74 Cardiac Drug Therapy Drug name: Felodipine Trade names: Plendil, Renedil Supplied: 2.5, 5, 10 mg Dosage: Hypertension: 2.5–5 mg once daily; max. 10 mg; reduce dosage in the elderly and in hepatic impairment With isradipine and felodipine, interactions occur with cimetidine, antiepileptic agents, and grapefruit juice. Felodipine (Plendil) was the calcium antagonist used in the Hyper- tension Optimal Treatment (HOT) study (27). The drug proved remarkably safe and in combination with other agents was effective in decreasing diastolic pressures to the desired goal; it resulted in a significant reduction of fatal and nonfatal strokes. Drug name: Nicardipine Trade name: Cardene Dosage: 5–30 mg twice daily Nicardipine has actions, effects, and indications similar to those of nifedipine. Drug name: Nimodipine Trade name: Nimotop Dosage: 0.35 mg/kg four times hourly; see text for further advice Nimodipine is useful in the management of cerebral arterial spasm after subarachnoid hemorrhage (28). Dosage (Further Advice) For patients over 70 kg, use an IV central line, 1 mg/h initially, increasing after 2 h to 2 mg/h, if hypotension does not occur. Halve the dose in patients weighing less than 70 kg. Use the IV route for 5 d and then give orally 60 mg every 4 h starting within 4 d of subarach- noid hemorrhage and for 21 d. Drug name: Nisoldipine Trade names: Sular, Syscor (UK) Dosage: 10 mg daily; max. 40 mg Nisoldipine has been observed to cause enhanced platelet aggregation as well as exac- erbation of myocardial ischemia on abrupt withdrawal. Other DHPs include azodipine, diazodipine, flordipine, iodipine, and lacidipine (Motens, UK); the dose is 2–4 mg daily, maximum 6 mg once daily. Also available are mesudipine, niludipine, nilvadipine, nitrendipine, oxodipine, riodipine, ryosidine, and vadipine. What has been described in the earlier discussion of actions, advice, and adverse effects for nifedipine should apply to the aforementioned drugs, except for their duration of action. Mibefradil (Posicor), a T channel blocker, has caused severe bradycardia and torsades de pointes; caution was necessary. In addition, rhabdomyolysis occurred when a statin was used in combination. The drug has been withdrawn. Chapter 5 / Calcium Antagonists 75 WHEN TO CHOOSE A CALCIUM ANTAGONIST These cardioactive agents, which were favorites in the 1980s, have fallen from grace. Controversies raged during the early 1990s as to their safety. It became clear that the short-acting rapid-release agents increase cardiovascular mortality in some categories of patients, and their use has been curtailed by cardiologists and virtually all internists in the United States and Canada. During 1996 and 1997, the extended-release formulations, when indicated, were con- sidered effective and safe by most internists and expert panels, but opinions today vary. The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) study (29) indicated that, although amlodipine treatment did not show improvement in total cardiac mortality in patients treated for HF, the drug did not increase total mortality. The drug was considered safe in patients with EF > 30%. The drug, however, caused a significant increase in pulmonary edema in patients with a low EF. Thus, caution is necessary with any DHP in patients with HF. Amlodipine is not approved by the FDA for the treatment of HF. Other calcium antagonists are contraindicated in patients with HF and in patients with LV dysfunction. The following discussion relates only to extended-release calcium antagonists. Rapid- release formulations are not recommended for clinical use except in special circumstances. • Although calcium antagonists are excellent antihypertensive agents, effective for all grades of hypertension (grades I–III and emergencies), RCTs have not shown a significant decrease in overall mortality. The Systolic Hypertension in Europe (Syst-Eur) study (30) showed a 42% reduction in fatal and nonfatal strokes with the use of nitrendipine; overall mortality and cardiovascular mortality rates, however, were not