Cardio Medical Intervention
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Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men.
Strandberg TE, et al.
JAMA 1991 Sep 4;266(9):1225-9.In this study, 1,222 healthy individuals with risk factors for cardiovascular disease were randomized into an intervention and a control group. Those in the intervention group were visited by physicians every fourth month, were prescribed intensive dietetic-hygienic measures, and frequently received cholesterol-lowering medications (clofibrate and/or probucol) and antihypertensive (beta-blockers and/or diuretics) drugs. The control group was untreated. The intervention trial lasted 5 years. Fifteen-year overall mortality rates increased by 45% in individuals followed and treated by physicians compared to those who received no intervention. In particular, mortality due to cardiovascular disease increased by 2.4 times, and that due to violence by 13 times, in treated versus untreated individuals. Cancer death rates were 38% lower in the treated group.
Is blood pressure treatment as effective in a population setting as in controlled trials? Results from a prospective study.
Thurmer HL, et al.
J Hypertens 1994 Apr;12(4):481-90.This study evaluated the impact of blood pressure treatment on survival in the general population, where several factors such as physician' personal choice of treatment, patient selection, compliance to treatment, and time to follow-up, may vary individual response to therapy. Over 21,000 individuals aged 35-49 were screened for blood pressure values in 1974-76 and were followed up until 1990. Of this group, 840 patients were initiated on treatment after a second blood pressure screening was performed in 1977-1981. Individuals with cardiovascular disease, diabetes, or on blood pressure medications were excluded. Treatment was associated with only small reductions of blood pressure, and targeted blood pressure was rarely achieved. Rates of coronary heart disease mortality were 80% higher in the treated versus the untreated group. The highest incidence of death occurred in patients with systolic blood pressure before treatment below 184 mmHg and in those with increasing blood pressure in spite of treatment. According to the authors' own conclusions "The benefit experienced from the trials turned into an adverse effect of treatment in the population setting, particularly at low pretreatment blood pressure, and when blood pressure increased during treatment."
Long-term outcome of the Malmo preventive project: mortality and cardiovascular morbidity.
Berglund G, et al.
J Intern Med 2000 Jan;247(1):19-29.The results of this study show that an intervention program consisting of screening and treatment of individuals with cardiovascular risk factors had no effect in reducing rates of cardiovascular morbidity and cardiovascular or total mortality. Over 14,000 individuals aged 32-51 years were invited to screening examination in the period 1974-1992; those with identified risk factors for cardiovascular disease, diabetes and breast cancer were referred to specialists for treatment. Mortality and morbidity rates of the population in the intervention group were compared to those of a control group, consisting of 10,945 individuals who were not invited to screening. Overall mortality and cardiovascular mortality rates were similar in the two groups, and so were those of nonfatal myocardial infarction and stroke, indicating that screening and treatment of cardiovascular risk factors is not associated with improved health outcomes.
Survival in treated hypertension: follow up study after two decades.
Andersson, OK. et al.
BMJ 1998;317:167-171 ( 18 July ).The results of this study conducted on 686 middle-aged, hypertensive men and 6810 non-hypertensive controls, show that men with hypertension who received appropriate drug treatment had, over a 20-22 year period, higher mortality rates than non-hypertensive man (37.4% vs. 29.2%), despite good blood pressure control achieved through medication. Hypertensive patients on medications had higher mortality from cardiovascular disease, especially coronary heart disease, compared to non-hypertensive men. Initial blood pressure was not correlated to future incidence of coronary heart disease. This study presents information on long-term prognosis of medicated hypertensive patients, of which little is known since most clinical trials focus on shorter period, usually 3-5 years. It has been hypothesized that treatment with diuretics and beta-blockers may increase cardiovascular risks through adverse effect on lipid and glucose metabolism.
Excess mortality associated with diuretic therapy in diabetes mellitus.
Warram JH, Laffel LM, Valsania P, Christlieb AR, Krolewski AS.
Arch Intern Med 1991 Jul;151(7):1350-6.The results of this study indicate that use of blood pressure-lowering medications in diabetic patients with hypertension is associated with a significant increase in mortality from cardiovascular diseases. The study was conducted on a cohort of 759 patients aged 35 to 69 years with diabetes. Individuals were divided in 5 groups according to whether they had: normal blood pressure, untreated high blood pressure, high blood pressure (HBP) treated with diuretics only, HBP treated with other class of drugs only, and HBP treated with a combination of diuretics and other class of drugs. Mortality rates were significantly higher in treated versus untreated hypertensive diabetic patients. Diuretics had the most detrimental effect on survival, as shown by a 4-fold increase in mortality from cardiovascular diseases in patients taking diuretics, compared to those receiving no treatment. The authors call for a revision of current practices employing continuous use of diuretics for the management of hypertension in diabetic patients.
Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS).
Liebson PR, et al.
Circulation 1995 Feb 1;91(3):698-706.This double-blind, placebo-controlled study evaluated the effects of different intervention programs in reducing left ventricular mass (LVM), a parameter associated with increased risk of cardiovascular disease. Eight hundred forty-four hypertensive patients were randomly assigned to nutritional-hygienic (NH) intervention plus placebo or plus one of the following antihypertensive drugs: diuretic, beta-blocker, alpha-antagonist, calcium antagonist or angiotensin-converting enzyme inhibitor. NH plus placebo was as effective as NH plus drug treatment in reducing LVM.
Recent trends in hospital mortality of acute myocardial infarction--the Worcester Heart Attack Study. Have improvements been realized for all age groups?
Gurwitz JH, et al.
Arch Intern Med 1994 Oct 10;154(19):2202-8.This study, conducted on over 5,400 patients hospitalized for myocardial infarction (MI) during the years 1975-1990, shows that the chances of dying in the hospital during the acute phase of MI in patients younger than 65 decreased by 85% from 1975 to 1990. In patients aged 65-74 year old mortality rates decreased by 65% from 1975 to 1981 and remained unchanged thereafter, while patients aged 75 or older were more likely to die in the hospitals in 1990 than they were in 1975.
Twenty year trends (1975-1995) in the incidence, in-hospital and long-term death rates associated with heart failure complicating acute myocardial infarction: a community-wide perspective.
Spencer FA, et al.
J Am Coll Cardiol 1999 Nov 1;34(5):1378-87.This study shows that from 1975 to 1995 there was a small decline in the proportion of patients hospitalized for myocardial infarction (MI) that went on to develop heart failure (38% in 1975-78 vs. 33% in 1993-95). There was also a decline in the number of in-hospital deaths due to heart failure complicating MI (33% in 1975-78 vs. 18% in 1993-95). However, the one-year mortality rates of patients dismissed from the hospital with heart failure remained unchanged. The results of this study indicate that long-term survival of patients with heart failure after myocardial infarction was not improved by treatment in the 20-year period going from 1975 through 1995.
Diastolic blood pressure and the risk of primary cardiac arrest among pharmacologically treated hypertensive patients.
Siscovick DS, et al.
J Gen Intern Med 1996 Jun;11(6):350-6.This study shows that reduction of diastolic blood pressure below 85 mm Hg induced by antihypertensive drugs is associated with increased cardiac complications. In particular, patients with treated diastolic blood pressure of 80, 75, and 70 mm Hg had a 20%, 60%, and 2.3-fold increased risk of cardiac arrest compared to patients with treated diastolic blood pressure of 85 mm Hg.
Use of cardiac procedures and outcomes in elderly patients with myocardial infarction in the United States and Canada.
Tu JV et al.
N Engl J Med, 336(21):1500-5 1997 May 22.This study evaluated mortality rates in approximately 234,000 elderly individuals from U.S. and Canada who had a new myocardial infarction in 1991. American patients were 8 times more likely to undergo angioplasty and bypass surgery compared to Canadian patients (11.7% vs. 1.5% and 10.6% vs. 1,4%, respectively). Although mortality rates one month after the heart attack were slightly lower for Americans (21.4% vs. 22.3%), one-year death rates were virtually identical (34.3% for American patients vs. 34.4% for Canadian patients). These data indicate that high rates of angioplasty and bypass surgery in elderly patients do not translate in improved long-term survival.
Health outcomes associated with antihypertensive therapies usedas first-line agents. A systematic review and meta-analysis.
Psaty BM, et al.
JAMA 1997 Mar 5;277(9):739-45.In this study, the efficacy of various antihypertensive drugs was assessed through evaluation of long-term studies, placebo-controlled randomized trials and meta-analysis performed from 1980 to 1995. Only low-dose diuretic therapy was shown to reduce mortality, and it did so by 10%. Low-dose diuretic therapy, high-dose diuretic therapy, and beta-blockers were effective in reducing the incidence of stroke and congestive heart failure. Calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors were associated with meager health outcomes. Short-acting CCBs were shown to cause harm.
