend life or prevent serious cardiac complications, it makes sense to optimize medical therapy first. But even with cardiologists, the US National Cardiovascular Data Registry found that <50% of patients getting PCI done had optimal medical therapy 

--There are several other advantages to optimizing medical therapy over PCI:

    --saving the patient an invasive procedure with its (small) potential of immediate serious adverse events and also the potential for later stent thrombosis. i am a bit more concerned about stent thrombosis now, since i seem to be seeing more patients who run out of their medications since they get only a one month supply, happen to be out of town in the narrow window that they can refill their meds or are having some problem with their insurance (which may well get worse with Trump undermining the ACA and enrollment in insurance), and therefore not taking their dual antiplatelet therapy regularly.

    --likely decreasing the medicalization of some patients. my guess is that a surgical procedure is more likely to cause some patients to feel that there is something very wrong with them, that they are more susceptible to cardiac problems in the future, that they see themselves as disabled, and potentially disempowering them/making them more passive in their own health care.

    --and, on the other side, the medical/lifestyle approach may well empower the patients to take control of their health more than the quick-fix of the stent. Medical care focuses on long-term aggressive lifestyle modifications: diet, weight loss, exercise, not smoking... which have many positive health effects beyond cardiac ones.

    ​--also, this current study and the COURAGE study reinforce to me that stable angina is mostly a medical, not a surgical condition(since the culprit arteries causing acute coronary syndromes are typically the ones not getting stented because the atherosclerotic lesions are too small). so, unless there is a clear indication, i think it is reasonable to consider aggressive medical therapy even with more extensive lesions than in a single coronary artery (the case for left main disease is more complex.  it clearly has a high risk for cardiac deaths, but the data showing aggressive intervention, such as CABG, are based on studies from the 1970s mostly, where optimal medical therapy would now be considered to be suboptimal....  but, without good data to support medical therapy, i would be hesitant to just treat medically. and stenting may work, but the EXCEL and NOBLE studies looking at this came to different conclusions as to whether stenting is as effecting as CABG.)

    --in this light, i recently saw a 53 yo man with exercise-induced chest pain on no meds and then had a stress test which was positive for ischemic changes, with both a small irreversible and a small reversible area in the mid-LAD region. The cardiologist recommended stenting. But when i spoke and asked for evidence that stenting was indicated (given the COURAGE trial), she agreed that maximal medical management was reasonable and appropriate. On discussing this with the patient, he agreed to try medical therapy to see how it went, did great, and is taking meds but still many months later is doing very regular exercise, eating well, losing weight, and happy....

But to optimize anginal therapy further, maybe we primary-care physicians should also make small incisions over the femoral or brachial artery to achieve the same results as invasive cardiologists??​

also, for other articles on placebo, including the placebome (areas of the genome which may predispose individual patients to a placebo response), seehttp://gmodestmedblogs.blogspot.com/search/label/placebo