significantly reduced. • In patients with coexisting disease, particularly diabetes, patients with ischemic heart dis- ease (IHD), and those with LV dysfunction, caution is required (29,31–37). RCTs in hyper- tensive patients with diabetes have shown increased mortality and cardiovascular mortality rates with the use of isradipine (34) and nisoldipine (Table 5-4) (35). Diabetic patients are at high risk for IHD events. • The HOT study was reported in 1998 (27). INDICATIONS FOR CALCIUM ANTAGONISTS Isolated hypertension without organ damage or coexisting disease is an indication (see Chapter 8). • In older African-American people, an RCT by Matterson and associates (38) showed that diltiazem was slightly more effective than hydrochlorothiazide (HCTZ). Thus, in older black patients with isolated hypertension, diltiazem or a DHP calcium antagonist is indicated if HCTZ does not achieve goal blood pressure. • In younger black people, in the study by Matterson and colleagues (38), diltiazem was effec- tive in 64% compared with 47% for atenolol and 40% for HCTZ. Thus, diltiazem or amlod- ipine should be tried if a small dose of a beta-blocking agent fails to control blood pressure. Failure to reach goal blood pressure should prompt the combination of a DHP and a beta- blocker. • In older white people with isolated systolic hypertension, diltiazem showed a 64% effective- ness versus 68% for atenolol. Thus, a calcium antagonist is a second- or third-line drug after a trial of a beta-blocker or a diuretic and/or combination. • Patients with severe, stage II and III, hypertension require the combination of several agents, and calcium antagonists are appropriate, except in patients with LV dysfunction. 76 Cardiac Drug Therapy • In the presence of renal disease or renal failure with or without proteinuria (nondiabetic), if ACE inhibitors are contraindicated or poorly effective, DHPs have a role. Caution: Calcium antagonists appear to possess diabetogenic effects and are not generally advisable in diabetic patients unless other agents are ineffective or intolerable. RCTs in hypertensive diabetic patients have shown an increase in cardiovascular events (see Table 5-4) (34–37), but beneficial effects with beta-blockers or ACE inhibitors. (For the results of NORDIL, INSIGHT, and other trials, see Chapter 8.) Stable Angina These drugs are considered second-line agents in • The management of angina added to a beta-blocker or a nitrate (see Chapter 1, Table 1-1). • Silent ischemia: combined with a beta-blocker, they decrease the occurrence of silent ischemia. • Prinzmetal’s variant angina (coronary artery spasm). These agents are useful and are first- line drugs in the management of this category of patients; they may be used in combination with nitrates. This condition is rare, however. Because of the widespread discussion of coronary artery spasm in the 1980s, calcium antagonists became commonly used agents in patients with stable angina. Coronary artery spasm is no longer considered to play an impor- tant role in stable or unstable angina; thus, the role of these agents has been downgraded. • Caution: DHPs are contraindicated in unstable angina. Diltiazem is also contraindi- cated, but diltiazem may be tried if a beta-blocker is contraindicated. These agents are not recommended for acute MI. Diltiazem was thought to be useful following non-Q-wave MI. In a clinical trial, diltiazem decreased early reinfarction rates, but the incorrect use of a one-tailed probability test brought about statistical doubt. Further studies have not con- firmed the usefulness of diltiazem in non-Q-wave MI. In addition, the drug increases the incidence of pulmonary edema in patients with acute MI and LV dysfunction (19). Verapamil is contra-indicated in unstable angina or acute MI. • Supraventricular tachycardia: Verapamil is well known for its excellent effect on AV nodal reentrant tachycardia. • Diltiazem IV has a role for emergency ventricular rate control of atrial fibrillation. • Hypertrophic cardiomyopathy: Verapamil is advisable in selected