Relationship between low blood pressure and depressive symptomatology in older people.
Stroup-Benham CA, Markides KS, Black SA, Goodwin JS.
J Am Geriatr Soc 2000 Mar;48(3):250-5.The results of this study show that elderly individuals with low blood pressure have a significantly increased risk of being depressed. The authors evaluated blood pressure levels, symptoms of depression, self-rated global health and sense of self-esteem in 2,723 Mexican Americans aged 65 or over. Approximately 30% of individuals reported low diastolic blood pressure, 16% had low systolic blood pressure, and 10% had both diastolic and systolic low pressure. Low blood pressure was significantly associated with depression. In particular, subjects who had both diastolic and systolic hypotension had a 2.4-fold increased incidence of depression, compared to those with normal blood pressure. In addition, individuals with low blood pressure were also significantly more likely to report low self esteem and score poorly on global self-reported health. These data suggest that excessive drug treatment of hypertension resulting in low blood pressure may be associated with the occurrence of depressive symptoms and worsening of quality of life in elderly individuals.
WHITE-COAT HYPERTENSION
Clinical implications of white coat hypertension: an ambulatory blood pressure monitoring study.
Manning G, et al.
J Hum Hypertens 1999 Dec;13(12):817-22.The results of this study, conducted on a group of 186 patients, show that white coat hypertension (high blood pressure induced by fear or anxiety of being in a doctor's office e.g. a blood pressure that is high when measured by a doctor or nurse and normal when measured outside medical settings) is present in 23% of patients diagnosed with hypertension. The rate of white coat hypertension is higher among patients with borderline hypertension (33%) and lower in those with mild-moderate hypertension (9%). The authors warn about the possibility of needlessly treating a considerable number of patients based on office blood pressure readings that may falsely indicate the presence of hypertension.
How common is white coat hypertension?
Pickering TG, et al.
JAMA 1988 Jan 8;259(2):225-8.The results of this study, conducted on a sample group of 292 individuals, show that 21% of them had white coat hypertension (blood pressure that was high when measured in a physician's office and normal when measured in ambulatory setting). This finding is important because individuals with white coat hypertension may be inaccurately diagnosed as hypertensive and may receive unnecessary treatment.
Frequency of white coat arterial hypertension in mild hypertension.
Profile of cardiovascular risk and early organic involvement. Spanish.
Hernandez del Rey R, et al.
Med Clin (Barc) 1996 May 11;106(18):690-4.This study evaluated 24 hours blood pressure in a group of 106 individuals diagnosed as having mild hypertension, and found that 46% of them had white coat hypertension.
Overtreatment of hypertension in the community?
Myers MG, et al.
Am J Hypertens 1996 May;9(5):419-25.This study was based on the premise that many patients may receive unnecessary blood pressure medications because of white coat hypertension. Drug withdrawal was initiated in 98 patients who had been on long-term treatment for hypertension and who were free of signs of organ damage. After 1 year, 50 individuals had not resumed treatment and had blood pressure levels that were significantly lower than those registered by their physician. Of the remaining 48 patients, 35 redeveloped hypertension and went back on medication, and 13 restarted treatment for reasons other than blood pressure. These data indicate that more than 50% of individuals who are currently taking blood pressure drugs may be receiving unnecessary treatment.
White coat hypertension.
Pickering TG.
Curr Opin Nephrol Hypertens 1996 Mar;5(2):192-8.This review comments that results from a large number of studies indicate that white coat hypertension affects 20% or more of the population and that it is not associated with increased risk of cardiovascular disease.
Clinical implications of white coat hypertension.
Carek PJ, et al.
Am Fam Physician 1995 Jul;52(1):163-8.This article reports on several studies showing that white coat hypertension is present in 20%-40% of patients diagnosed with hypertension.
Prevalence of white coat effect in treated hypertensive patients in the community.
Myers MG, et al.
Am J Hypertens 1995 Jun;8(6):591-7.This study evaluated the prevalence of white coat hypertension in a randomly chosen sample population of 147 individuals with hypertension. White coat hypertension was present in 91 subjects (62%). Of note, the white coat effect was observed significantly more often when pressure readings were taken by routine family physicians (91 of 147 patients), rather than by the research physician participating in the study (54 of 147) or the research nurse (30/147). These data indicate that the prevalence of white coat hypertension is high in routine clinical practice.
White coat hypertension diagnosed by 24-h ambulatory monitoring.
Examination of 159 newly diagnosed hypertensive patients.
Hoegholm A, et al.
Am J Hypertens 1992 Feb;5(2):64-70.This study evaluated the prevalence of white coat hypertension in a group of 159 consecutive patients scheduled for initiation of drug therapy for newly diagnosed hypertension. When blood pressure was evaluated in ambulatory settings, about 1/4 of patients had normal blood pressure (white coat hypertensive).
CALCIUM CHANNEL BLOCKERS
The unnecessary controversy.
Eur Heart J. 1996 Aug;17(8):1142-7.
Furberg CD, et al.This review reports on several trials demonstrating an increase in mortality rates in patients with angina, myocardial infarction, or hypertension, using the calcium channel blocker (CCB) nifedipine. In addition, the CCB nimodipine, has been shown to increase death rates in patients with subarachnoidal haemorrhage and to worsen their functional and neurological outcomes, and to increase death rates in patients undergoing heart valve replacement. The CCBs verapamil and diltiazem have been shown to increase mortality and to worsen congestive heart failure in patients with myocardial infarction and left ventricular dysfunction; also, they have been associated with a 2-3-fold increase in rates of hospitalization for congestive heart failure among elderly hypertensive patients, compared to beta-blockers. Besides presenting data on the questionable value of CCBs, the authors also point to the enormous costs associated with use of these drugs. Monthly wholesale prices of CCBs range from $38 to $65, compared to $1 for generic diuretics. Since, according to the Hypertension Detection and Follow-up Program, 76 hypertensive people need to be treated for 5 years to prevent one death, it would take $173,000 to $300,000 worth of slow-acting calcium blockers to save one life compared to just $4,500 for diuretics. The authors point to several factors responsible for the current situation; drug manufacturers for failing to conduct long-term trials to detect the occurrence of adverse events, the regulatory agencies for failing to request proof of long-term safety; some opinion leaders for pushing weak data in support of pharmaceutical companies; clinicians for uncritically giving credit to drug manufacturers' claims of CCBs efficacy and safety. All these factors led to such a rise in CCB use, that as much as two-thirds of patients with myocardial infarction in the early '90s were receiving CCBs instead of safer, better documented, and cheaper alternatives.
Conflict of interest in the debate over calcium-channel antagonists.
Stelfox HT, et al.
N Engl J Med 1998 Jan 8;338(2):101-6.This study investigated the relationship between the pharmaceutical industry and the authors of 70 articles published in medical journals between March 1995 and September 1996, on calcium channel blockers. In 1995 a controversy arose on the safety of calcium channel blockers (CCBs). Some physicians and researchers were supportive of CCBs, some were neutral, and others were critical. The results of this study revealed that 96% of researchers and doctors who defended CCBs had financial ties with the drugs' manufacturers, as compared to 60% and 37% of those who were neutral and critical towards the drugs. Only 2 of the 70 articles revealed the authors' potential conflict of interest. Furthermore, 100% of supportive authors had financial relationships with the pharmaceutical industry, regardless of the product, compared to 67% and 43% of those who wrote neutral or critical articles. These data indicate that financial interest with pharmaceutical companies might influence the content of the articles published on scientific journals.
1995: the year of the calcium antagonist controversy.
Cohen JD.
Curr Opin Nephrol Hypertens 1996 May;5(3):214-8.This article reports on several studies demonstrating that calcium channel blockers increase the risk of myocardial infarction and mortality in hypertensive patients. It also emphasizes that there is little evidence indicating that this class of drug reduces cardiovascular morbidity and mortality in the first place, and that there is need of adequate data to support current treatment guidelines recommending calcium antagonists as first line agents in the management of hypertension.
Cost-minimization and the number needed to treat in uncomplicated hypertension.
Pearce KA, et al.
