Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Reproduced

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

N Engl J Med 2019; 381:2497-2505

Jean-Claude Tardif, M.D., Simon Kouz, M.D., David D. Waters, M.D., Olivier F. Bertrand, M.D., Ph.D., Rafael Diaz, M.D., Aldo P. Maggioni, M.D., Fausto J. Pinto, M.D., Ph.D., Reda Ibrahim, M.D., Habib Gamra, M.D., Ghassan S. Kiwan, M.D., Colin Berry, M.D., Ph.D., José López-Sendón, M.D., et al.

Abstract: Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis.

METHODS: We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.

RESULTS: A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P=0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P=0.03).

CONCLUSIONS: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094. opens in new tab.)

Eyeing Profits

Reproduced from India Legal, Published May 6, 2019, pg. 29

With hospitals and pharma companies charging heavily for medical devices, a PIL in the Delhi HC seeks direction to cap lens prices

Medical devices have often come under the scanner for being overpriced. A PIL filed in the Delhi High Court late last year challenged such overpricing with a specific plea that intraocular lenses, among the essential medical devices, be listed under the National Pharmaceutical Pricing Authority.

India has for long been known as the “blind capital” of the world. Around 15 million people here are blind, which is 50 percent of the world’s blind population. According to the data published by the National Programme for Control of Blindness and Visual Impairment, cataract alone accounts for 62.6 percent of all causes of curable blindness in India.

The cataract surgery rate is pinned at above one percent of the total population of the country every year. That means millions of people are getting intraocular lenses implanted each year. But there is a huge gap between the cost of procuring these lenses and the price a patient has to pay for correcting his vision.

The PIL came up for hearing in the Court last week and there was talk of the need for incorporating implantation of intraocular lenses into the definition of a “drug” in the National List of Essential Medicines (NLEM) and price capping it in the interest of public health. The National Pharmaceutical Pricing Authority (NPPA) was set up in August 1997 to act as an independent regulator for the pricing of drugs and ensure availability and accessibility of medicines at affordable prices. The Drug Price Control Orders (DPCO) are issued by the government to declare a ceiling price for essential and lifesaving medicines (as per a prescribed formula) so as to ensure that these medicines are available at a reasonable price to the general public.

The criteria for inclusion of a drug in NLEM includes, among other things—it should be approved/licensed in India; it should be useful in case of a disease which is a public health problem in India; it should have proven efficacy and a safety profile based on valid scientific evidence; it should be cost effective; and it should be stable under storage conditions in India.

The Union Ministry of Health and Family Welfare prepared and released the first NLEM in 1996, consisting of 279 medicines. This list was subsequently revised in 2003 and included 354 medicines. Later in 2011, the list was further revised and had 348 medicines. Till June 2018, 851 medicines (including four medical devices—cardiac stents, drug eluting stents, condoms and intra uterine devices) are regulated under the revised schedule.

Currently intraocular lenses, which fall under the ambit of notified devices and are widely used in cataract surgeries, are being priced ten times higher than the market at the point of care. Consumers are charged Rs 8,000 for a brand of intraocular lens which has a landing cost of Rs 800.

Medical experts have been insisting that intraocular lenses, catheters, orthopaedic implants, dental implants and ophthalmic medication be brought into the NLEM in order to make them affordable for the common man.

It is now the High Court’s turn to take a call.

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

NEJM study provides evidence of greater efficacy of e-cigarettes vis-à-vis conventional NRTs

One of the most pressing unanswered questions in public health has been "Do e-cigarettes actually help smokers quit?"

The first, large rigorous assessment now answers this question.

A study, published Wednesday in the New England Journal of Medicine, found that e-cigarettes were nearly twice as effective as conventional nicotine replacement products, like patches and gum, for quitting smoking, reports New York Times. The success rate was 18% among the e-cigarette group, compared to 9.9% among those using traditional nicotine replacement therapy.