patients when beta-blockers are contraindicated. • Aortic regurgitation: The unloading effect of nifedipine has been shown to reverse LV dila- tion and hypertrophy; this therapy may delay the need for valve surgery (12). • Pulmonary hypertension: Calcium antagonists have shown a variable response in patients with primary pulmonary hypertension. The beneficial effect of nifepidine and verapamil, however, carries a risk of causing HF. • Raynaud’s phenomenon. Table 5-4 Relative Risk of Cardiovascular Events or Death for Calcium Antagonists versus Other Agents a Study Agents Relative risk b ABCD (35) Nisoldipine versus enalapril 5.5 (2.1–14.6) FACET (36) Amlodipine versus fosinopril 2.04 (1.05–3.84) MIDAS (34) Isradipine versus HCTZ 2.7 (1.07–6.86) a Randomized controlled trials in hypertensives with diabetes or impaired glucose tolerance. b Values in parentheses are 95% confidence intervals. Chapter 5 / Calcium Antagonists 77 The clinical application of calcium antagonists versus beta-blockers is shown in Table 5-5. WHICH CALCIUM ANTAGONIST TO CHOOSE • Amlodipine is indicated for isolated systolic hypertension in the elderly if a beta-blocker and diuretic are contraindicated or fail to achieve blood pressure goal. Combination with a beta-blocker is relatively safe, except in patients with EF < 40%. Patients with stable angina with mild LV dysfunction, EF > 40%, may be tried on amlodipine. The PRAISE study (29) indicated that amlodipine is relatively safe in patients with EF > 30%. Pulmonary edema was precipitated in some patients with EF < 30%, so caution is required to avoid all calcium antagonists if there is LV dysfunction. • RCTs indicate that amlodipine (29) and felodipine (27) possess the best safety profile among the currently available DHP calcium antagonists. • Other DHPs (e.g., nifedipine and amlodipine) may be used in combination with a beta- blocker and in other situations in which a beta-blocker is used in combination. The nifed- ipine combination should not be used in patients with EF < 40%. • Diltiazem is a mild vasodilator and has gained acceptance for the treatment of both hyper- tension and stable angina. The drug, however, is not advisable in patients with EF < 40%. • Verapamil has a role in patients with stable angina when beta-blockers are contraindicated. The drug is a more effective antianginal agent than diltiazem or DHPs. The combination of nitrates often proves effective in patients with class II or III angina. The drug should not be used in patients with EF < 40% or in those with unstable angina. COMBINATION OF CALCIUM ANTAGONISTS WITH BETA-BLOCKERS, NITRATES, OR DIGOXIN The combination of amlodipine and a beta-blocker has been well established as rela- tively safe and effective. A small dose of a beta-blocker combined with amlodipine 5– 10 mg once daily is an effective and generally safe combination. Caution is necessary, however, because amlodipine or another DHP added to a beta-blocker may precipitate HF in patients with serious impairment of LV contractility. There is a more serious risk when diltiazem is combined with a beta-blocker. Verapamil carries considerable risk when combined with beta-blockers because HF, severe bradycar- dia, or AV block may ensue in significant numbers of patients. In a randomized double- blind study, Subramanian and colleagues (40,41) have shown the combination of verap- amil with propranolol to be more effective than monotherapy with either drug in the management of severe angina pectoris. Among 40 treated patients, hypotension occurred in four, cardiac failure in three, bradycardia in one, and junctional rhythm in two (i.e., 25% side effects, serious enough to require withdrawal in 15% of the patients). The frequency of similar side effects with the combination of propranolol and nifedipine or another DHP is less than 1%. Therefore, the combination of verapamil and a beta-blocker in more than minimal doses should be used only in selected patients with angina pectoris unresponsive to or intolerant of beta-blockers plus DHP. If side effects require the withdrawal of the DHP, then diltiazem may be added to the beta-blocker, provided there are no contraindi- cations to this combination, but it is, as a rule, wise to reduce the dose of the beta-blocking agent by half at the time of the change in therapy. Contraindications to the aforementioned combination are the same as those for the use of beta-blockers or verapamil independently. 