Am J Hypertens 1998 May;11(5):618-29.This study shows that the wholesale costs of different anti-hypertensive drugs vary greatly. In particular, the wholesale price of a 5-year supply of the diuretic hydrochlorothiazide is $55 per person while that of the calcium channel blocker (CCB) nifedipine is $4,026 per person. Based on the assumption that both drugs have similar efficacy, the estimated wholesale cost to prevent one major cardiovascular event (myocardial infarction, stroke or death) among middle-aged hypertensive patients would be $4730 for diuretics and $346,236 for the CCB nifedipine. Corresponding costs to prevent major events in elderly patients would be $1595 for diuretics and $116,754 for CCBs. Of note, according to the April 13, 1998 edition of the Business Week, in 1995 the drug nifedipine (procardia), produced by Pfizer Inc.'s, was the most frequently prescribed antihypertensive drug and the seventh most frequently prescribed drug in the U.S.
The costs and effects of switching calcium channel blockers: evidence from Medicaid claims data.
Simons WR, et al.
Clin Ther 1995 Jan-Feb;17(1):154-73.This study calculated that switching treatment for Medicaid patients from one form of slow-release, once-a-day dose of the calcium channel blocker nifedipine to another, i.e. from Procardia XL to Adalat CC, would be associated with savings of $2.5 million per year in the state of Pennsylvania alone without changes in efficacy or side effects.
Trends in antihypertensive drug advertising, 1985-1996.
Wang TJ, et al.
Circulation 1999 Apr 20;99(15):2055-7.This study shows that, between 1985 and 1996, the number of advertising pages for calcium channel blockers (CCBs) in the New England Journal of Medicine, increased from 4.6% to 26.9%, while advertising for beta-blockers and diuretics decreased from 12.4% and 4.2%, respectively, to 0%. The authors conclude that this pattern of drug advertising might explain why physicians have been increasingly prescribing CCBs instead of better-substantiated therapies for hypertension.
Temporal patterns of antihypertensive medication use among elderly patients. The Cardiovascular Health Study.
Psaty BM, et al.
JAMA 1993 Oct 20;270(15):1837-41.This study, conducted on a sample population of 4406 hypertensive individuals aged 65 or older, shows that between June 1990 and June 1991, newly treated patients were about half as likely to receive diuretics and beta-blockers and about twice as likely to receive calcium channel blockers and angiotensin converting enzymes inhibitors, compared to previously treated patients. These results reveal a changing pattern of antihypertensive drug prescribing occurring within a year-period among U.S. physicians.
Influences of educational interventions and adverse news about calcium-channel blockers on first-line prescribing ofantihypertensive drugs to elderly people in British Columbia.
Maclure M, et al.
Lancet 1998 Sep 19;352(9132):943-8.This study, conducted on a sample population of 4403 physicians, shows that calcium channel blockers and angiotensin-converting enzyme inhibitors were prescribed as first line therapy to 42% of hypertensive patients without signs of cardiovascular disease. This practice occurred against current guidelines recommending thiazide diuretics as first-line treatment for such patients.
Trends in antihypertensive drug use in the United States: do the JNCV recommendations affect prescribing?
Fifth Joint National Commission on the Detection, Evaluation, and Treatment of High Blood Pressure.
Siegel D, Lopez J.
JAMA 1997 Dec 3;278(21):1745-8.The results of this study show that in 1992, of the prescriptions written for antihypertensive drugs, 33% were for calcium channel blockers (CCBs), 25% for angiotensin-converting enzyme (ACE)-inhibitors, 18% for beta-blockers, and 16% for diuretics. In 1995, CCBs and ACE-inhibitors made up 71% of all hypertensive prescription filled by retail drugstores (38% due to CCBs and 33% to ACE-inhibitors) while that of beta-blockers and diuretics fell to 11% and 8%, respectively. These prescribing practices did not adhere to current published guidelines recommending beta-blockers and diuretics as first-line therapy for hypertension. The economic implications of such practices are staggering: in 1995 wholesale costs for CCBs and ACE inhibitors were $2.86 and 1.67 billion, respectively, while that of beta-blockers and diuretics were $433 and $168 million, respectively.
Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study.
Hansson L, et al.
Lancet 1999 Nov 20;354(9192):1751-6.
The results of this study show that the newer and more expensive blood lowering medications are not more effective than the older and cheaper anti-hypertensive drugs in preventing cardiovascular events in elderly patients. The study was conducted on 6614 hypertensive patients aged 70-84 years, who were randomly assigned to receive either conventional treatment with diuretics or beta-blockers, or newer treatment with ACE inhibitors and calcium antagonists. No differences in rates of fatal and nonfatal myocardial infarction and stroke were observed between the two groups, indicating that increased health care costs associated with use of these drugs do not translate in improved cardiovascular outcome.
Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study.
Philipp, T. et al.
BMJ 1997;315:154-159 (19 July).This study evaluated the effectiveness of diuretics, beta-blockers, calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors in hypertensive patients. The results showed that the newer antihypertensive drugs such as calcium channel blockers and ACE inhibitors are not superior to diuretics and beta-blockers in lowering blood pressure. Furthermore, although being widely used as first line agents, there are no studies proving that they reduce morbidity and mortality in hypertensive patients.
The risk of myocardial infarction associated with antihypertensive drug therapies.
Psaty BM, et al.
JAMA 1995 Aug 23-30;274(8):620-5.The results of this study, conducted on 623 treated hypertensive patients with fatal and nonfatal myocardial infarction, and 2032 treated hypertensive controls, show that use of calcium channel blockers is associated with a 60% increased rate of myocardial infarction, compared to use of diuretics or beta-blockers. This might result in 36,000 more heart attacks occurring each year among the 6 million Americans currently taking calcium channel blockers.
Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women: the Nurses' Health Study.
Michels KB, et al.
Circulation 1998 Apr 28;97(16):1540-8.The results of this study, conducted on a cohort of 14,617 hypertensive women, show that those taking calcium channel blockers had a 64% increased incidence of myocardial infarction, compared to those taking thiazide diuretics.
Calcium channel blockers and cardiac mortality in the treatment of hypertension
A report from the Department of Health Hypertension Care Computing Project (DHCCP).
Bulpitt CJ, et al.
J Hum Hypertens 1997 Apr;11(4):205-11.This study, conducted on a cohort of 9328 hypertensive individuals, shows that those treated with calcium channel blockers, beta-blockers, methyldopa, or angiotensin-converting enzyme inhibitors, had a 32% increase in mortality rates from ischemic heart disease and a 5% increase in mortality rates from cardiovascular disease, compared to those treated with diuretics.
Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction.
Kostis JB, et al.
Am Heart J 1997 May;133(5):550-7.The results of this study, conducted on a cohort of 3396 individuals with left ventricular dysfunction, show that users of calcium channel blockers had a 37% increased incidence of fatal and nonfatal myocardial infarction, and a 14% increased rate of overall mortality, compared to nonusers.
Long-term survival after myocardial infarction: relationship with thrombolysis and discharge medication.
Results of the Augsburg Myocardial Infarction Follow-up Study 1985 to 1993.
Koenig W, et al.
Eur Heart J 1996 Aug;17(8):1199-206.The results of this study show that use of calcium channel blockers in patients with coronary heart disease is associated with a 23% increased rate of overall mortality. Mortality rates in patients with a history of myocardial infarction taking the calcium channel blocker nifedipine were 20% higher than those of patients who received beta-blockers, and those of patients who received the calcium channel blocker diltiazem were almost 3 times higher than those of patients who received beta-blockers.
Effect of long-acting and short-acting calcium antagonists on cardiovascular outcomes in hypertensive patients.
Alderman MH, et al.
Lancet 1997 Mar 1;349(9052):594-8.This case-control study, conducted on a cohort of 4350 individuals with hypertension, shows that users of short-acting calcium antagonists had an almost 4-fold increased incidence of cardiovascular events including death, compared to users of beta-blockers.
Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS).
A randomized controlled trial.
Borhani NO, et al.
JAMA 1996 Sep 11;276(10):785-91.This double-blind study evaluated the three-year outcome of hypertensive patients treated with the calcium channel blocker isradipine or with low-doses of a thiazide diuretic. After three years, the incidence of major vascular events (myocardial infarction, stroke, congestive hearth failure, angina and sudden death) was almost doubled in patients receiving isradipine compared to those receiving thiazides (5.65% vs 3.17%) and so was that of non-major vascular events and procedures (9.05% vs 5.22%).
The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.
Estacio RO, et al.
N Engl J Med 1998 Mar 5;338(10):645-52.The results of this study, conducted on a cohort of diabetic, hypertensive patients, show that users of the calcium channel blocker nisoldipine had a 9.5-fold higher incidence of fatal and non-fatal infarction, compared to users of the angiotensin-converting-enzyme-inhibitor enalapril.
Calcium channel blockers in acute myocardial infarction and unstable angina: an overview.
Held PH, et al.
