User:Andrew73/Clinical trials with surprising outcomes

Medicine is an evolving field as new knowledge is acquired through discoveries in the laboratory and clinical trials. With the acceptance of evidence-based medicine, some practices that were thought to be standard of care or represent best clinical practice have fallen out of favor as data from randomized clinical trials using placebo control groups emerged.

The following represents some important negative clinical studies:

Cardiac Arrhythmia Suppression Trial

Flecainide and encainide are antiarrhythmic drugs used to prevent and treat arrhythmias (irregularities in the heart beat). Initially, it was felt that suppressing ventricular arrhythmias after a myocardial infarction would reduce the incidence of sudden death. However, a randomized clinical trial called the Cardiac Arrhythmia Suppression Trial (CAST) compared flecainide or encainide to placebo and found that these drugs increased mortality.^[1] As a result, medications of this specific drug class are no longer routinely given to suppress ventricular ectopy after myocardial infarction. (However, a different class of drugs which do have anti-arrhythmic properties, beta blockers, are routinely prescribed after a myocardial infarction.)

Inotropic agents for congestive heart failure

Multiple inotropic agents (drugs that stimulate heart contraction) have been studied in congestive heart failure in an effort to improve symptoms and survival. Physiologically, it would have been anticipated that drugs that enhance heart contraction would improve outcome. However, with the notable exception of digoxin, many of these agents have had disappointing results in clinical trials, and in some cases have actually increased mortality.

One inotropic agent in particular is vesnarinone. Initially, a short term study showed promising results. However, when enrolled in a long term, randomized clinical trial, vesnarinone was associated with a dose-dependent increase in mortality.^[2] This was attributed to an increase in deaths from arrhythmias.

Liberal v. restrictive red blood cell transfusions

Initially, it was felt that hematocrits closer to the physiologic range were better than lower, more anemic hematocrits, along the lines of "more is better." However, the Transfusion Requirements in Critical Care (TRICC) trial demonstrated that a "restrictive" transfusion policy was at least as effective as a "liberal" transfusion policy in the critical care setting. In this trial, a restrictive transfusion strategy gave red blood cell transfusion when the hemoglobin concentration dropped below 7.0 g/dL. The liberal strategy mandated transfusions when the hemoglobin fell below 10 g/dL. In fact, in subset analysis, patients younger than 55-years-old had improved outcomes with a restrictive strategy.^[3]

Bone marrow transplant for breast cancer

Given the partial success of chemotherapy to treat breast cancer, it was felt that increasing the doses of chemotherapy would lead to better outcomes. This led to the application of high dose chemotherapy followed by rescue with the patient's own stem cells, or autologous bone marrow transplant. However, later studies found that autologous bone marrow transplant did not improve overall survival.^[4]

Hormone replacement therapy

Epidemiologic studies showed that women who take hormone replacement therapy (HRT) had reduced rates of developing coronary artery disease. However, a landmark randomized clinical trial, the Women's Health Initiative, demonstrated that hormone replacement therapy did not reduce the rates of coronary artery disease, and furthermore increased the risk of stroke.^[5] As a result, HRT is no longer routinely recommended for prevention of coronary artery disease.

Vitamin supplements and lung cancer

Evidence from observational studies strongly suggested that dietary supplements of beta-carotene and vitamin A (naturally found in fruit and vegetables) reduced the incidence of cancer, especially lung cancer. These supplements are antioxidants, with good laboratory evidence for prevention of DNA damage due to carcinogens. However, two large placebo-controlled clinical trials in people at high risk of lung cancer showed the opposite effect - that is, supplementation increased the incidence of lung cancer and the risk of death. Long-term follow-up confirms these findings. Another study found neither harms nor benefits in people at low risk of lung cancer. One explanation for these surprising results is that a healthy diet (increased fruit and vegetable intake) is associated with a reduced incidence of cancer, but beta-carotene and vitamin A are not the "active" components. ^[6]

References

1. ^ Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL (1991). "Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial". N Engl J Med. 324 (12): 781–8. doi:10.1056/NEJM199103213241201. PMID 1900101.{{cite journal}}: CS1 maint: multiple names: authors list (link)
2. ^ Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, Gottlieb SO, McGrew F 3rd, DeMets DL, White BG (1998). "A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators". N Engl J Med. 339 (25): 1810–6. doi:10.1056/NEJM199812173392503. PMID 9854116.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
3. ^ Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E (1999). "A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group". N Engl J Med. 340 (6): 409–17. doi:10.1056/NEJM199902113400601. PMID 9971864.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. ^ Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH (2000). "Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group". N Engl J Med. 342 (15): 1069–76. doi:10.1056/NEJM200004133421501. PMID 10760307.{{cite journal}}: CS1 maint: multiple names: authors list (link)
5. ^ Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA. 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397.{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. ^ "Beta-Carotene Supplements Confirmed as Harmful to Those at Risk for Lung Cancer". National Cancer Institute.