78 Cardiac Drug Therapy Table 5-5 Clinical Applications of Calcium Antagonists versus Beta-Blockers Hypertensive Heart with Diabetics Lone Systolic failure nephropathy with Diabetics hypertension/ Unstable Post-MI I–III and proteinuria hypertension with IHD elderly Angina angina Acute MI prevention Amlodipine Not FDA Indicated Not Not Second-line Second-line Cl Not FDA Not FDA approved if ACE advisable advisable therapy therapy Not FDA approved approved inhibitor CI approved Diltiazem Cl Cl Not Not Second-line Second-line Cl advisable advisable therapy therapy Nifedipine Cl Cl Not Not Second-line Cl Not FDA advisable advisable therapy approved Verapamil Cl Cl Not Not Not Second-line Cl Not FDA Not FDA advisable advisable advisable therapy approved Cl approved Isradipine Cl Cl Not Not Second-line Cl advisable advisable therapy Beta-blocker FDA Second-line Advisable Advisable First-line First-line First-line First-line First-line approved a therapy if not if not therapy therapy therapy therapy therapy prone to prone to approved approved approved approved approved hypoglycemia hypoglycemia a Carvedilol. Cl, contraindicated; ACE, angiotensin-converting enzyme; IHD, ischemic heart disease; MI, myocardial infarction. 78 Chapter 5 / Calcium Antagonists 79 Long-acting oral nitrates (isosorbide dinitrate or mononitrate) added to calcium antagonists may be necessary in patients with Prinzmetal’s variant angina who fail to respond to high doses of DHP, diltiazem, or verapamil. There is no need to give a nitrate preparation routinely when using calcium antagonists, but the combination may, of course, be employed when shown to be necessary in the individual patient. Because DHPs cause extensive peripheral arterial dilation, and nitrates cause venous dilation with reduc- tion in preload, there will be an increase in the probability of dizziness and/or light-headed- ness when the drugs are combined. Note: Prinzmetal’s variant angina often undergoes spontaneous remission, and episodes may recur similar to those of cluster headache. Théroux and colleagues (42) suggest that low-risk patients who are free of angina for 1 yr during treatment may be slowly weaned from calcium antagonists. REFERENCES 1. Fleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Annu Rev Pharmacol Toxicol 1977;17:149. 2. Braunwald E. Mechanism of action of calcium-channel-blocking agents. N Engl J Med 1982;307:1618. 3. Krikler DM, Harris L, Rowland E. Calcium-channel blockers and beta blockers: Advantages and dis- advantages of combination therapy in chronic, stable angina pectoris. Am Heart J 1982;104:702. 4. Terry RW. Nifedipine therapy in angina pectoris: Evaluation of safety and side effects. Am Heart J 1982; 104:681. 5. Lette J, Gagnon RM, Lemire TG, et al. Rebound of vasospastic angina after cessation of long-term treat- ment with nifedipine. Can Med Assoc J 1984;130:1169. 6. Choong CYP, Roubin GS, Shen WF, et al. Effects of nifedipine on arterial oxygenation at rest and during exercise in patients with stable angina. J Am Coll Cardiol 1986;8:1461. 7. Ballester E, Roca J, Rodriquez-Roisin R, et al. Effect of nifedipine hypoxemia occurring after metacholine challenge in asthma. Thorax 1986;41:468. 8. Diamond JR, Cheung JT, Fang LST. Nifedipine-induced renal dysfunction: Alteration in renal hemody- namics. Am J Med 1984;77:905. 9. Bhatnagar SK, Amin MM, Al-Yusuf AR. Diabetogenic effects of nifedipine. BMJ 1984;289:19. 10. McKenney JM, Goodman RP, Wright JT Jr. Use of antihypertensive agents in patients with glucose intol- erance. Clin Pharm 1985;4:649. 11. Steele RM, Schuna AA, Schreiber RT. Calcium antagonist-induced gingival hyperplasia. Ann Intern Med 1994;120:663-664. 