BMJ 1989 Nov 11;299(6709):1187-92.This study reviewed data from 28 randomized trials investigating the effects of calcium channel blockers (CCBs) on mortality, in patients with myocardial infarction or unstable angina. The results of the analysis revealed that mortality rates were 6% higher in patients with myocardial infarction taking CCBs compared to controls (873 deaths among 8870 patients on CCBs vs, 825 deaths among 8889 control patients). Mortality rates were also higher in patients with unstable angina taking CCBs compared to controls (14 deaths among 591 treated compared with 9 deaths among 578 controls).
Use of calcium channel blockers and breast carcinoma risk in postmenopausal women.
Fitzpatrick AL, et al.
Cancer 1997 Oct 15;80(8):1438-47.The results of this study, conducted on a sample population of 3198 women of 65 or more years of age, show that users of calcium channel blockers (CCBs) had an overall 2.6-fold increased incidence of breast cancer, compared to nonusers. Women taking high doses of CCBs or using a CCB in combination with estrogens had a 4.5-fold increased risk of breast cancer, and such risk was 8.5 times higher in users of immediate release CCBs in combination with estrogens.
Calcium-channel blockade and incidence of cancer in aged populations.
Pahor M, et al.
Lancet 1996 Aug 24;348(9026):493-7.The results of this study, conducted on a cohort of 5052 individuals of 71 or more years of age, show that use of calcium channel blockers (CCBs) was associated with a 72% increased risk of cancer compared to nonuse. The risk increased with increasing doses of CCBs.
Do calcium channel blockers increase the risk of cancer?
Pahor M, et al.
Am J Hypertens 1996 Jul;9(7):695-9.The results of this study, conducted on a cohort of 750 individuals of 71 or more years of age, shows that the incidence of cancer in those taking calcium channel blockers is more than doubled compared to that of individuals taking beta-blockers.
Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the nurses' health study.
Michels KB, et al.
Cancer 1998 Nov 1;83(9):2003-7.The results of this study, conducted on a cohort of 18,635 women taking cardiovascular medications, show that users of calcium channel blockers had a 60% increased incidence of lung cancer and a 25% increase in cancer mortality, compared to nonusers.
Calcium channel blockers and the risk of cancer.
Rosenberg L, et al.
JAMA 1998 Apr 1;279(13):1000-4.This study, conducted on a sample population of 9513 patients, investigated the possible association between use of calcium-channel blockers and cancer. Users of calcium-channel blockers were shown to have an 80% increased risk of kidney cancer, compared to nonusers. In addition, use of beta-blockers and angiotensin-converting enzyme inhibitors was associated with an 80% and 90% increased risk of kidney cancer, respectively, compared to nonuse.
Use of calcium channel blockers and risk of suicide: ecological findings confirmed in population based cohort study
Lindberg, G. et al.
BMJ 1998;316:741-745 ( 7 March ).The results of this study, conducted on approximately 3,400 individuals, show that users of calcium channel blockers have a 5.4-fold increased risk of suicide compared to non-users. These findings add to the results of previous epidemiological and case reports studies, demonstrating an increased incidence of depression requiring pharmacological treatment in individuals treated with calcium channel blockers, and suggest that these drugs might be an important cause of depression and suicide in the general population.
Cardiovascular drug prescriptions and risk of depression in diabetic patients.
Rathmann W, et al.
J Clin Epidemiol 1999 Nov;52(11):1103-9.This case-control study shows that diabetic patients taking calcium channel blockers, beta-blockers or ACE inhibitors have a 2.2-, 2.6-, and 1.3-fold increased incidence of depression, compared to those not on these medications.
Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis.
Hallas J.
Epidemiology, 7(5):478-84 1996 Sep.The results of this study indicate that users of calcium channel blockers and ACE-inhibitors have a 30% increased incidence of depression requiring medication, compared to non-users.
Depression associated with nifedipine-induced calcium channel blockade.
Hullett FJ. et al.
Am J Psychiatry, 145(10):1277-9 1988 Oct.This article reports on 4 individuals who reported substantial depression while using calcium channel blockers. In all cases, depression resolved upon discontinuation of treatment.
Calcium-channel blockers and cognitive function in elderly people: results from the Canadian Study of Health and Aging.
Maxwell CJ, et al.
CMAJ 1999 Sep 7;161(5):501-6.This 5-year-long prospective study was conducted on a group of hypertensive individuals of 65 or more years of age, without signs of dementia at the beginning of the study. The results of the trial demonstrated that patients taking calcium channel blockers (CCBs) were significantly more likely to develop cognitive decline than patients taking other anti-hypertensive drugs. Seventy-five percent of patients who took CCBs exhibited poor cognitive performance, compared to 59% of those who took other anti-hypertensive drugs. Overall use of CCBs was associated with a 2.3-fold increased risk of deterioration of cognitive function. Such risk was increased by 3.7 times among users of the CCB diltiazem and verapamil.
Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs.
Garcia Rodriguez LA, et al.
Arch Intern Med 1998 Jan 12;158(1):33-9.This study, conducted on a sample population of 1505 patients hospitalized for upper gastrointestinal (GI) tract bleeding and 20,000 controls, shows that patients who took calcium channel blockers had a 70% increased rate of GI bleeding compared to non-users. After adjusting for confounders, the estimated risk was 40%. Past use of calcium antagonists was associated with a 50% increased risk of bleeding.
Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old.
Pahor M, et al.
Lancet 1996 Apr 20;347(9008):1061-5.The results of this study, conducted on a cohort of 1636 hypertensive individuals of 68 or more years of age, show that users of calcium channel blockers have a 86% increased incidence of gastrointestinal bleeding compared to users of beta-blockers. The authors warn that physicians be cautious when prescribing this class of drugs to older patients at risk of gastrointestinal hemorrhage.
Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers.
Mullins ME, Horowitz BZ, Linden DH, Smith GW, Norton RL, Stump J.
JAMA 1998 Jul 8;280(2):157-8.This article reports on the case of 4 patients with cardiogenic shock (of whom one died) in individuals simultaneously taking beta-blockers and mibefradil, a new calcium channel blocker approved in the United States in 1997. Postmarketing surveillance exposed potentially serious interactions between mibefradil and beta-blockers, digoxin, verapamil, and diltiazem, resulting in withdrawal of the drug from the U.S. market on June 8, 1998.
BETA-BLOCKERS
Beta-blockers and diuretics: to use or not to use.
Messerli FH, et al.
Am J Hypertens 1999 Dec;12(12 Pt 1-2):157S-163S.This review discusses the results of a recent meta-analysis, showing that beta-blockers, although effective in reducing blood pressure, are ineffective in reducing coronary events and cardiovascular and overall mortality. The addiction of a beta-blocker to a diuretic drug regimen consistently increased morbidity and mortality in hypertensive patients.
Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review.
Messerli FH, et al.
JAMA 1998 Jun 17;279(23):1903-7.In this study, analysis of 10 previously reported trials involving 16,164 elderly hypertensive patients, reveals that treatment with beta-blockers is ineffective in preventing coronary heart disease, cardiovascular mortality and all cause mortality, while being associated with high rates of complications. Dr. Franz Messerli, leading author of the article, in an interview released to the Wall Street Journal (Wednesday, June 17, 1998) stated; "Beta blockers needlessly expose more than six million elderly with hypertension to the cost, inconvenience and side effects of drug treatment without providing any true benefits".
Beta-blockers for hypertension: time to call a halt.
Beevers DG.
J Hum Hypertens 1998 Dec;12(12):807-10.The results of this study show that beta-blockers are rather ineffective in treating high blood pressure in elderly individuals and in Afro-Caribbeans; in addition, these drugs cause several side effects and can even be dangerous to many patients. It is concluded that beta-blocker use, with the possible exception of selected individuals, should be avoided and replaced by safer and more effective alternatives.
Evidence is needed that ß blockade alone reduces mortality in hypertension. Letter.
Opie, LH.
BMJ 1997;315:1544. Dec 6.In this letter, Dr. L.H. Opie remarks that the common claim found in scientific articles that beta-blockers reduce mortality in hypertensive patients is unfounded. He highlights that the largest study ever conducted on the subject -the Medical Research Council's mega-study- has shown that the beta-blocker atenolol not only did not reduced mortality rates in elderly people when compared to placebo, but it actually increased cardiovascular mortality. In middle-aged individuals, the beta-blocker propranolol had only modest effects in non-smokers and meager or no effects in smokers. Furthermore, mortality was not reduced. The author ironically concludes asking where, in this era of evidence-based medicine, is the evidence that single therapy with a beta-blocker reduces mortality in hypertensive patients.