The study was conducted in Britain and funded by the National Institute for Health Research and Cancer Research UK. For a year, it followed 886 smokers assigned randomly to use either e-cigarettes or traditional nicotine replacement therapies. Both groups also participated in at least four weekly counseling sessions, an element regarded as critical for success.

E-cigarettes provide the nicotine smokers crave without the toxic tar and carcinogens that come from inhaling burning tobacco. But, it is still not approved as smoking cessation tools. 

Doctors up till now were reluctant to recommend their use because of the lack of clear evidence from randomized controlled trials. This is now likely to change.

The New England Journal devoted much of its current issue to e-cigarettes, publishing two editorials and a letter, and the collection embodies the tangled public health debate over the devices.  One editorial — written by Belinda Borrelli, a behavioral health expert and Dr. George T. O’Connor, a pulmonologist — pumped the brakes on inclinations to embrace e-cigarettes.

The editorial recommended that e-cigarettes be taken up when other cessation approaches, including behavioral counselling have failed; that patients use the lowest dose of nicotine possible and that health care providers establish a clear timeline for
e-cigarette use.

The clinical trial took place from May 2015 to February 2018. Because the smokers were recruited at the clinics, they were already predisposed to quitting, a feather on the scale that could slightly have affected results. The participants were typically middle-aged, smoked between half a pack and a pack a day and had already tried quitting.

Because self-reports of smoking abstinence are not considered reliable, researchers measured the quantities of carbon monoxide in the participants’ breath, a more precise validation. Higher quit rates and compliance among e-cigarette users could be additionally explained because those subjects expressed more satisfaction with the devices than did the other group with their products.

Some researchers hypothesize that because a body takes in only the amount of nicotine it needs to maintain a certain level, high-nicotine products could have the advantage of delivering that power punch with fewer puffs, decreasing the amount of harmful aerosol a vaper would inhale.

(Source: New York Times)

NEJM Abstract A randomized trial of e-cigarettes vs nicotine-replacement therapy Hajek P, Phillips-Waller A, Przulj D, et al. N Engl J Med. 2019 Jan 3. Epub ahead of print Background: E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited regarding their effectiveness as compared with that of nicotine products approved as smoking-cessation treatments. Methods: We randomly assigned adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, including product combinations, provided for up to 3 months, or an e-cigarette starter pack (a second-generation refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength of their choice. Treatment included weekly behavioral support for at least 4 weeks. The primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included participant-reported treatment usage and respiratory symptoms. Results: A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath. Conclusions: E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support. (Funded by the National Institute for Health Research and Cancer Research UK; Current Controlled Trials number, ISRCTN6047760)

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

#AskDrKK:Can patient with hypertrophic cardiomyopathy be given Viagra or Sildenafil?

#DrKKAnswers:
The decrease in preload and after load by Viagra can increase the outflow obstruction in patients with hypertrophic cardiomyopathy culminating in an unstable hemodynamic state.

Source: N Engl J Med 1999; 341:700.

#AskDrKK:Is Viagra (sildenafil) in heart patients not on nitrates?

#DrKKAnswers:
1. Viagra is generally well tolerated in men with severe coronary disease not using nitrates. [1].
2. Sildenafil is also safe during exercise in patients with stable coronary disease. [2].

References
1. N Engl J Med 2000; 342:1622.
2. JAMA 2002; 287:719.

#AskDrKK: Can Sildenafil (Viagra) cause acute heart attack?

#DrKKAnswers:
1. Acute heart attack and sudden death have been described after sildenafil therapy [1, 2].
2. Seventy percent of the men who developed MI of SCD had known cardiovascular disease and several were using a nitrate concurrently with sildenafil [3].

References
1. Lancet 1998; 352:957.
2. N Engl J Med 1999; 341:700 .
3. Circulation 2000; 102:2516.

#AskDrKK: Does exercise reduces chances of heart attack after sex in heart patients?