12. Khan M Gabriel. Angina. In: Heart Disease, Diagnosis and Therapy. Baltimore, Williams & Wilkins, 1996. 13. Farringer JA, Green JA, O’Rourke, et al. Nifedipine-induced alterations in serum quinidine concentra- tions. Am Heart J 1984;108:1570. 14. VanLith RM, Appleby DH. Quinidine-nifedipine interaction. Drug Intell Clin Pharm 1985;19:829. 15. Verapamil in acute myocardial infarction: The Danish Study Group on Verapamil in Myocardial Infarc- tion. Eur Heart J 1984;5:516. 16. Scheidt S, Frishman WF, Packer M, et al. Long term effectiveness of verapamil in stable and unstable angina pectoris: One year follow-up of patients treated in placebo-controlled, double-blind randomized clinical trial. Am J Cardiol 1982;50:1185. 17. Gulamhusein S, Ko P, Klein GJ. Ventricular fibrillation following verapamil in the Wolff-Parkinson- White syndrome. Am Heart J 1983;106:145. 18. Zalman F, Perloff TK, Durant NN, et al. Acute respiratory failure following intravenous verapamil in Duchenne’s muscular dystrophy. Am Heart J 1983;105:510. 19. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1989;319:385. 20. Goldstein RE, Boccuzzi ST, Cruess D, et al. Diltiazem increases late onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation 1991;83:52. 21. Palat GK, Hooker EA, Morahed A. Secondary mania associated with diltiazem. Clin Cardiol 1984;7:611. 22. Terwee PM, Rosman JB, Van Der Geest S. Acute renal failure due to diltiazem. Lancet 1984;2:1337. 80 Cardiac Drug Therapy 23. Lee TH, Friedman PL, Goldman L, et al. Sinus arrest and hypotension with combined amiodarone-diltia- zem therapy. Am Heart J 1985;109:163. 24. Kuhlmann J. Effects of nifedipine and diltiazem on plasma levels and renal excretions of beta-acetyldig- oxin. Clin Pharmacol Ther 1985;37:150. 25. Singh S, Doherty J, Udhop V, et al. Amlodipine versus nadolol in patients with stable angina pectoris. Am Heart J 1989;118:1137. 26. Lorimer AR, Smedsrud T, Walker P, Tyler HM. Comparison of amlodipine and verapamil in the treat- ment of mild to moderate hypertension. J Cardiovasc Pharmacol 1988;12(Suppl 7):S89. 27. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755. 28. Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm: A controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 1983;308:619. 29. PRAISE: Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure: For the Prospective Randomised Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335:1107. 30. Staessen JA, Fagard R, Lutgarde T, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension: For the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757. 31. Michels KB, Rosner BA, Manson JE, et al. Prospective study of calcium channel blocker use, cardiovas- cular disease, and total mortality among hypertensive women: The Nurses’ Health Study. Circulation 1998;97:1540. 32. Califf RM, Kramer JM. What have we learned from the calcium channel blocker controversy? Circu- lation 1998;97:1529. 33. Cutler JA. Calcium-channel blockers for hypertension: Uncertainty continues. N Engl J Med 1998;338: 679. 34. Borhani NO, Mercury M, Borhani PA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): A randomised controlled trial. JAMA 1996;276:785. 35. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardio- vascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med 1998; 338:645. 36. Tatti P, Pahor M, Byington RP, et al. Results of the Fosinopril Amlodipine Cardiovascular Events Trial (FACET) in hypertensive patients with non-insulin dependent diabetes mellitus (NIDDM). Circulation 1997;96(Suppl I):I-764. 37. Pahor M, Kritchevsky SB, Zuccla G, et al. Diabetes and risk of adverse events with calcium antagonists. Diabetes Care 1998;21:193. 38. Matterson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men: A comparison of six hypertensive agents with placebo. N Engl J Med 1993;328:914. 39. Khan M Gabriel. Valvular heart disease. In: Heart Disease, Diagnosis and Therapy. Baltimore, Williams & Wilkins, 1996. 40. Subramanian B, Bowles MJ, Davies AB, Raftery EB. Combined therapy with verapamil and propranolol in chronic stable angina. Am J Cardiol 1982;49:125. 