The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers.
Psaty BM, et al.
JAMA 1990 Mar 23-30;263(12):1653-7.This study shows that patients with uncomplicated hypertension who have been recently less than 80% compliant with their beta-blocker drug regimen experience a 4.5-fold transient increased risk of angina and myocardial infarction. It is therefore important to recognize the existence of a beta-blocker withdrawal syndrome that may follow discontinuation of drug use and that may precipitate a first episode of angina or myocardial infarction.
Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study.
Gress TW, Nieto FJ, Shahar E, Wofford MR, and Brancati FL.
N Engl J Med. 2000 Mar 30;342(13):905-12.The results of this study show that patients treated with beta-blockers for hypertension have a 28% increased risk of developing type 2 diabetes compared to untreated hypertensive patients.
Adrenergic mechanisms in control of plasma lipid concentrations.
Day JL, et al.
Br Med J (Clin Res Ed) 1982 Apr 17;284(6323):1145-8.The results of this study show that treatment with beta-blockers induces negative changes in blood lipid profile. In particular, patients treated with beta-blockers exhibited increased levels of total and VLDL-cholesterol and triglycerides and decreased levels of HDL-cholesterol (protective cholesterol), compared to baseline. The authors recommend monitoring of serum lipid concentrations within 3-6 months of drug treatment initiation.
Comparison of effects on lipid metabolism of antihypertensive drugs with alpha- and beta-adrenergic antagonist properties.
Leren P.
Am J Med 1987 Jan 5;82(1A):31-5.This article reports on the results of clinical trials demonstrating that beta-blockers lower the ratio of HDL-cholesterol (a protective factor) to total cholesterol by 11.7% while increasing serum triglyceride levels by 25.8%. Both effects may be a significant risk factor for the development of coronary heart disease.
Effect of propranolol and prazosin on blood lipids. The Oslo Study.
Leren P, et al.
Lancet 1980 Jul 5;2(8184):4-6.This study shows that treatment with beta-blockers in hypertensive men, was associated with a 13% reduction of serum HDL-cholesterol, a 15% reduction in the ratio of HDL-cholesterol to LDL- and VLDL-cholesterol, a 24% increase in tryglicerides, and a 10% increase in serum uric acid levels. These effects should be taken into special consideration when long-term treatment is contemplated.
Increased prescribing of antidepressants subsequent to beta-blocker therapy.
Thiessen BQ, et al.
Arch Intern Med 1990 Nov;150(11):2286-90.The results of this study, conducted on a group of over 3,000 individuals started on beta-blocker therapy, show that within the following 34 days, 6.4% of them also received a new prescription for antidepressants (a sign of depressive symptoms). These rates are more than 2-fold greater than those of a control group, in which only 2.8% of individuals were started on antidepressant treatment. The risk of depression was particularly high with the beta-blocker propranolol. In particular, propranolol users had an almost 5-fold increased risk of receiving a concomitant antidepressant compared to controls, and the risk of receiving antidepressants was increased by over 17 times in individuals aged 20 to 39 years. These data indicate that beta-blocker use may be an important cause of depression in the general population.
Patients' and physicians' assessment of risks associated with hypertension and benefits from treatment.
Kjellgren KI, et al.
J Cardiovasc Risk 1998 Jun;5(3):161-6.The results of this study show that patients commonly perceive the risk of cardiovascular complications from untreated hypertension to be higher than what their doctors believe. On the other hand, patients perceive the benefits derived from therapy to be higher than what their doctors believe. These differences in opinion may influence patients' decision of starting therapy based on the analysis of treatment benefits and side effects.
ALPHA-BLOCKERS
Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.
JAMA. 2000;283:1967-1975.This study reports on the results of a trial conducted on over 24,000 patients with hypertension and at risk of cardiovascular disease, who were randomized to receive either the a-blocker drug doxazosin (sold under the brand name of Cardura® by Pfizer Inc.) or the diuretic chlortalidone. After an average follow-up of 3.3 years, the trial was prematurely interrupted when preliminary analysis revealed that patients taking the a-blocker had a significantly higher risk of cardiovascular disease events, compared to those taking the diuretic. In particular, doxasosin patients had a two-fold increased incidence of congestive heart failure, and a 19%, 16%, 15% and 7% higher incidence of stroke, angina, coronary revascularization, and peripheral arterial disease, respectively. In addition, patients taking the a-blocker had significantly more difficulty in being compliant to treatment, compared to those taking the diuretic. The implications of these findings are substantial, especially if we consider that a-blockers are first line agents in the management of hypertension, and are currently being prescribed to approximately 1 million Americans. Of note, a-blockers are significantly more expensive than diuretics, as shown by the sales generated by Cardura® in 1999 alone, some $794 million.
DIURETICS
Non-potassium-sparing diuretics and risk of sudden cardiac death.
Grobbee DE; Hoes AW.
J Hypertens, 13(12 Pt 2):1539-45 1995 Dec.This article presents the results of two case-control studies demonstrating that hypertensive patients receiving non-potassium sparing diuretics (thiazides) have a two-fold increased risk of sudden death compared to patients treated with potassium-sparing diuretics.
Sudden cardiac death in patients with hypertension. An association with diuretics and beta-blockers?
Hoes AW; Grobbee DE; Lubsen J.
Drug Saf, 16(4):233-41 1997 Apr.This review article reports on the results of 7 trials demonstrating that hypertensive patients receiving thiazide diuretics have a 50% increased risk of sudden death compared to those receiving placebo. This result may be due to the potassium-depleting effect of these drugs. The article also reports on two case-control studies showing that not only use of thiazide diuretics, but also that of beta-blockers, is associated with increased risk of sudden death.
Association between diuretic use, clinical response, and death in acute heart failure.
Philbin EF; Cotto M; Rocco TA Jr; Jenkins PL.
Am J Cardiol, 80(4):519-22 1997 Aug 15.This study, conducted on 1,150 patients hospitalized for congestive heart failure (CHF), evaluated the impact of diuretic treatment on CHF survival. The highest mortality rates were observed in patients receiving more doses of diuretics or experiencing less net weight loss (an indicator of diuretic resistance).
Diet or diuretic? Treatment of newly diagnosed mild to moderate hypertension in the elderly.
Koopman H, Deville W, van Eijk JT, Donker AJ, Spreeuwenberg C.
J Hum Hypertens 1997 Dec;11(12):807-12.In this study, 42 individuals with systolic and diastolic blood pressure in the range of 160-180 and 95-100 mm HG, respectively, were randomly assigned to two intervention programs: one consisting of a sodium-reduced, potassium enriched, and weight reduction diet, the other consisting of 25 mg of chlorthalidone a day. Blood pressure fell within normal limits in about 50% of individuals in the diet group, and in about 80% of those in the diuretic group. However, the latter group, compared to the former, experienced deterioration of lipid spectrum and blood glucose concentration. In addition, two subjects dropped out from the chlorthalidone group, one for side effects, and the other after a myocardial infarction.
Diuretics, beta-blockers, and the risk for sudden cardiac death in hypertensive patients.
Hoes AW, et al.
Ann Intern Med 1995 Oct 1;123(7):481-7.The results of this study show that patients treated with non-potassium-sparing diuretics or beta-blockers have an 80% and 70% increased risk of sudden cardiac death, respectively, compared to patients treated with potassium-sparing diuretics.
The risk of death among users of non-potassium-sparing diuretics was particularly high in patients younger than 76 years of age and in those who were using the drug since less than a year.
Diuretic therapy for hypertension and the risk of primary cardiac arrest.
Siscovick DS, et al.
N Engl J Med 1994 Jun 30;330(26):1852-7.This study shows that hypertensive patients treated with moderate (50 mg daily) or high doses (100 mg daily) of non-potassium-sparing diuretics (thiazides) have a 70% and a 3.6-fold increased risk of sudden cardiac death, compared to patients treated with low doses of thiazides. The addition of a potassium-sparing diuretic to low-dose thiazide therapy further decreased the risk of sudden death by 60%.
Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction.
Cooper HA, et al.
Circulation 1999 Sep 21;100(12):1311-5.The results of this study, conducted on a sample population of approximately 6800 individuals with left ventricular dysfunction, show that users of non-potassium sparing diuretics had a 33% increased incidence of death due to arrhythmia, compared to nonusers. These results indicate that electrolyte disturbances induced by diuretics may cause fatal arrhythmias in susceptible patients.
The place of diuretics in the treatment of hypertension in 1993: can we do better?
Johnston CI.