#DrKKAnswers:

1. The risk of acute heart attack after sexual act is reduced in patients who exercise regularly (1,2).
2. Regular physical exercise should be done at levels of ≥6 METs to reduce the risk (3).
3. The more regularly a person exercises the lower will be the heart attack risk.
4. Regular exercise also reduces the risk of heart attack and sudden death from heavy physical exertion (4,5)
5. Exercise training increases the aerobic capacity and decreases the peak heart rate in post-heart attack subjects engaging in sexual act (6).

References
1. JAMA 1996; 275:1405.
2. Heart 2001; 86:387.
3. Am J Cardiol 2000; 86:14F.
4. N Engl J Med 1993; 329:1677.
5. N Engl J Med 2000; 343:1355.
6. Circulation 1977; 55:738.

Emedinews:Intensive medical treatment prevents second stroke not intra cranial stenting

Patients at a high risk for a second stroke who received intensive medical treatment had fewer strokes and deaths than patients who received a brain stent in addition to the medical treatment. The investigators published the results in the online first edition of the New England Journal of Medicine.

The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, funded the trial. The medical regimen included daily blood-thinning medications and aggressive control of blood pressure and cholesterol.

New enrolment in the study was stopped in April because early data showed significantly more strokes and deaths occurred among the stented patients at the 30-day mark compared to the group who received the medical management alone.

In addition to the intensive medical program, half of the patients in the study received an intervention of a self-expanding stent that widens a major artery in the brain and facilitates blood flow. One possible explanation for the higher stroke rate in the stented group is that patients who have had recent stroke symptoms sometimes have unstable plaque in their arteries which the stent could have dislodged, the study authors suggest. The study device, the Gateway-Wingspan intracranial angioplasty and stenting system, is the only system currently approved by the U.S. Food and Drug Administration (FDA) for certain high-risk stroke patients. The study participants were in the highest risk category, with blockage or narrowing of arteries of 70 to 99 percent.

Intensive medical management included a daily dosage of 325 milligrams of aspirin; 75 milligrams a day of Clopidogrel, for 90 days after enrollment; and aggressive management of key stroke risk factors—high blood pressure and high levels of low density lipoprotein (LDL), the unhealthy form of cholesterol. All patients also participated in a lifestyle modification program which focused on quitting smoking, increasing exercise, and controlling diabetes and cholesterol.

"The SAMMPRIS study results have immediate implications for clinical practice. Stroke patients with recent symptoms and intracranial arterial blockage of 70 percent or greater should be treated with aggressive medical therapy alone.

(New England Journal of Medicine, published online September 7, 2011).

Dr KK Answers: Can olmesartan prevent microalbuminuria in type 2 diabetes?

In type 2 diabetes (ROADMAP trial) patients assigned to receive olmesartan had significant reductions in systolic blood pressure and microalbuminuria but there was a significantly higher risk of cardiovascular death.

N Engl J Med 2011; 364:907

Dr KK Answers: Can I go for percutaneous repair for mitral regurgitation?

Percutaneous implantation of a clip is an experimental technique that focally approximates the edges of the mitral leaflets.

In a study comparing it with surgery (valve repair or replacement) in patients with chronic moderately severe or severe (3+ or 4+) mitral regurgitation at 12 months the efficacy was greater for surgery than percutaneous repair.

However, more major adverse events occurred within 30 days after surgery. Quality of life improved from baseline to 12 months in both groups, but surgery was associated with a transient decrease in quality of life at 30 days. 

Source: N Engl J Med 2011; 364:1395

Dr KK Answers: Should I refer my patient for transcatheter aortic valve implantation (TAVI) or opt for traditional aortic valve replacement (AVR) surgery?

A randomized trial comparing TAVI and surgical AVR in patients with severe symptomatic aortic valve stenosis ha shown similar one-year survival rates.