41. Subramanian VB. Calcium Antagonists in Chronic Stable Angina Pectoris. Amsterdam, Excerpta Medica/ Elsevier, 1983, p 213. 42. Theroux P, Taeymans Y, Waters DD. Calcium antagonists: Clinical use in the treatment of angina. Drugs 1983;25:178. Chapter 6 / Calcium Antagonist Controversies 81 81 From: Contemporary Cardiology: Cardiac Drug Therapy, Seventh Edition M. Gabriel Khan © Humana Press Inc., Totowa, NJ 6 Calcium Antagonist Controversies CALCIUM ANTAGONISTS AND HEART FAILURE Calcium Antagonists Cause an Increased Incidence of Acute MI or HF: True or False? Calcium antagonists without doubt cause an increased incidence of heart failure (HF) as observed in several well-run randomized controlled trials (RCTs): • Amlodipine in Antihypertensive and Lipid-Lowering Treatment (ALLHAT): HF 38% ver- sus diuretic (1). • Nifedipine in Intervention as a Goal in Hypertension Treatment (INSIGHT): HF 46% ver- sus diuretic (2). • Verapamil in Controlled Onset Verapamil Investigation of Cardiovascular End Points (CON- VINCE): HF 30% (3). • Amlodipine in Prospective Randomized Amlodipine Survival Evaluation (PRAISE) caused significant increased pulmonary edema in patients with left ventricular (LV) dysfunction (4). • Diltiazem caused a significant increase in HF in a non-Q-wave infarction study (5). The short-acting preparations of nifedipine and other dihydropyridines have been shown in RCTs to cause an increased incidence of myocardial infarction (MI), and controversies raged during the 1990s. These formulations are no longer used. • Although the sustained-release formulations have been shown to be much safer than the rapid-acting older preparations, these agents are contraindicated in patients with unstable angina or acute MI. Verapamil is also contraindicated in patients with acute ST-elevation MI (STEMI) and non-STEMI. • Diltiazem is contraindicated in patients with LV dysfunction but may be used in patients with unstable angina if beta-blockers are contraindicated. Newer Calcium Antagonists Are Better Than Older Agents: True or False? Lercanidipine was introduced into the United Kingdom a few years ago and is not avail- able in the United States and Canada. It appeared to have major advantages over amlo- dipine and older dihydropyridines. Because the drug dilates both afferent and efferent arterioles, the high incidence of peripheral edema caused by older calcium antagonists was reportedly reduced more than 50%. The balanced effect of lercanidipine and manid- ipine on efferent and afferent arterioles was believed to be important in renoprotection; older calcium antagonists dilate only afferent arterioles. Lercanidipine is only indicated for hypertension and is contraindicated in patients with LV dysfunction; sick sinus syndrome (if pacemaker not fitted); hepatic impairment; aortic stenosis; unstable angina; uncontrolled HF; within 1 mo of MI; and renal impairment. 82 Cardiac Drug Therapy Adverse effects include: flushing, peripheral edema, palpitations, tachycardia, head- ache, dizziness, and asthenia; also gastrointestinal disturbances, hypotension, drowsiness, myalgia, polyuria, and rash. Thus, such agents are not more effective and do not possess more safety than older agents. Most important, the combination of lercanidipine and digoxin is potentially hazardous. ARE CALCIUM ANTAGONISTS USEFUL FOR HYPERTENSIVES WITH CAD? Calcium antagonists have been used in patients to treat coronary artery disease (CAD) events, particularly stable angina, since about 1981. Their role in patients with unstable angina is limited, and caution is required for acute MI. Post-MI prophylaxis with verapa- mil has been advocated by few in the field and remains controversial. The author does not recommend verapamil post-MI. Their use in hypertensive patients with unsuspected or stable CAD has been widespread for more than two decades because they cause more effective and consistent lowering of blood pressure than angiotensin-converting enzyme (ACE) inhibitors/ARBs, beta-blockers, and