Clin Exp Hypertens 1993 Nov;15(6):1239-55.The authors of this study reviewed the current literature on antihypertensive treatment and concluded that the only class of drugs that has convincingly shown to reduce long-term morbidity and mortality from cardiovascular diseases are low-dose diuretics, particularly when treatment with thiazides is associated with a potassium-sparing diuretic.
Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients.
Sonnenblick M, et al.
Chest 1993 Feb;103(2):601-6.This article emphasizes that thiazide diuretics are responsible for 94% of cases of severe diuretic-induced hyponatremia (low levels of sodium in the blood) reported in the literature. This complication occurs in women 4 times more frequently than in men, is age-independent, and may lead to neurological deficits and death. The authors warn that rapid correction of sodium levels may lead to higher mortality rates or demyielinating syndrome.
Effect of diuretics on the plasma lipid profile.
Weidmann P, et al.
Eur Heart J 1992 Dec;13 Suppl G:61-7.This article shows that diuretics such as thiazides and loop diuretics may increase serum levels of LDL-cholesterol and triglycerides and adversely affect glucose metabolism.
Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients: a double-blind controlled trial.
Grimm RH Jr, et al.
Ann Intern Med 1981 Jan;94(1):7-11.This article reports on the results of a cross-over, randomized trial demonstrating the adverse effects on blood lipid profile induced by diuretics in mildly hypertensive men. Treatment with thiazide diuretics has been shown to increase total cholesterol levels by 6-8% and triglyceride levels by 15-17%. These effects can be long-term, and may interfere with the potential benefits associated with diuretic therapy in the treatment of hypertension.
Beta-blockers and diuretics: to use or not to use.
Messerli FH, et al.
Am J Hypertens 1999 Dec;12(12 Pt 1-2):157S-163S.This review presents the results of recent studies demonstrating an increased risk of renal cell cancer in patients treated with diuretics. The risk would be increased by over 50%, according to the results of 9 case-control studies, or by over 2-folds, according to results from three cohort studies. Since the risk increases with increasing cumulative doses of diuretics, the authors recommend that this class of drug be avoided in middle-aged patients, particularly women, who are at higher risk of this complication.
Risk of renal cell cancer in relation to diuretics, antihypertensive drugs, and hypertension.
Chow WH, et al.
Cancer Epidemiol Biomarkers Prev 1995 Jun;4(4):327-31.The results of this study indicate that use of diuretics and other antihypertensive drugs is associated with a 40% and a 2-fold increased risk of renal cell cancer, respectively.
Does diuretic therapy increase the risk of renal cell carcinoma?
Grossman E, et al.
Am J Cardiol 1999 Apr 1;83(7):1090-3.This study reviewed all published articles evaluating the relationship between diuretic use and renal cell cancer risk. Nine case control studies described an overall 55% increased risk of renal cell cancer in patients treated with diuretics, and 3 cohort studies conducted on over 1,200,000 patients reported a 2.2-fold increased risk of renal cancer in diuretic users, compared to non-users. The risk was particularly elevated in women. The authors recommend a careful risk/benefit evaluation before initiating long-term treatment of systemic hypertension.
Adverse reactions to prescribed drugs in the elderly: a multicentre investigation.
Williamson J, Chopin JM.
Age Ageing 1980 May;9(2):73-80.The results of this study show that diuretics are the single most common cause of adverse drug reactions in elderly patients. The study, conducted on a sample population of 1998 elderly individuals, detected the occurrence of adverse drug reactions in over 15% of those who were receiving medications. Drugs that carried the greatest risk of adverse events were psychotropic, antiparkinson, and antihypertensive drugs. Diuretics however, being the most frequently prescribed medication, were responsible for the largest number of adverse reactions.
Excess mortality associated with diuretic therapy in diabetes mellitus.
Warram JH, Laffel LM, Valsania P, Christlieb AR, Krolewski AS.
Arch Intern Med 1991 Jul;151(7):1350-6.The results of this study indicate that hypertensive diabetic patients treated with diuretics have an almost 4-fold increased risk of death from cardiovascular disease, compared to those who are untreated. The authors call for a revision of current practices employing continuous use of diuretics for the management of hypertension in diabetic patients.
Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium.
Helderman JH, et al.
Diabetes, 32(2):106-11 1983 Feb.The results of this study show that the diabetogenic effects of thiazide diuretics may be mediated by the loss of potassium that this class of drugs induce, and may be prevented by potassium supplementation.
Metabolic adverse effects of thiazide diuretics: the importance of normokalaemia.
Andersson OK, et al.
J Intern Med Suppl 1991;735:89-96.This article discusses the metabolic complications associated with long-term use of diuretics in hypertensive patients. The authors emphasize that potassium depletion induced by diuretics may increase cardiac arrhythmias and may mediate disruption of glucose and lipid metabolism. The diabetogenic effects of thiazide diuretics seem related to a decreased pancreatic secretion of insulin in response to glucose and to increased tissue insulin resistance.
Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism.
Perez-Stable E, et al.
Am Heart J 1983 Jul;106(1 Pt 2):245-51.This article emphasizes that long-term treatment with thiazide diuretics has been shown to increase glucose, LDL-cholesterol and triglyceride levels, effects these that are more prevalent among younger patients. The adverse effects on glucose and lipid metabolism associated with use of these drugs seem to be mediated by diuretic-induced potassium depletion.
Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study.
Helgeland A, et al.
Am J Med 1984 May;76(5):802-5.The results of this study, conducted in mildly hypertensive men aged 40-49 years followed-up for 5 years, show that combined drug treatment with thiazide diuretics and beta-blockers is associated with significant increase in blood glucose and triglyceride levels.
Do antihypertensive drugs precipitate diabetes?
Bengtsson C et al.
Br Med J (Clin Res Ed), 289(6457):1495-7 1984 Dec 1.This study shows that hypertensive patients taking diuretics and beta-blockers have a significant increased risk of developing diabetes compared to control subjects who do not take anti-hypertensive medications.
Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly.
Fletcher AE.
Am J Med, 90(3A):42S-44S 1991 Mar.This article reports on some of the adverse effects observed in a cohort of 840 elderly patients randomly assigned to receive either placebo or the diuretics triamterene and hydrochlorothiazide. One third of treated patients also received methyldopa. Patients receiving pharmacological treatment experienced significantly more dry mouth, nasal stuffiness, diarrhea, high serum creatinin levels (a sign of kidney dysfunction), hypokalemia, gout and diabetes, compared to those receiving placebo.
Antihypertensive drugs and the risk of gastrointestinal bleeding.
Suissa S, Bourgault C, Barkun A, Sheehy O, Ernst P.
Am J Med 1998 Sep;105(3):230-5.This study found a 40% increased risk of gastrointestinal bleeding in hypertensive patients treated with diuretics compared to individuals currently not on blood-lowering medications.
ACE INHIBITORS
Randomised, double blind, multicentre comparison of hydrochlorothiazide,
atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study.
Philipp, T. et al.
BMJ 1997;315:154-159 (19 July).This study evaluated the effectiveness of diuretics, beta-blockers, calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors in hypertensive patients. The results showed that the newer antihypertensive drugs such as calcium channel blockers and ACE inhibitors are not superior to diuretics and beta-blockers in lowering blood pressure. Furthermore, although being widely used as first line agents, there are no studies proving that they reduce morbidity and mortality in hypertensive patients.
Health outcomes associated with antihypertensive therapies usedas first-line agents. A systematic review and meta-analysis.
Psaty BM, et al.
JAMA 1997 Mar 5;277(9):739-45.In this study, the efficacy of various antihypertensive drugs as first-line agents was assessed through evaluation of long-term studies, placebo-controlled randomized trials and meta-analysis performed from 1980 to 1995. The results of the analysis of these trials revealed that use of angiotensin-converting enzyme inhibitors in patients with hypertension is associated with poor health outcomes.
Predisposition to and late onset of upper airway obstruction following angiotensin-converting enzyme inhibitor therapy.
Jain M, Armstrong L, Hall J.
Chest 1992 Sep;102(3):871-4.This article presents angioedema of the face and neck as a possible fatal adverse effect of angiotensin-converting enzyme inhibitor use, and describes 5 such cases presented to the hospital during a 2 1/2-year period. Symptoms arose from two days to ten months after treatment.
Angioedema due to ACE inhibitors: increased risk in patients of African origin.
Gibbs CR, et al.
Br J Clin Pharmacol 1999 Dec;48(6):861-5.This study reports on 20 patients who, within a 7-year period, presented to a U.K. hospital with ACE-inhibitors induced angioedema. In most cases angioedema occurred in the 4 weeks following initiation of therapy, although 3 patients developed this complication after 24-48 months of treatment. Eight patients had to be admitted to the hospital, and one died for severe laryngeal obstruction. Sixty-five percent of patients were black/Afro-Caribbean.
Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry?
Reardon LC, Macpherson DS.
Arch Intern Med 1998 Jan 12;158(1):26-32.The results of this study show that 11% of 1818 individuals treated with ACE-inhibitors developed hyperkalemia (increased serum potassium levels), a potential life-threatening complication associated with use of this class of drugs. At one-year follow-up, 10% of individuals with hyperkalemia who continued taking ACE-inhibitors, developed severe hyperkalemia (potassium levels >6.0 mmol/L). The risk was particularly elevated in patients older than 70 years and in those with impaired renal function.
Rapid life-threatening hyperkalemia after addition of amiloride HCl/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy.
Chiu TF, et al.
Ann Emerg Med 1997 Nov;30(5):612-5.This study warns about the dangers of inducing severe hyperkalemia (increased potassium concentration) in at-risk patients treated with both angiotensin-converting enzyme (ACE) inhibitor and potassium-sparing diuretics. The case of 5 individuals (2 of whom died) who presented to the emergency room with severe hyperkalemia due to this treatment combination is presented.
Case-control studies of cardiovascular medications as risk factors for clinically diagnosed depressive disorders in a hospitalized population.
Patten SB, et al.
Can J Psychiatry 1996 Sep;41(7):469-76.This article presents the results of two case-control studies (one among patients with congestive heart failure and another among patients with hypertension) investigating the effects of antihypertensive treatment on the incidence of depression. In both studies, individuals using ACE-inhibitors had a significant increased risk of developing depression compared to non-users. The risk was particularly elevated in women and in individuals over the age of 65.
ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes.
DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside, Scotland. Medicines Monitoring Unit.
Morris AD, et al.
Diabetes Care 1997 Sep;20(9):1363-7.This study investigated whether use of ACE-inhibitors in diabetic patients is associated with an increased risk of developing hypoglycemia (abnormally low blood glucose levels) requiring hospitalization. Users of ACE-inhibitors were found to have a 3.2-fold increased risk of being hospitalized for hypoglycemia, compared to non-users. These data confirm the results of a previous study indicating that as much as 14% of all hospital admission for hypoglycemia in diabetic patients may be attributed to ACE-inhibitor use.
Association between antihypertensive drug use and hypoglycemia: a case-control study of diabetic users of insulin or sulfonylureas.
Thamer M, et al.
Clin Ther 1999 Aug;21(8):1387-400.This case-control study shows that diabetic, hypertensive patients taking the ACE-inhibitor enalapril have a 2.4-fold increased risk of being hospitalized for hypoglycemia, compared to non-users. Health care costs were approximately 3 times higher in patients hospitalized for hypoglycemia versus controls, indicating that this preventable complication is associated with significantly increased use of health care resources.
ANTIARRHYTHMIC DRUGS
Class III drugs and congestive heart failure: focus on the congestive heart failure-survival trial of antiarrhythmic therapy.
Singh SN, Fletcher RD.
Am J Cardiol 1999 Nov 4;84(9A):103R-108R.This article reviews current information on antiarrhythmic drug treatment to prevent arrhythmias and death in patients with congestive heart failure. Among the drugs approved by the FDA for this purpose were the sodium-channel blockers. This class of drug not only failed to prevent arrhythmic deaths but actually increased mortality. Subsequently, a new type of antiarrhythmic drug was developed: the potassium-channel blockers, which included d-sotalol, amiodarone, and dofetilide. D-sotalol was associated with increased mortality, dofetilide was of no benefit, and only amiodarone might prove beneficial.
Meta-analysis of antiarrhythmic drug trials.
Connolly SJ.
Am J Cardiol 1999 Nov 4;84(9A):90R-93R.This article explains that there is still no clear proof that antiarrhythmic drug therapy reduces mortality from arrhythmia in at-risk patients. In fact, several antiarrhythmics have been shown to actually increase the incidence of death from arrhythmia. Amiodarone is the only drug that may be associated with benefits, but data are still conflicting. Among 13 trials investigating the effects of this drug, 3 reported a reduction in mortality, and the others revealed no benefit. A meta-analysis of these trials showed reduction in total and arrhythmic death among amiodarone users.
Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction
EMIAT. European Myocardial Infarct Amiodarone Trial Investigators.
Julian DG, et al.
Lancet 1997 Mar 8;349(9053):667-74.This study investigated the effects of the antiarrhythmic amiodarone on overall mortality and cardiac and arrhythmic mortality in patients with myocardial infarction. Of 1486 patients, 743 received amiodarone and 743 received placebo. There were 103 deaths in the amiodarone group and 102 deaths in the placebo group. Although there was a reduction in mortality due to arrhythmia in the amiodarone group, the overall cardiac and total mortality did not change between the two groups.
Role of antiarrhythmic agents after myocardial infarction with special reference to the EMIAT and CAMIAT trials of amiodarone.
European Myocardial Infarct Amiodarone Trial. Canadian Amiodarone Myocardial Infarction Trial.
Jafri SM, et al.
Prog Cardiovasc Dis 1998 Jul-Aug;41(1):65-70.This article reports on three trials evaluating the effects of amiodarone on total, cardiovascular and arrhythmic mortality in patients with myocardial infarction (MI). One study, the BASIS trial, reported reduction in total mortality, sudden death, and ventricular arrhythmias in patients assigned to amiodarone therapy. Both the EMIAT and CAMIAT trials did not reveal any reduction in overall mortality in patients receiving amiodarone compared to those taking placebo, although there were fewer deaths due to arrhythmia. Based on these results amiodarone treatment is not recommended for routine use in post MI patients.
Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction.
The SWORD Investigators. Survival With Oral d-Sotalol.
Waldo AL, et al.
Lancet 1996 Jul 6;348(9019):7-12.This study evaluated the efficacy of the antiarrhythmic drug d-sotalol in preventing mortality in patients with cardiac dysfunction with a history of cardiac infarction. Five percent of patients receiving d-sotalol died compared to 3.1% of those receiving placebo. The risk of death among patients taking the drug was 65% higher compared to that of patients taking placebo. The results of this study show that d-sotalol, in spite of previous study suggesting its positive effects on survival, is associated with increased mortality in patients at-risk of cardiovascular events.
Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction.
TheSWORD Investigators. Survival With Oral d-Sotalol.
Waldo AL, et al.
Lancet 1996 Jul 6;348(9019):7-12.This study evaluated the effects of the potassium-channel blocker d-sotalol on mortality in patients with recent or remote myocardial infarct and left ventricular ejection fraction (LVEF) of 40% or less. The trial was stopped when it was shown that patients assigned to d-sotalol had an overall 65% increase in rates of mortality, compared to those assigned to placebo. Of note, individuals with LVEF between 30% and 40% taking d-sotalol had a four-fold increase in mortality compared to those taking placebo.
Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die?
Pratt CM, et al.
Am J Cardiol 1998 Apr 1;81(7):869-76.This study shows that mortality rates in patients taking d-sotalol in the Survival With ORal D-sotalol (SWORD) trial were greatest among patient who had non-recent myocardial infarction (> 42 days) ad a certain degree of cardiac dysfunction (indicated by left ventricular ejection fraction of 31% to 40%). Among these patients mortality rates were almost 8 times higher than in correspondent patients taking placebo. Use of this drug in women was associated with a 4.7-fold increase in mortality.
Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction.
The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST).
Epstein AE, et al.
JAMA 1993 Nov 24;270(20):2451-5.The results of this randomized, placebo controlled trial, conducted on 3549 individuals with myocardial infarction and left ventricular dysfunction, show that 1 year after initiation of trial, mortality rates in patients taking antiaarhythmic drugs were twice as high as those of patients receiving placebo (10% vs. 5%). Dr. Epstein, author of the study, reported to the New York Post (11/24/1993) that based on conservative estimates, every year approximately 4,000 extra deaths occurred among users of these drugs (over 100,000 patients).
Congestive heart failure induced by six of the newer antiarrhythmic drugs.
Ravid S, et al.
J Am Coll Cardiol 1989 Nov 1;14(5):1326-30.
The results of this study show that each of the 6 newer antiarrhythmic drugs tested on a group of 407 patients (encainide,ethmozine, lorcainide, mexiletine, propafenone and tocainide) increased the incidence of congestive heart failure in patients with compromised cardiac function. The incidence of congestive heart failure ranged from 0.7% with lorcainide to 4.7% with propafenone.
Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II Investigators.