1.    Major vascular complications were more frequent following TAVI.

2.    Major bleeding and atrial fibrillation were more common after AVR. 

Source: N Engl J Med 2011; 364:2187

Dr KK Answers: Which is better coronary artery bypass surgery or angioplasty for angina relief?

A prospective quality of life sub study of the SYNTAX trial of patients with three vessel or left main coronary artery blockage compared the relief of angina after the bypass or angioplasty. At 12 months, both interventions were associated with substantial relief of angina, although there was a statistically significant lower angina frequency with bypass surgery. 

Source: N Engl J Med 2011; 364:1016.

Dr KK Answers: Should I opt for surgery of angioplasty in left main lesion?

In patients with left main coronary artery disease bypass surgery is the golf standard. Angioplasty is increasingly being used as an alternative. The PRECOMBAT trial, randomly assigned 600 such patients to either drug-eluting stents or bypass surgery. At one year, the rate of major adverse cardiac or cerebrovascular events (death from any cause, heart attack, paralysis, or ischemia-driven target vessel revascularization) was similar in both groups. 

Source: N Engl J Med 2011; 364:1718.

Dr KK Answers: Which is better continuous IV infusion or intermittent bolus dosed of furosemide?

The DOSE trial found that no single intravenous dosing regimen for a loop diuretic is superior in treating acute heart failure.

Patients were assigned to receive furosemide via bolus versus continuous infusion at either a low dose (equivalent to the patient’s previous oral dose) or high dose (2.5 times the previous oral dose).

1.    There was no significant difference in efficacy or safety for bolus versus continuous infusion.
2.     There was significant greater improvement in symptoms with high-dose therapy.
3.    The mean change in serum creatinine was similar at the two-dose levels.

Source: N Engl J Med 2011; 364:797

Dr KK Answers: What to opt: Medical or surgical revascularization in patients with coronary heart blockages with reduced left ventricular function (heart pumping)?

Up to 50% of patients with low pumping function of the heart due to coronary heart blockages have a significant amount of viable hibernating heart muscles. Many earlier studies have shown that, when compared to drugs, surgical revascularization of hibernating heart muscles improves both survival and heart function. The Surgical Treatment for Ischemic Heart Failure (STICH) trial was the first randomized trial to compare the combination of optimal medical therapy and surgical revascularization with optimal medical therapy alone in patients with stable heart disease, heart pumping function 0f 35 percent or less, and coronary artery blockages amenable to coronary artery bypass graft (CABG) surgery.

Compared to optimal medical therapy alone, optimal medical therapy plus CABG surgery resulted in no significant improvement in all-cause mortality at a median follow-up of 56 months (36 versus 41 percent with medical therapy alone). 

In all patients with heart pumping function of 35 percent or less and coronary artery blockages amenable to CABG surgery, one should opt for an initial course of optimal medical therapy alone rather than optimal medical therapy plus CABG surgery. This is based on the significant morbidity associated with CABG surgery. 

However one should opt for CABG surgery in presence of ongoing anginal symptoms despite optimal medical therapy.
(N Engl J Med 2011; 364:1607)

Dr KK Answers: What is the role of apixaban in AF?

Anticoagulant (blood thinner) such as apixaban, a factor Xa inhibitor, is being tested. In the AVERROES trial, 5599 atrila fibrillation (irregular heart rhythms of the smaller atrial chamber) patients in whom warfarin was felt to be unsuitable were randomly assigned to either apixaban or aspirin. The study was stopped prematurely because of a clear benefit in favor of apixaban (lower rate of paralysis or systemic embolism).
 ( N Engl J Med 2011; 364:806)

Dr KK Answers : For patients with atrial fibrillation which is the drug of choice?

Many patients with atrial fibrillation (irregular heart rhythms of the smaller atrial chamber) who are started on long-term anticoagulation (blood thinners) with warfarin or acitrom are unable to continue due to difficulty with regular monitoring. Dabigatran is an approved alternative anticoagulant for these patients.

[ N Engl J Med 2011; 364:806]