diuretics. Their salutary effects on adverse cardiovascular disease (CVD) outcomes appear sim- ilar to the other three classes in patients without CAD. The large RCT International Verap- amil-Trandolapril (INVEST) trial (6) studied hypertensive patients with CAD. • 22,576 hypertensive CAD patients aged 50 yr or older were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). However, at 24 mo, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release, 4934 (62.9%) were taking trandolapril, and 3430 (43.7%) were taking hydrochlorothiazide. • In the NCAS group, 6083 patients (77.5%) were taking atenolol, 4733 (60.3%) were taking hydrochlorothiazide, and 4113 (52.4%) were taking trandolapril. • Primary outcomes: First occurrence of death (all cause), nonfatal MI, or nonfatal stroke; others: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pres- sure control at 24 mo. • Results: 2269 patients had a primary outcome event with no statistically significant dif- ference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk (RR), 0.98; 95% confidence interval (CI), 0.90–1.06). It is impossible to draw conclu- sions about the contribution of any single agent in this complex, open-label study that used blunderbuss drug combinations. • The exception was patients with prior HF: those assigned to the NCAS strategy appeared to have fewer events (p = 0.03 for interaction). Most important, verapamil, as expected, increased the incidence of HF even when combined with an angiotensin-converting enzyme (ACE) inhibitor and diuretic. Thus, calcium antagonists are not the drugs of choice to treat hypertensive patients who have significant CAD, particularly those with LV dysfunction. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial (3) were as follows: • Aim: To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician’s choice of atenolol or hydrochlorothiazide in pre- venting cardiovascular disease. Chapter 6 / Calcium Antagonist Controversies 83 • An RCT of 16,602 hypertensive patients who had one or more additional risk factors for CVD was conducted. After a mean of 3 yr of follow-up, the sponsor closed the study before unblinding the results. • Initially, 8241 participants received 180 mg of COER verapamil, and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (e.g., a diuretic, beta- blocker, or ACE inhibitor) could be added in specified sequence if needed. • Primary outcomes: First occurrence of stroke, MI, or cardiovascular disease (CVD)-related death. • Results: • 364 primary CVD-related events occurred in the COER verapamil group versus 365 in the atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% CI, 0.88–1.18; p = 0.77). • Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54; 95% CI, 1.16–2.04; p = 0.003). • Most important, verapamil caused a 30% increase in HF. • Importantly, more CVD-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups. I must emphasize that atenolol often has a less than 22-h duration of action, and studies have shown that it fails to quell early morning catecholamine surge, which is suppressed by other beta-blockers including metoprolol, timolol, bisoprolol, and carvedilol. Because most MIs occur during the hours of 6 AM and 11 AM, caution should be used with adminis- tration of poorly cardioprotective verapamil and atenolol. • Clinicians should recognize that both verapamil and atenolol are not suitable anti- hypertensive agents, particularly in patients with CAD; verapamil is potentially harm- ful in the elderly who are at high risk for HF, and atenolol has only mild cardiovas- cular protective effects. See the discussion of atenolol’s poor effectiveness in Chapters 2 and 9, Hypertension Controversies. REFERENCES 1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major out- comes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997. 2. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment. Lancet 2000;356:366–372. 3. CONVINCE: Black HR, Elliott WJ, Grandits G, et al. for the CONVINCE Research Group. JAMA 2003; 289:2073–2082. 4. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure: For the Prospective Randomised Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335:1107. 5. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and rein- farction after myocardial infarction. N Engl J Med 1989;319:385. 6. INVEST: Pepine CJ, Handberg EM, Rhonda M, et al. for the INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290: 2805–2816. [...]... 8b 8b 20 8 10 Ingredients Liquids Kay Ciel; Kay-Cee-L 1 mmol/mL Potassium chloride 10% K-Lor (paquettes) K-Lyte Cl Kaochlor 10% (or sugar free) Klorvess 10% Kolyum Kaon Elixir Kaon Cl 20% K-Lyte (effervescent) Potassium triplex Potassium sandoz Rum K Tables/capsules: slow release K-Long Kalium durules Kaon Leo K Nu-K Sando K Slow-K K-Dur 20 Micro-K Micro-K-10 a Dosage: usual range 20–60 mEq (mmol) K... later criticisms of RCTs) • For example, the beta-blocker atenolol is the main beta-blocker that has been compared with other agents However, the non-lipid-soluble atenolol may not be as cardioprotective From: Contemporary Cardiology: Cardiac Drug Therapy, Seventh Edition M Gabriel Khan © Humana Press Inc., Totowa, NJ 1 03 104 Cardiac Drug Therapy Fig 8-1 Common detrimental effects of hypertension *,... REFERENCES 1 Maclean D, Tudhope GR Modern diuretic treatment BMJ 19 83; 286:1419 2 Kerry RJ, Ludlow JM, Owen G Diuretics are dangerous with lithium BMJ 1980;281 :37 1 100 Cardiac Drug Theapy 3 Yeung Laiwah AC, Mactier RA Antagonistic effect of non-steroidal anti-inflammatory drugs on frusemide-induced diuresis in cardiac failure BMJ 1981;2 83: 714 4 Puschett JB Renal effects of bumetanide J Clin Pharmacol... or androgen receptors ( 23) • In EPHESUS, patients 3 14 d post acute MI were randomly assigned to eplerenone (25 mg daily titrated to a maximum of 50 mg (33 13 patients) or placebo (33 19 patients) in addition to optimal medical therapy (22) • The primary end points were death from any cause and death from cardiovascular causes or hospitalization for HF acute MI At 16-mo follow-up, there were 478 deaths... essential for adequate diagnosis and patient care NONDRUG THERAPY Nondrug therapy should be tried rigorously before drug therapy in all patients with mild hypertension Nondrug therapy low-sodium diet, weight reduction, cessation of smoking, reduction in alcohol intake, removal of stress and/or learning to deal with stress, relaxation, exercises, and a potassium-enriched diet—may result in adequate control... ventricular izquierdo post-infarto: randomizado y dobleciego Rev Med Chile 1997;125:64 3- 6 52 22 EPHESUS: Pitt B, Remme W, Zannad F, et al for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 20 03; 348: 130 9– 132 1 23 de Gasparo M,... Table 7-4 K+-Enriched Foods Food Amount Orange juice Milk (skim-powdered) Milk (whole-powdered) Melon (honeydew) Banana Tomato Celery Spinach Potato (baked) Beans Strawberries Meats, shellfish, and avocado K+ (mEq) Half cup Half cup Half cup Quarter One One One Half cup Half Half cup Half cup All contain increased K+ 6 27 20 13 10 6 5 8 13 10 3 POTASSIUM CHLORIDE SUPPLEMENTS To physicians caring for cardiac. .. disease (see Table 8-1 ) Isolated systolic hypertension in individuals aged over 65 yr is a major cause of stroke, left ventricular failure (LVF), and mortality from IHD 106 Cardiac Drug Therapy Table 8-2 Classification and Management of Blood Pressure for Adults a Initial drug therapy BP classification SBP a mmHg DBP a mmHg Life style modification Normal Prehypertension . advisable therapy Beta-blocker FDA Second-line Advisable Advisable First-line First-line First-line First-line First-line approved a therapy if not if not therapy therapy therapy therapy therapy prone. Lancet 1984;2: 133 7. 80 Cardiac Drug Therapy 23. Lee TH, Friedman PL, Goldman L, et al. Sinus arrest and hypotension with combined amiodarone-diltia- zem therapy. Am Heart J 1985;109:1 63. 24. Kuhlmann. calcium-channel-blocking agents. N Engl J Med 1982 ;30 7:1618. 3. Krikler DM, Harris L, Rowland E. Calcium-channel blockers and beta blockers: Advantages and dis- advantages of combination therapy