N Engl J Med 1992 Jul 23;327(4):227-33.The results of this study show that treatment with the antiarrhythmic drug moricizine is associated with increased mortality rates in patients with myocardial infarction (MI). In particular, 17 deaths or cardiac arrests were recorded among a cohort of 665 post-MI patients taking moricizine for two weeks, while only 3 deaths or cardiac arrests occurred among a cohort of 660 post-MI patients taking placebo.
Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial.
CAST Investigators.
Akiyama T; et al.
Am J Cardiol, 68(17):1551-5 1991 Dec 15.This study shows that patients with non-Q-wave acute myocardial infarction treated with the antiarrhytmics encainide and flecainide, have an 8.7-fold increased risk of death and cardiac arrest compared to patients receiving placebo.
Sudden death during empiric amiodarone therapy in symptomatic hypertrophic cardiomyopathy.
Fananapazir L; Leon MB; Bonow RO; Tracy CM; Cannon RO 3d; Epstein SE.
Am J Cardiol, 67(2):169-74 1991 Jan 15.The results of this study, conducted on a cohort of 50 patients with hypertrophic cardiomyopathy, show that treatment with the antiarrhythmic drug amiodarone was associated with the occurrence of ventricular tachycardia in 42% of patients. Sudden death occurred in six patients (12%) within 5 months of starting treatment.
Antiarrhythmic therapies for the prevention of sudden cardiac death.
McAlister FA; Teo KK.
Drugs, 54(2):235-52 1997 Aug.In this study, analysis of the results of 61 trials evaluating the effects of preventive antiarrhythmic treatment on a total of 23,486 patients at risk of cardiovascular events, revealed that use of these drugs is associated with an overall 13% increased risk of sudden death. In addition, results from 26 trials showed a slight increase in risk of sudden death in patients treated with calcium channel blockers, while data from 56 trials demonstrated a decreased risk of sudden death in high-risk patients treated with beta-blockers.
Can sudden cardiac death be prevented by treatment with anti-arrhythmia drugs?
Zrenner B; Koller B; Rudolph W.
Herz, 15(2):90-102 1990 Apr.This article reviews the results of nine large randomized controlled studies evaluating mortality rates in hypertensive patients treated with antiarrhythmic drugs. Eight of these studies revealed no differences in mortality rates or sudden cardiac death rates among patients receiving antiarrhythmic drugs or placebo. The ninth study, the CAST trial, was interrupted after it was shown that patients receiving the antiarrhythmic drugs encainide and flecainide had, compared to those taking placebo, an over 2.5-fold increased rate of mortality (7.7% vs 3.0%) and an almost 4-fold incidence of sudden cardiac rate (4.5% vs 1.2%).
Effect of quinidine or procainamide versus no antiarrhythmic drug on sudden cardiac death, total cardiac death, and total death in elderly patients with heart disease and complex ventricular arrhythmias.
Aronow WS; Mercando AD; Epstein S; Kronzon I.
Am J Cardiol, 66(4):423-8 1990 Aug 15.This study was conducted on a cohort of 406 elderly patients with heart disease and asymptomatic complex ventricular arrhythmias, on antiarrhythmic therapy with quinidine and procainamide. Within two weeks of starting treatment, adverse reactions necessitating discontinuation of therapy occurred in 46% of patients taking quinidine, and in 22% of those taking procainamide. Long-term antiarrhythmic treatment resulted in the occurrence of adverse events in an additional 2% and 33% of patients on quinidine and procainamide, respectively. Patients on antiarrhythmic therapy had the same mortality rates compared to patients who did not receive treatment.
Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence.
Ebert SN; Liu XK; Woosley RLJ.
Womens Health, 7(5):547-57 1998 Jun.This article shows that women, much more than men, are at risk of developing the life-threatening ventricular arrhytmia torsades de pointes (TdP) as a complication of treatment with antihistamines, antibiotics, antimalarials, antiarrhythmics, and a variety of other drugs.
Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide.
The Pediatric Electrophysiology Group.
Fish FA et al.
J Am Coll Cardiol, 18(2):356-65 1991 Aug.This study shows that 7.5% of young patients with heart arrhythmias treated with the antiarrhythmic drug encainide and 2.2% of those receiving the antiarrhythmic flecainide experienced cardiac arrest or died during treatment.
Amiodarone induced epididymitis in children.
Hutcheson J, Peters CA, Diamond DA
J Urol 1998 Aug;160(2):515-7This article emphasizes that up to 11% of adult patients treated with the antiarrhythmic drug amiodarone develop sterile epididymitis (inflammation of the tubules of the testicles). Here the case of two children with amiodarone-induced epididymitis is presented, thus indicating the occurrence of this complication in this age group too.
CHOLESTEROL-LOWERING DRUGS
Cholesterol lowering and mortality: the importance of considering initial level of risk.
Smith GD, et al.
BMJ 1993 May 22;306(6889):1367-73.This study is a meta-analysis of published and unpublished trails investigating the effects of cholesterol-lowering medications on overall mortality. The results of the analysis revealed that cholesterol-lowering drugs are beneficial only in a minority of patients at very high risk of coronary heart disease (CHD), in whom treatment is associated with a 26% reduction in mortality. No benefit from drug therapy was observed in patients at medium risk of CHD, while in those at low risk of CHD treatment was associated with a 22% increase in overall mortality. The authors concluded that the cholesterol-lowering medications they evaluated seemed capable of improving outcome in a very small subgroup of patients at very high risk of CHD, and their routine use could result in overall harm. The authors conclude calling for judicious use of this class of drugs.
All mortality by cause of death. The challenge of coronary prevention.
Fern´andez-Cruz A.
Rev Esp Cardiol, 51 Suppl 6():23-9 1998.This review reports on the results of a meta-analysis conducted by Rossouw and colleagues and published in the New England Journal of Medicine in 1991, showing that use of cholesterol-lowering drugs is associated with a 15% increase in non-cardiovascular mortality. One of the proposed hypotheses suggests that low levels of plasma cholesterol may adversely affect brain function and lead to an increased incidence of violent behavior, suicide and accidents.
Low serum total cholesterol concentrations and mortality in middle aged British men.
Wannamethee G, Shaper AG, Whincup PH, Walker M.
BMJ 1995 Aug 12;311(7002):409-13.The results of this study, conducted on a sample population of 7,735 men aged 40-59, show that those with low serum cholesterol levels had the highest overall mortality rates, particularly due to a 40% increase in cancer mortality rates.
Higher prevalence of depressive symptoms in middle-aged men with low serum cholesterol levels.
Steegmans PH, Hoes AW, Bak AA, van der Does E, Grobbee DE.
Psychosom Med 2000 Mar-Apr;62(2):205-11.The results of this study show that individuals with low levels of cholesterol are significantly at higher risk of developing depression, compared to those with normal cholesterol levels. The study was conducted on approximately 30,000 men who were screened for cholesterol levels in 1990-1991 and again in 1993-1994. The investigators wanted to further evaluate the relation between low cholesterol and increased risk of suicide, documented by previous studies. Data analysis revealed that men with chronically low levels of cholesterol were at significantly increased risk of depression, even after adjustment for several confounders.
Cholesterol and violence: is there a connection?
Golomb BA.
Ann Intern Med, 128(6):478-87 1998 Mar 15.This study reviews the literature on the possible association between low or lowered cholesterol levels and violence. Observational studies, experimental studies, and meta-analyses of randomized trials have consistently shown an increased rate of violent death and violent behaviors in individuals with low cholesterol levels. Data from these studies fulfill Hill's criteria for defying this association as causal. The association between low cholesterol and increased violence should be taken in account when considering risk-benefits of cholesterol screening and treatment programs.
Low cholesterol and violence.
Mufti RM; Balon R; Arfken CL.
Psychiatr Serv, 49(2):221-4 1998 Feb.The results of this case-control study, conducted on a sample of 40 patients in a long-term psychiatric hospital, show that violent behavior was 15.5 times more likely to occur in patients with low cholesterol levels, than in those with normal or high levels.
DIGITALIS
Hospitalizations with adverse events caused by digitalis therapy among elderly Medicare beneficiaries.
Warren JL, McBean AM, Hass SL, Babish JD.
Arch Intern Med 1994 Jul 11;154(13):1482-7.This study evaluated the incidence of hospitalizations caused by digitalis in a cohort of over 3 million Medicare recipients taking the drug. During a seven-year period, 202,011 patients were hospitalized for digitalis-related adverse reactions, leading to an annual rate of 8.53 hospitalizations for 1,000 digitalis users. Women, older individuals, and African-American were particularly at risk of adverse events requiring hospitalization.
